Modified alginates for precision drug delivery: Advances in controlled-release and targeting systems

Abstract

Alginates have been modified to become a suitable platform for targeted drug release, triggering advances in targeted and controlled-release systems. Alginate chemistry and various structural modifications, including ionic crosslinking, cyclodextrin-linking, and chemical carboxyl and hydroxyl group modification, such as esterification, amidation, and sulfation, are covered in this review. These modifications are aimed at enhancing drug release mechanisms, like dissolution, diffusion, water penetration, and ion exchange-based systems. Application of modified alginates in controlled-release systems is extensive, from hydrogels, bioprinting approaches, nanofiber-based systems, in-situ gelling systems, to nanoparticle systems. Targeted drug delivery utilizes passive and active targeting strategies for numerous applications, including the treatment of cancer, inflammatory disease therapy, infectious disease, and wound healing. Emerging platforms such as hydrogels and nanoparticles provide evidence of the versatility of modified alginates. However, issues regarding scalability and biocompatibility remain as obstacles. In this review, the capabilities of alginate-based delivery systems and their role in making various release mechanisms for targeted delivery are discussed in relation to the future directions for precision medicine development.

Graphical abstract

1. Introduction

Natural polymers are garnering significant interest in biomedical applications due to their high biocompatibility and adaptable nature, which allows for easy modification to suit specific requirements(Feng et al., 2022). These advantages have made natural polymers promising candidates for various challenging drug delivery applications, such as tumor-targeted delivery(Kuna et al., 2024), brain-targeting(Elzoghby et al., 2016), and oral delivery of insulin(Sonia and Sharma, 2012).

Alginate (Alg) is a natural polymer that is mainly obtained from cell walls in brown macroalgae or red algae (Pawar and Edgar, 2012; Usov et al., 1995) and can also be synthesized by some alginate-producing microorganisms, such as Azotobacter (Gimmestad et al., 2009) and Pseudomonas(Jain and Ohman Dennis, 2005). Structurally, Alginate is an unbranched linear polysaccharide composed of two uronic acids: β-D-mannuronic acid (M) and α-L-guluronic acid (G). The anionic nature of alginates is attributed to the carboxylate groups present in their uronic acid residues. These groups facilitate gelation in the presence of divalent cations, such as calcium ions, via a crosslinking process. Alginate-based drug delivery systems are primarily derived from the foundational structure of these prepared alginate hydrogels(Tan et al., 2023).

Alginate has been used for different biomedical applications due to its numerous advantages, including biodegradability, biocompatibility, mucoadhesion, and availability(George and Abraham, 2006; Tang et al., 2012; Tønnesen and Karlsen, 2002; Gheorghita Puscaselu et al., 2020). Alginates have been applied for the treatment of wounds attributed to their capacity to generate gel as an interaction with wound exudate(Boateng et al., 2008). Alginates play important roles as tumor-targeting agents by encapsulation of different anticancer drugs in various vehicles, such as the encapsulation of 5-fluorouracil in alginate microspheres (Raza et al., 2016) and doxorubicin (DOX) in alginate-polydopamine shell hydrogels(Wei et al., 2020). Moreover, alginate-based drug delivery systems have demonstrated enhanced therapeutic efficacy for anti-diabetic treatments. Notable examples include insulin-producing cells encapsulated within alginate beads(Hoesli et al., 2012), calcium alginate microspheres containing metformin hydrochloride niosomes(Maestrelli et al., 2017), and hydrogels composed of alginate and graphene oxide incorporating beta-pancreatic cells(Moreno-Castellanos et al., 2023). Furthermore, alginates have been recognized as acceptable vehicles for the peroral delivery of proteins, which is challenging due to protein instability(George and Abraham, 2006).

Modification of alginates is used to achieve two main goals: first, improve existing characteristics, for instance, by strengthening ionic gel through crosslinking, increasing hydrophobicity of the backbone, or improving biodegradation; second, introduce entirely novel properties not found in conventional alginates, such as anticoagulant properties, chemical/biochemical anchors for cell surface interactions, or temperature-dependent characteristics like lower critical solution temperature(Pawar and Edgar, 2012).

Conventional drug release systems often lead to burst drug release and short-lived peaks in blood concentration, necessitating frequent dosing to maintain therapeutic levels, which can be overcome by controlled release systems(Huynh and Lee, 2015). A typical controlled release formulation consists of an active agent combined with a carrier, often a polymer, designed to enable the active agent's release at a controlled rate over a specified period(Himmelsten, 1991). Controlled release systems are designed to enhance drug efficacy by facilitating drug transport across physiological barriers, protecting drugs against early elimination. The controlled release systems might be based on dissolution, diffusion, water penetration, chemical structures, or ion exchange(Jantzen and Robinson, 2002; Scher, 1999; Siegel and Rathbone, 2012).

Targeted drug delivery selectively transports medication to desired sites within the body while minimizing exposure to non-target areas. This approach effectively reduces side effects associated with non-specific drug exposure, enhancing overall therapeutic outcomes(Freeman and Mayhew, 1986; Manish and Vimukta, 2011; Rosenblum et al., 2018). Targeted drug delivery is primarily achieved through two mechanisms: passive targeting, which exploits physiological characteristics such as the enhanced permeation and retention (EPR) effect for drug accumulation, and active targeting, which involves modifying carriers with specific ligands to enhance cellular binding and uptake(Nagpure et al., 2023; Torchilin, 2010). Polymers have proven to be valuable in targeted drug delivery, with their successful integration into various nanostructures like polymersomes and polymeric micelles, showcasing their versatility and potential in advancing precision medicine(Abasian et al., 2020). Due to their unique properties, alginates can be used in the design of controlled release and targeted drug delivery systems, which will be discussed in this review.

Alginate's ability to improve the delivery of various drugs has been explored widely in the literature. Various review studies have explored alginate for different biomedical applications, in a broad context, including drug delivery, but have not investigated its modifications separately for drug delivery(Lee and Mooney, 2012; Raus et al., 2021; Szekalska et al., 2016). In 2019, Severino et al. reviewed the general potential of alginates for drug delivery, which lacked a proper focus on various modification techniques of alginate(Severino et al., 2019). Rostami, in 2021, authored an updated review on sodium alginate's ability, which was dedicated to pH-sensitive delivery of anticancer drugs and peptide-conjugates, as well as magnetic targeted drug delivery(Rostami, 2022). Hariyadi and Islam, in 2020, prepared a review paper updating the application of alginate in drug delivery, which was mainly on different delivery routes and the method of producing different alginate-based particles(Hariyadi and Islam, 2020). Furthermore, a large body of review papers is narrowly focused, as some review studies have explored the advantages of alginate-based carriers in a specified form, such as microparticles(Agüero et al., 2017), microcapsules(Wani et al., 2023), nanofibers(Zhang et al., 2024), beads(Swain et al., 2012), and microspheres(Amiruddin et al., 2025; Uyen et al., 2020). Some of the reviews have focused on a specified type of drug, like bioactive compounds (Karim et al., 2022), proteins (Wawrzyńska and Kubies, 2018), and biomacromolecules (Poojari and Srivastava, 2013). Several reviews have studied the treatment of a specific disease, such as cancer (He et al., 2020b; Suryani et al., 2021) and tuberculosis(Ahmad and Khuller, 2008), and a number of studies have reviewed alginate in different drug delivery systems, including transdermal (Manna et al., 2023) and ocular(Karmakar et al., 2022). Although alginate's advantages in improving drug delivery have garnered attention and are well-explored in different review papers, a comprehensive review of various modifications on alginates and their role in controlled- and targeted-release remains a gap to be addressed.

This review paper will study the contributions of various modifications, such as ion cross-linking, cyclodextrin linking, and modification of the carboxyl and hydroxyl groups, to the development of alginate-based drug delivery systems. By exploring these modifications and their impact on drug delivery, this paper aims to provide a comprehensive understanding of the potential of modified alginates as a versatile material for micro- and nano-drug delivery systems, and to distinguish their impact on controlled-release and targeted drug delivery.

2. Physicochemical properties of Alginate

Alginates are salts of alginic acid, a natural heteropolysaccharide. Commercially, alginates are extracted from brown algae and soil bacteria and are available as sodium, calcium, and magnesium salts. Due to their acidic properties, alginates are soluble in alkaline environments but insoluble in acidic and ethanolic solutions and as calcium salts. This feature has been used to extract these biopolymers from natural sources(Tao et al., 2024).

Alginic acid, like alginates, is composed of M-, G-, and MG-blocks. The equatorial β (1 → 4) linkages in the M-blocks form flexible linear sequences, while the axial α (1 → 4) linkages in the G-blocks are steric glycosidic bonds. Depending on the natural source, the linear structure, as well as M- and G-block contents, of alginate vary. Therefore, the physicochemical properties are influenced by these structural variations. A key factor to describe the structural variations is the M/G ratio, which is commonly between 0.33 and 0.90 (Tao et al., 2024). The rigid backbone and folded structure of the polymer are due to the special bonds in the G-block (Fig. 1a)(Akshaya and Nathanael, 2024; Yang et al., 2011). Furthermore, the intermolecular cross-linking with divalent cations and thereby hydrogel formation is dedicated to G-blocks of alginate(George and Abraham, 2006). For instance, Azotobacter-based alginates have a high G-block proportion, enabling them to produce gels that are gradually stiffer, more brittle, and more mechanically stable(Draget et al., 1993; Fu et al., 2011; Hay et al., 2010). The mechanical strength and volume stability of alginate gels were reported to be in proportion to the content of G-blocks(Martinsen et al., 1989). On the other hand, alginates with a high concentration of M-block form relatively elastic and soft gels. Additionally, these alginates can exchange ions more easily due to their high absorption of water(Draget et al., 1994; Jørgensen et al., 2007; Niekraszewicz and Niekraszewicz, 2009). Although alginates made of only M-block or G-block were at low pH, MG-block alginates demonstrated proper solubility under the condition(Szekalska et al., 2016).

Fig. 1.

A) Structures of alginate. B) Egg-box structure in alginate gels. C) The most important chemical modifications of alginate.

In general, the molecular formula of alginic acid and sodium alginate (SA) is (C₆H₈O₆)_n and (C₆H₇O₆Na)_n, respectively. Algal alginates have a molecular weight of 48–186 kDa. Bacterial alginates have higher molecular weights, up to 4000 kDa from Azotobacter vinelandii(Tao et al., 2024). The gels composed of higher molecular weight alginates were more brittle and stronger(Kuo and Ma, 2001). Furthermore, the viscosity of alginate gels increases as the molecular weight increases, provided the molecular weight is under 240,000, at which point the gel viscosity becomes independent(Martinsen et al., 1989; Martinsen et al., 1991).

As alginic acid is an acidic polysaccharide, its main functional groups are hydroxyl (-OH) and carboxyl (-COOH). The acidic hydrogen in the carboxyl group could be replaced by cations to form alginate salts. The polymers derived from algae have two hydroxyls and one carboxyl group in each of the M and G monomers. Despite algae, bacterial alginates undergo acetylation of the C2 and C3 hydroxyl groups in the M monomer(Tao et al., 2024).

The interaction of certain divalent and trivalent cations (e.g., Ca²⁺, Ba²⁺, Sr²⁺, Al³⁺, Pb²⁺, Cu²⁺, Co²⁺, Co³⁺, Ni²⁺, Zn²⁺, Mn²⁺, and Mn³⁺) with functional groups leads to gelation of this natural polymer, one of its unique properties(Akshaya and Nathanael, 2024; Dalheim et al., 2016; Hecht and Srebnik, 2016). Due to the axial linkage between G-blacks, consequent folding creates a cavity in a 3-dimensional structure, which could be intact with cross-linker ions(Akshaya and Nathanael, 2024). Thus, these cations interact strongly with G blocks rather than M and MG blocks, forming a biodegradable gel(Dalheim et al., 2016; Hecht and Srebnik, 2016). Alginates could bind selectively to Ca^2+, and the selectivity increases as the M/G ratio decreases, indicating an increased G content(Hecht and Srebnik, 2016).

3. Alginate modifications

Despite the unique properties of alginate, appropriate physical and chemical modifications can improve its properties for use in drug delivery and the manufacture of controlled-release and targeted drug delivery systems. Alginates have numerous hydroxyl and carboxyl groups that are suitable for chemical modification. This functionalization can affect the properties of alginates, including hydrophobicity, solubility, and biological properties. Modifications can be physical, such as ionic cross-linking and chemical modifications based on functional groups. In Fig. 2, various modification strategies of alginates are provided. Also, in Fig. 1c, chemical modifications are categorized based on the modification of carboxyl and hydroxyl groups of alginates, which are the main groups. Furthermore, Table 1 provides an overview summary of the release behaviors of various alginate modifications. (See Table 2.)

Fig. 2.

Various modification strategies of alginates.

Table 1.

A comparative overview of common alginate modifications.

Alginate modifications	Release behavior	Improvement	Challenges	Ref.
Esterification	Prolonged release for hydrophobic drugs (slower diffusion)	↑ Hydrophobic drug loading Form amphiphilic particles	Harsh synthesis can degrade the polymer Loss of gelation at high DS Reproducibility	(Babak et al., 2000; Chen et al., 2021; Rastello De Boisseson et al., 2004; Rosiak et al., 2021; Wang et al., 2021b; Yang et al., 2011; Yang et al., 2007)
Amidation	Controlled release (pH-stimuli release)	Targeted GI delivery (pH-sensitivity) ↑ Loading of lipophilic drugs	Complex coupling purification Consistency	(Banks et al., 2019; Rosiak et al., 2021; Tosuwan et al., 2024)
Oxidation	Long-term sustained	Biodegradation Increasing cell adherence	Gelation is lost if over-oxidized Aldehyde reactivity Synthetic control needed	(Abka-Khajouei et al., 2022; Akshaya and Nathanael, 2024; Ayub et al., 2019; Chang et al., 2012; Córdova et al., 2018; Gao et al., 2017; Hauptstein et al., 2015; Pawar, 2017; Rosiak et al., 2021; Tao et al., 2024; Volpatti et al., 2023; Wang et al., 2022; Yang et al., 2011)
Sulfation	Very slow, affinity-based release (cationic medicine)	Mimics heparin – binds growth factors	Highly anionic Blood compatibility concerns Reduced gelling ability Molecular weight loss	(Gionet-Gonzales et al., 2021; Mutch et al., 2024; Tao et al., 2024; Yang et al., 2011)
Copolymerization	Tunable	Enhanced loading Customized release	Complex synthesis Removal of residual monomers Scalability of polymerization	(Cheaburu-Yilmaz et al., 2019; Laurienzo et al., 2005; Rosiak et al., 2021)
Cyclodextrin-linkage	Stimuli-triggered release (mechanical)	On-demand dosing Improved solubility of hydrophobic drugs	Specialized chemistries Scalability	(Izawa et al., 2013; Omidian et al., 2025; Spiridon and Anghel, 2025; Wong, 2011)

Table 2.

Recent publications on alginate-based controlled-release drug delivery systems.

Type of CR-DDS	Components	Alginate modification	Aim of the modification	Release kinetic model	Encapsulated substance	Preclinical/clinical stage	In vivo data	Main result	Ref.
Hydrogel	Modified gelatin with phenylboronic acid-attached polyethyleneimine	Alginate oxidation + covalent crosslinks	Forming aldehyde groups for attachment as a result of oxidation and establishing a stimuli-responsive hydrogel with promoted mechanical strength by triple crosslinks	first-order	BSA, Congo red, and doxorubicin	In vitro study on Breast cancer cells (4 T1 cells) and L929 mouse fibroblast cells	–	The release rate of the components in acidic pH (pH = 6.5) was sustained even in the presence of hydrogen peroxide.	(Shen et al., 2023)
semi-interpenetrating hydrogel	–	Alginate grafting with 2-hydroxyethyl acrylate crosslinked by polyethylene glycol diacrylate	Better mechanical strength and modifying the morphology of the alginate surface	Not mentioned	BSA and 5-amino salicylic acid	In vitro study on MC3T3 cells	–	The release of the substances depended on the medium pH. The higher content of polyethylene glycol diacrylate led to a more prolonged release.	(Das et al., 2019)
Hydrogel	Octylamine	Carbodiimide reaction	hydrophobic alginate generation	apparent zero-order	Sulindac	–	–	The hydrophobic alginate hydrogel showed sustainable release of sulindac over 5 days, which was more prolonged than the alginate gel without modification.	(Choudhary et al., 2018)
Hydrogel	β-cyclodextrin	Covalent binding of the β-cyclodextrin with alginate	To form a mechanical stimuli-responsive hydrogel	Not mentioned	Ondansetron	–	–	Applying the external stress and the alternation in cyclodextrin conformation facilitates the release of ondansetron, as it is attached to cyclodextrin by van der Waals interaction.	(Izawa et al., 2013)
Bioprinting patch	–	Covalent crosslinking of the VEGF and chondroitin sulfate	Sustained release and better mechanical strength	Not mentioned	VEGF	In vitro Analysis: Drug release test in vitro, Tube formation analysis, Live/dead assay, Hemolysis assay, and Migration assay In vivo study on type 1 diabetes mice (T1DM)	↑ wound healing ↑ epithelial regeneration and neovascularization ↑ collagen deposition ↑ angiogenesis ↑ tissue repair ↑ M2 macrophages ↓ inflammation	The release rate of BSA as a marker gradually decreased during 15 days.	(Liao et al., 2023)
Bioprinting hydrogel	Gelatin	Chemically crosslinked with glutaraldehyde	Improved controlled-release	Zero-order along with a first-order kinetic	Chlorhexidine	In vitro study on HaCaT cells Examined antibacterial activity on Staphylococcus aureus and Pseudomonas aeruginosa	–	A zero-order kinetic during the initial 30–60 min and a first-order kinetic after this period were seen for rhodamine as a release marker.	(Mirek et al., 2022)
Nano-fiber	PVA	Oxidation-reductive amination reaction	Facilitating the electrospinning	Non-fickian	Ibuprofen	Cytotoxicity assay on the mouse fibroblasts L929 cells	–	Swelling, degradation, and ibuprofen self-diffusion were the release mechanisms of ibuprofen.	(Chen et al., 2022)
Nano-fiber	PVA	Covalently attached to octylamine (amidation)	Developing a carrier for hydrophobic molecule delivery and better electrospinnability	Non-fickian	Cyhalothrin	–	–	The initial drug release was inhibited in the chemically modified formulation. For sustaining the release of lipophilic drugs, PVA was not appropriate.	(Chen et al., 2015)
In situ gel	AuNPs coated with chitosan along with beta glycerophosphate as a crosslinker	Oxidation of alginate	To form a hydrogel with gelatin through a Schiff-base reaction	Not-mentioned	doxorubicin	Cytotoxicity assay on the MCF-7 cells	–	The pH-responsive hydrogel sustained the release of the drug for 48 h with a minimum burst release in the initial 30 min.	(Ziaei et al., 2023)
Nanoparticle	ZIF 7/8	Oxidation of alginate	To coat the NPs through a Schiff-base reaction	Not-mentioned	Inactivated pseudorabies virus	–	–	Firstly, the part of pseudorabies viruses attached to the surface was rapidly released, while the other part encapsulated in ZIF pores would be released in an acidic medium, such as lysosomes.	(Yin et al., 2024)
Nanoparticle	Deoxycholic acid	Amination of the alginate	To form succinimide deoxycholate	Not-mentioned	Insulin	In vitro study on Caco-2 cell	–	During the initial 30 min, a burst release occurred at about 3.5 %, which was dependent on the unencapsulated insulin. Due to the release profile, a pH-sensitive formulation was designed. Hence, in acidic pH, the system was shrunk, creating an obstacle to the diffusion of insulin out and the permeation of pepsin in.	(Razmjooei et al., 2024)
Nanoparticle	BSA	Amination of the alginate	To perform carbodiimide reaction with N-hydroxysuccinimide ester of folic acid	First-order model	Paclitaxel	In vitro study on MCF7, MDA-MB-231, and HeLa cells	–	The folate-targeted NPs with an equal amount of the alginate and BSA indicated an extended and rapid release of paclitaxel in the presence of the surfactant.	(Martínez-Relimpio et al., 2021)
Nanoparticle	Superparamagnetic iron oxide nanoparticles (SPIONs)	Modifying alginate with disulfide	To create a dual-responsive Alg	Not-mentioned	Doxorubicin	In vitro study on HepG2 and LO2 cells	–	In acidic media that simulate a tumor environment, the electrostatic interactions decreased, and doxorubicin release increased. By increasing the amount of glutathione, disulfide bonds are cleaved, and the drug release increases.	(Peng et al., 2019)
Nanoparticle	Halloysite nanotubes (HNTs)	The carboxylic acid groups of sodium alginate were chemically reacted with amine groups of the nanotubes modified with (3-aminopropyl)triethoxysilane	To hinder the burst release	Korsmeyer–Pepas	Phenytoin sodium	–	–	By coating alginate on the nanotubes, the rate and amount of burst release in the initial time were reduced.	(Zeraatpishe et al., 2019)
Nano-composite	Pickering emulsion and chitosan as NP coating	Free radical polymerization with diacetone acrylamide	To prepare hydrophobic alginate as a surface stabilizer	Fickian diffusion	Ibuprofen	–	–	In acidic pH simulating gastric fluid, 2.5 % was released over 5 h, while in higher pH, it reached 36.2 % during 5 h.	(Mao et al., 2020)

Abbreviations: BSA: bovine serum albumin; VEGF: vascular endothelial growth factor; PVA: polyvinyl alcohol; ZIF: zeolitic imidazolate frameworks; SPIONs: superparamagnetic iron oxide nanoparticles; HNTs: Halloysite nanotubes.

3.1. Ionic Crosslinking

Alginate functions as a chelating agent due to its carboxyl and hydroxyl groups, enabling gelation by ionic crosslinking through different techniques using various cations. Gel formation occurs through external or internal methods, resulting in hydrogels with varying concentrations of ions. Divalent cations like calcium, zinc, and magnesium form an “egg-box” structure in alginate gels (Fig. 1b), which swell in water and bond through intercommunication zones(Askari et al., 2024a; Ching et al., 2017; Li et al., 2015).

Alginates create hydrophilic gels by cross-linking with divalent cations such as Ca²⁺, Zn²⁺, and Mg²⁺, swelling in 3D shapes without dissolving. Alginates can be cross-linked with calcium ions in two ways. The diffusion method involves cross-linking ions diffusing into the alginate solution from an external source. The internal setting method has the Ca²⁺ ion source within the alginate solution, releasing cross-linking ions through a controlled trigger. The diffusion method leads to hydrogels with a gradient of Ca²⁺ ion concentrations, while the internal setting method results in hydrogels with a uniform concentration of Ca²⁺ ions(Borgogna et al., 2013; Grant et al., 1973; Sikorski et al., 2007).

Gelation can also happen through photo-crosslinking, thermal gelation, or a combination of both, bonding with compounds like glutaraldehyde. Safety concerns may arise with these methods compared to ion cross-linking, especially in biomedical uses. Photo-crosslinking with argon ions and methacrylate can produce flexible hydrogels for surgical applications like sealing corneal perforations without sutures(Cellesi et al., 2004; Hennink and van Nostrum, 2012; Jeon et al., 2012).

3.2. Modification of Carboxyl Group

3.2.1. Esterification

Esterification of the alginates can be performed via various mechanisms, based on the functional groups involved and reactants utilized. Esterification is typically employed to introduce hydrophobic alkyl or lipid moieties, leading to an increment in polymer hydrophobicity.

Carboxyl groups of alginate are more reactive for esterification with alcohol (classical method), usually catalyzed with acids, such as H₂SO₄; this reaction yields alkyl esters. For example, alginate-butyl esters were shown to encapsulate both hydrophilic and hydrophobic drugs without losing Ca²⁺-gelation or causing toxicity(Broderick et al., 2006).

Nucleophilic substitution reactions (S_N2) are another procedure that results in the preparation of alkyl alginate esters using alkyl halides. Firstly, the carboxyl groups of the alginate are neutralized with tetrabutylammonium hydroxide (TBAOH) to form tetrabutylammonium (TBA) alginate. Subsequently, the S_N2 reaction of the alkyl halide results in the efficient esterification of the alginates (Fig. 3a)(Chen et al., 2021; Yang et al., 2011). This method is widely used for offering hydrophobicity on the alginate surface by introducing various alkyl chain lengths.

Fig. 3.

A) Preparation of alkyl alginate esters via nucleophilic substitution (S_N2) reactions using alkyl halides. B) Formation of curcumin micelles via the reaction of the hydroxyl group of curcumin with the carboxyl group of uronic acid with the aid of N,N′-dicyclohexylcarbodiimide (DCC) and 4-dimethylaminopyridine (DMAP).

Despite the chemoselectivity of various alginate esters, the organic solvent system typically used may introduce cytotoxic effects due to incomplete solvent removal. Additionally, the probability of forming stable derivatives is a consequence of the side reactions(Babak et al., 2000; Rastello De Boisseson et al., 2004).

Carbodiimide-mediated esterification with reagents, such as N,N′-dicyclohexylcarbodiimide (DCC), usually accompanied by catalysts like 4-dimethylaminopyridine (DMAP), triggers carboxyl groups to form reactive intermediates; these intermediates facilitate the formation of ester bonds under mild conditions. For instance, Wang et al. developed an alginate-based colon delivery system by reacting the hydroxyl group of curcumin with the carboxyl group of alginate via carbodiimide chemistry esterification (Fig. 3b). The resulting hydrophobic derivative self-assembled into micelles, which increased curcumin solubility, provided enzyme-stimulated degradation of the ester bonds by gut microbiota, and provided targeted release(Wang et al., 2021b).

Additionally, water-soluble amphiphilic esters of alginates, such as cholesterol-alginate esters, can be synthesized by this strategy and demonstrate self-assembly into nanoparticles due to hydrophobic interactions(Yang et al., 2007).

Overall, Esterification can enhance the hydrophobicity of the alginate, promote the loading of poorly water-soluble drugs, and might slow down the release (sustained kinetic). However, the esterified alginate is susceptible to esterase under physiological conditions. Only partial esterification preserved gelability, while high degrees of esterification can abolish calcium ions-crosslinking. In the classical method of esterification, the alginate chain might be degraded under acidic conditions; however, the other two methods are milder and enable esterification under non-destructive conditions(Rosiak et al., 2021). Esterification based on carbodiimide and nucleophilic substitution with alkyl halides needs organic solvents; hence, the cytotoxicity effect of solvent residue is possible(Babak et al., 2000; Chen et al., 2021; Rastello De Boisseson et al., 2004; Yang et al., 2011). Another challenge is reproducibility and scale-up; controlling the degree of substitution and purification of the byproducts requires optimized and set reactions.

3.2.2. Amidation

An Amine group could react efficiently with carboxyl groups to prepare amide derivatives of alginates. As studies report, amidation could happen with the aid of two different reagents: (1) carodiimide-mediated coupling using 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (EDC-HCl), often in combination with N-hydroxysuccinimide, (2) activation with 2-chloro-1-methylpyridinium iodide (CMPI), an alternative coupling reagent(Tao et al., 2024; Yang et al., 2011).

Using the first method, Banks and colleagues demonstrated the coupling of 4-(2-aminoethyl) benzoic acid to an alginate backbone. The resulting derivative forms a hydrogel that is resistant to acidic gastric fluid and responsive to neutral and basic pH. This novel derivative was suitable for enteric delivery systems(Banks et al., 2019).

Vallée et al. conducted a comparative analysis between a dodecyl ester and a synthesized dodecyl amide derivative of alginates. The amidation process was performed using dodecyl amine and CMPI following the formation of tetrabutylammonium (TBA)⁺(Alginate)⁻ salt. The resulting amphiphilic polymer exhibited enhanced stability in comparison to the ester derivatives' hydrogels. It is important to highlight that the CMPI method is associated with unwanted inter- and intramolecular hydrolysable esterification of the alginate backbone(Vallée et al., 2009). This side reaction leads to ester bond formation between neighboring hydroxyl and carboxyl groups within the polymer.

In general, amidated alginates can improve loading of the hydrophobic drugs by increasing the hydrophobicity and provide pH-sensitivity and targeted release(Banks et al., 2019; Rosiak et al., 2021). Incorporating the hydrophobic alkyl amines slows down the diffusion rate of encapsulated medicines and decreases burst release. Hence, amidation of alginates might offer applications in oral drug delivery and barrier coatings(Banks et al., 2019; Tosuwan et al., 2024). However, batch-to-batch variation due to the complex synthetic steps and tough purification exists. In addition, unwanted side reactions can impact the structural variations and polymer stability.

3.3. Modification of hydroxyl groups

3.3.1. Oxidation

Alginate uronic monomers can be oxidized commonly using sodium periodate (NaIO₄) in a dark environment and aqueous solution. The oxidation of two hydroxyl groups at C2 and C3 leads to the formation of a dialdehyde and the breaking of the C2-C3 bond in the sugar ring. The limiting agent of this process is NaIO₄, so increasing its amount will increase the number of dialdehydes and decrease the molecular weight and viscosity. It is also known that oxidation leads to more rapid degradation of alginates. The oxidized monomers give more flexibility to the backbone of the alginates and introduce crosslinkable sites. The carbonyl group is more reactive than the hydroxyl group, which allows further functionalization steps, especially amination(Akshaya and Nathanael, 2024; Pawar, 2017; Tao et al., 2024; Yang et al., 2011).

Utilization of oxidized alginate derivatives for functionalization capitalizes on the reactivity of aldehyde groups over hydroxyl groups. A common approach involves the formation of imines. Following oxidation, the generated aldehyde groups can undergo reactive amination; primary amines react with aldehyde to form imine intermediates via a Schiff base reaction and are subsequently reduced with sodium cyanoborohydride (NaCNBH₃) to stable secondary amine linkages covalently grafted to the polymer(Akshaya and Nathanael, 2024; Huamani-Palomino et al., 2021; Yang et al., 2011).

Numerous alginate derivatives synthesized through reductive amination have been tailored for drug delivery purposes. For example, copolymers incorporating polyethylene glycol (PEG) derivatives showed great potential for applications in microencapsulation(Laurienzo et al., 2005; Szabó et al., 2020). The conjugation of amino-thiophenol, cysteine, or cysteamine to alginate led to the formation of self-assembled nanospheres. Furthermore, alginate nanoparticles functionalized with imines were designed for the simultaneous delivery of drugs to tumor cells, activated by changes in pH (Ayub et al., 2019; Chang et al., 2012; Córdova et al., 2018; Gao et al., 2017; Hauptstein et al., 2015). Finally, the formation of imines on oxidized alginate has been employed to develop hydrogels for protein delivery and cardiac tissue engineering, often in combination with chitosan or hyaluronic acid (Dahlmann et al., 2013; Szabó et al., 2020; Xing et al., 2019).

Oxidized alginate can be formed into various platforms by conjugating with other functional groups, such as amines, and enabling covalent cross-linking for drug delivery and regenerative medicine applications with controlled release properties. Oxidized alginate renders alginate biodegradable and facilitates eventual clearance. Notably, alginates oxidized more than 10 % lose their gelation in the presence of calcium ions, while partial oxidation (2–5 %) preserves this ability along with in vivo degradation(Rosiak et al., 2021; Volpatti et al., 2023). Hence, oxidation can offer customizable mechanical properties, influencing stiffness, gelation, and swelling(Wang et al., 2022). In addition, aldehyde groups can enhance the bioadhesive properties of alginate, promoting its interaction with biological tissues and cells(Abka-Khajouei et al., 2022). However, free aldehyde groups can be cytotoxic, addressed by subsequent crosslinking(Abka-Khajouei et al., 2022). Moreover, achieving uniform oxidation at scale is technically demanding and requires an optimized oxidation level.

3.3.2. Sulfation

The hydroxyl group of the M and G monomers could be sulfated to form a more soluble alginate derivative. The reaction takes place in an organic solvent, such as formamide, using reagents like chlorosulfonic acid(Tao et al., 2024; Yang et al., 2011).

This process is associated with a decrease in intermolecular hydrogen bonding and an increase in water solubility; however, contrary to some reports, sulfation often reduces the gelling ability of alginate, as the sulfated groups can interfere with calcium crosslinking(Gionet-Gonzales et al., 2021; Tao et al., 2024). Sulfated alginates have a similar structure to glycosaminoglycans, such as heparin. Hence, sulfation imparts blood anticoagulant activity(Yang et al., 2011).

A carbodiimide coupling reaction also prepares alginate sulfate. The DCC and sulfuric acid could react to produce an intermediate that can sulfate the hydroxyl group of alginates. Due to the use of a highly acidic environment, this process is also associated with a significant decrease in the molecular weight of the polymer. Alternatively, milder sulfating agents such as sodium bisulfite and sodium nitrite in an aqueous medium have been employed to achieve better molecular weight retention. However, these methods are less commonly used and studied(Pawar, 2017).

Sulfated alginate can bind strongly to heparin-binding growth factors and cationic drugs, providing long-term and affinity-based drug release(Mutch et al., 2024). Sulfated alginate may exhibit weakened or altered gelation properties compared to the native polymer. Additionally, Sulfated alginate can raise the risk of bleeding due to its anticoagulant activity. To address this issue, hiding these groups with other cationic modifications might improve the safety profile. Moreover, the possibility of residual reagents should be considered by evaluating precise toxicity assessments. Finally, industrial scalability and reproducibility remain an obstacle due to the environmental hazards of the utilized reagents.

3.3.3. Esterification

Anhydride acids are capable of reacting with hydroxyl groups, forming ester bonds in the process. Bahraminejad et al. employed esterification using 4–12 % octenyl succinic anhydride to enhance the barrier properties of the polymer(Bahraminejad et al., 2023). Esterification can affect not only the overall physicochemical properties of alginates but also the surface of their hydrogels. Eskhan and Banat employed esterification of the surface of calcium alginate hydrogels using maleic anhydride as a means of enhancing their oil adsorption properties(Eskhan and Banat, 2018).

The overall properties of alginate after esterification at the hydroxyl groups resemble those of alginate esterified at the carboxylic groups discussed above.

3.3.4. Copolymerization and Grafting

Copolymerization of other polymers, which are covalently crosslinked or grafted onto alginate, can generate multifunctional hybrids. Common examples are the thermosensitive or PEGylated alginates. For example, in a study, novel alginate/poly(N-isopropyl acrylamide) (PNIPAAm) matrices for controlled delivery of theophylline were developed. The matrices were prepared in both interpolymeric complexes (IPC) and graft copolymers forms via hydrogen bonding and EDC/HOBt chemistry, respectively. Due to the results, graft copolymers exhibited higher loading efficiency than IPC. Additionally, graft copolymers showed prolonged release times (235.4–302.3 min) compared to IPC release (77.6 min). The graft copolymerization had a more stable network than IPC, leading to strengthened drug-polymer interaction and prolonged release. Moreover, the graft copolymers responded to physiological stimuli, temperature, and pH(Cheaburu-Yilmaz et al., 2019).

PEG-alginate copolymers can also be made from oxidized alginate that is reductively aminated and PEGylated, retaining the gelation capability with calcium ions(Rosiak et al., 2021). For instance, a hydrogel comprising alginate-g-PEG graft copolymers was synthesized to retain the gelation capability of alginate with calcium ions, along with hydrophilicity and cell anchorage properties. To approach this aim, alginate was functionalized with dialkyl amine groups, and then, PEG-COOH reacted with the amine groups on modified alginate to form covalent amide bonds. The developed hydrogel showed increased hydrophilicity and pore size, enhancing water uptake and providing a cellular retention microenvironment(Laurienzo et al., 2005).

Generally, copolymerization extends release duration and improves loading efficiency. Grafting provides the capability to tune mechanical, swelling, and diffusion properties. In addition, grafting another polymer can lead to the preparation of smart delivery systems or tissue engineering scaffolds. However, controlling the degree of polymerization and also purification should be optimized at scale to ensure consistency and safety, respectively.

3.4. Cyclodextrin-linked Alginate

Cyclodextrin is a cyclic oligosaccharide comprising glucopyranose units connected by (1 → 4)-glycoside bonds. The cyclic structure gives rise to an internal cavity with an inner diameter of between 6 and 10 Å, exhibiting a relatively hydrophobic character. Non-polar drugs of a smaller size can be captured and formed into complexes with specific binding properties, which enables the solubilization, stabilization, and transportation of medications with triggered release capabilities(Wong, 2011). For example, β-cyclodextrin (β-CD) was covalently cross-linked to alginate via EDC/NHS chemistry to create a hydrogel with the capability of on-demand and mechanically triggered drug release. The ondansetron release was conducted under passive conditions and compressive force. The results showed that the compression cycle established pulsatile release, exceeding the rate of spontaneous release(Izawa et al., 2013). This patient-controlled concept offers the external modulation of the drug release profile(Omidian et al., 2025). However, achieving stimuli-responsiveness with cyclodextrin requires complex synthesis and modifications, which can be costly and time-consuming, thereby reducing scalability(Spiridon and Anghel, 2025).

4. Controlled-release drug delivery systems

4.1. Mechanisms of controlled drug release

Controlled-release drug delivery systems (CR-DDSs) have attracted researchers' attention compared to conventional ones, as CR-DDSs are being used to overcome conventional disadvantages. Maintaining the level of medicine in the therapeutic window for a longer time with minimum plasma fluctuation and adverse effects, specific targeting, increasing bioavailability, and better patient compliance are the general advantages of CR-DDSs(Park et al., 2022). These profits are the consequence of releasing a specific dose of the medicine in a determined time, and following the zero-order kinetics mostly(Hardenia et al., 2019; Park, 2014). The release of the payload might depend on various mechanisms, which are discussed as follows(Nicorandil, 2014; Siepmann and Siepmann, 2012).

Alginate-based systems have stood at the edge of biomedical applications among various natural polymers used in CR-DDSs. Due to its biocompatibility, mucoadhesiveness, and ability to form gels in the presence of divalent cations, alginate has become an indispensable component in drug delivery. However, unmodified alginate usually indicates uncontrolled breast release, poor mechanical strength(Xie et al., 2024), and restricted responsiveness to external stimuli(He et al., 2020a). Hence, a significant interest in chemically and physically modified alginate to promote its functionality and improve drug release behavior is growing.

The new generations of CR-DDSs can respond to the pH, redox, specific enzymes, temperature, and external stimulants (ultrasound, magnetic, and light). These factors trigger the release of bioactive molecules(Liu et al., 2016). Modified alginate systems are well-suited for these advanced applications. This section attempts to correlate specific alginate modifications with distinct mechanistic release behaviors.

4.1.1. Dissolution-based Systems

By manipulating the rate of drug separation from the solid structure and its diffusion from the interface barrier to the liquid bulk, the release of the drug will be controlled based on the dissolution rate. This phenomenon can be addressed by dispersing the medicine in slowly dissolving matrices, preserving it within the low-soluble membrane, or by combining these methods(Wang and Shmeis, 2006).

In encapsulated DDS, the rate of release is related to the membrane thickness and its composition. In contrast, in monolithic DDS, the rate of solvent penetration, wettability, and porosity are the main factors(Ummadi et al., 2013). Enteric-coated DDSs, Spansule, and subcutaneous or intramuscular solid particles with low solubility, such as penicillin G with the procaine and benzathine salt or zinc-insulin complexation, are the proper examples of dissolution-based systems(Buckwalter and Dickison, 1958; Hallas-Møller et al., 1952; Maurya et al., 2014).

In alginate-based delivery systems, dissolution is generally achieved via erosion or degradation of the polymer in physiological environments. The carboxylic acid groups of the alginate in acidic pH remain in salt form, and so unmodified alginate is poorly soluble. By increasing the pH from neutral to basic due to the cationic ions crosslinking, alginate forms a gel, which limits its responsiveness, and alginate gels ionically crosslinked dissolve over time via ion exchange(Lee and Mooney, 2012; Ozturk et al., 1988). Hence, the erosion of native alginate hydrogels provides the release of encapsulated therapeutic agents through the gradual breakdown of the hydrogel matrix.

Notably, copolymerization with hydrophilic polymers, such as PEG, might enable facilitated erosion(Hou et al., 2007; Liang et al., 2017). For example, controlled-release hybrid beads composed of alginate and inulin were developed to simulate oral delivery of peptides (bovine serum albumin). Negligible amount of protein was released in simulated gastric fluid with the pH of 1.2, while its release in simulated intestinal fluid (pH 7.4) reached 100 %. The incorporation of inulin helped to increase the erosion rate of alginate in alkaline environments. Therefore, a pH-sensitive dissolution-controlled release mechanism might protect peptide degradation in gastric conditions and provide intestinal absorption(Norudin et al., 2018).

4.1.2. Diffusion-based Systems

These types of CR-DDSs are similar to the previous ones, with a staple difference: the utilized polymer is water-insoluble, usually remains intact, and controls the diffusion of the drug. Fick's first and second laws govern diffusion in matrix diffusion-based systems; therefore, the flux directly relates to the gradient of the concentration, and with increasing distance, the flux will decrease(Siepmann and Siepmann, 2012). On the contrary, in reservoir systems, the release mostly obeys zero-order kinetics, but the probability of rupture and burst release is high(Adepu and Ramakrishna, 2021). Gliadel®, Iluvien™ (Perry et al., 2007), and Ocusert® (Schneider et al., 2017) are some of the marketed examples of these systems.

Unmodified alginate hydrogel typically exhibits an egg-box structure that is stabilized by cationic ions; however, this structure can be disrupted by ion exchange in physiological medium, leading to burst release. Hence, native alginate provides fast diffusion compared to chemically crosslinked alginate. Furthermore, hydrophobically modified alginate, such as esterification, reductive amination, copolymerization, and blending with hydrophobic polymers, introduces hydrophobic moieties which can enhance loading of poorly water-soluble drugs and slow down drug diffusion(Chen et al., 2021; Lee and Mooney, 2012).

Aziz et al. formed a hydrogel from oxidized sodium alginate and gelatin crosslinked via imine and borate ester bonds. They incorporated polydopamine-coated iron oxide NPs loaded with bovine serum albumin into the hydrogel. The protein is released in a sustained manner, which is controlled by desorption from the NPs and diffusion through the dynamic hydrogel network(Aziz et al., 2025). Actually, the presence of a stable and covalently crosslinked hydrogel network led to the diffusion-based release rather than erosion. Therefore, the primary mechanism for protein release is diffusion through the porosity and tortuosity of the hydrogel matrix.

4.1.3. Water penetration-based systems

In these systems, the release rate is determined to be controlled by water penetration. Osmotic pressure and swelling-based release systems are two prominent areas of this technology.

4.1.3.1. Osmotic pressure-based release

A drug core, a semipermeable membrane, a piston, and an osmogenic salt are the main components of the osmotic pumps. In osmotic-based delivery systems, water spontaneously moves from a solution of lower concentration to one of higher concentration through a semipermeable membrane, which allows water permeation but not solute passage. The expansion of the part containing osmogenic salts expelled the medicine from an orifice.

A zero-order release kinetics is seen in this technology; the release rate depends on the solubility of the solute and its concentration. Therefore, environmental conditions such as hydrodynamic conditions, food, and pH do not affect the release rate, and the in vivo-in vitro correlation is achieved to a large extent(Gupta et al., 2010; Patil et al., 2018; Stevenson et al., 2000). On the contrary, the risk of dose dumping and toxicity, drug tolerance with implantable pumps, and difficulty in distinguishing the orifice size are the disadvantages and limitations of this technology(Almoshari, 2022).

Cardura® XL, Sudafed 24®, Fortamet®, Acutrim®, and Altoprev® are some of the osmotic oral tablets on the market (Ogueri and Shamblin, 2022). The GemRIS™ and LiRIS® are two intravesical osmotic implants under clinical trial intravesical osmotic implants comprising gemcitabine and lidocaine, respectively, for bladder disease treatment, utilizing urine for osmotic flow creation(Pons-Faudoa et al., 2019). Various osmotic pumps are seen in Fig. 4, Fig. 5.

Fig. 4.

One-compartmental osmotic pumps.

Fig. 5.

Multi-compartmental osmotic pumps.

While there are no experiments that show alginate alone forms osmotic compartments, modified alginate composites can serve as an osmotic carrier. The hydrophilic structure of the alginate can attract and retain water molecules without dissolving. It creates a negative pressure at the interface with the osmotic membrane and draws water from the DI water reservoir. Moreover, alginate hydrogel acted as a transporter to provide a continuous flow of water through the interconnected hydrophilic channels. Besides the advantages of the alginate hydrogel, the density of hydrophilic sites and the interconnectivity between pores are limited. To tackle this issue, providing additional hydrophilic functional groups and increasing the connectivity between the hydrogel pores might facilitate smoother water pathways(Alabi et al., 2022).

For example, a sodium alginate hydrogel was developed, which was crosslinked with CaCl₂ and incorporated graphene oxide nanosheets. This hydrogel was placed under a cellulose triacetate osmotic membrane to separate the hydrogel from a DI water reservoir induced via surface energy gradient. The hydrogel drew approximately 23.4 g of water, without external pressure, which was 21.2 % more than the absorptive amount of water by the hydrogel without graphene oxide nanosheets(Alabi et al., 2022).

4.1.3.2. Swelling-based Release

In systems where the swelling mechanism controls the release, the dissolved or dispersed medicine will be delivered through the swollen hydrophilic cross-linked polymer as the polymer becomes rubbery at ambient temperature. The density of cross-links, ionic concentration, and hydrophilic content are the main factors in the swelling process. In a way, the high contents of the cross-links lead to minimum swelling. Additionally, a high concentration of ions within the system acts as an osmotic force and increases the amount of swelling, while high amounts of ions in the surrounding medium impede the system from swelling. Finally, the hydrophilicity of the delivery system will result in more water and hydrogel interaction and a higher swelling ratio(Omidian and Park, 2008).

In alginate-based systems, the entry of aqueous fluid swells the carrier, exchanges the ions, enables matrix erosion, and facilitates drug dissolution and diffusion. Therefore, a combination of the alginate modification is needed to promote the water penetration: introducing water-soluble polymers or modifications to soften the network, ease the swelling, and enhance water uptake, such as sulfation (Gachi et al., 2025) to increase hydrophilicity, oxidation to reduce molecular weight, and copolymerization with other polymers to trigger environmental-stimuli swelling and controlled release(Liu et al., 2025).

In a recent investigation, nanofibrous mats based on poly(vinyl alcohol) (PVA) and sulfated sodium alginate with the aim of wound dressing applications were designed. This formulation was fabricated with electrospinning and loaded with four cationic antibiotics: gentamicin, tetracycline, ciprofloxacin, and minocycline. The mats were stabilized with calcium chloride. Sulfated sodium alginate is hydrophilic and polyanionic, promoting water absorption. The rate of swelling was related to the hydrophilicity of the drug and ionic interaction with the sulfated sodium alginate network. Actually, positively charged and hydrophilic drugs, such as gentamicin, competed with calcium ions, weakened crosslinking, leading to enhanced swelling and faster drug release. In contrast, tetracycline, which formed stronger electrostatic interactions with the sulfated group of the hydrogel, limited swelling and sustained release (Gachi et al., 2025).

In another study, with the aim of reducing methotrexate cytotoxicity and targeted delivery, magnetic NPs (iron oxide) were coated with amino-functionalized silica, dispersed in sodium alginate solution, crosslinked with CaCl₂, and stabilized with chitosan and glutaraldehyde to minimize the leakage. Methotrexate was loaded into the beads; a sustained release of medicine over 72 h was seen under physiological conditions. Actually, alginate hydrogel beads swelled in the body, and the cargo diffused out from the matrix and chitosan coats(Taran et al., 2023). Swelling- and diffusion-based release are the two main mechanisms for this development.

4.1.4. Chemically-based systems

Degradation is expected to be a cause of drug release in these systems. Indeed, the chemical structure of a bio-erodible polymer will be changed when exposed to the physiological medium in contact with hydrolysis, redox, or enzyme-specific cleavage. Systems based on the dispersed drug in polymer and conjugated drug with polymer (pendant system) are the two main classifications of this type of delivery system.

4.1.4.1. Polymer-drug dispersion systems

Bulk erosion and surface erosion are two mechanisms that cause erosion in biodegradable polymer. Based on which mechanism is predominant, the behavior of the polymer will be discussed. In bulk erosion, the entire structure of the polymer is hydrolyzed. Therefore, both diffusion and erosion control the release of the drug, and its release is not constant and predictable. Polyesters, poly lactide-co-glycolide copolymers, and poly phospho-esters are examples of polymers with bulk erosion. On the other hand, in surface erosion, the rate of drug release can be controlled, as the rate of surface erosion determines the rate of drug delivery. Poly ortho-esters are the main example of surface erosion(Heller and Barr, 2005). In general, if the rate of solvent penetration is higher than the rate of decomposition of the polymer chains, the polymer will erode by bulk erosion; on the contrary, if the rate of degradation is faster, surface erosion will be dominant(Elenskaya et al., 2024).

Unmodified alginate generally relies on ion exchange for drug retention; thus, its chemically triggered release capabilities are limited. As mammals lack alginase (Lee and Mooney, 2012), some chemical modifications of the alginate, such as oxidation, can promote the hydrolytic degradation. Dialdehyde groups form via alginate oxidation, breaking the saccharide ring, enhancing chain flexibility, increasing solubility, and enabling hydrolytic degradation in physiological conditions. The oxidation degree results in degradation rate (Bouhadir et al., 2001); oxidized alginate usually forms stable covalent crosslinks, reducing burst release, providing controllable degradation, and actually a controlled release of the encapsulated medicine (Zhao et al., 2025). Additionally, disulfide crosslinking provides redox-responsiveness(Zhao et al., 2012).

Naeimipour and colleagues developed a thiolated alginate-based hydrogel for 3D bioprinting and dynamic tissue engineering applications. Notably, the introduction of cysteine residues with an enzyme-sensitive protection group was the key innovation, providing on-demand generation of free thiols via enzymatic deprotection. Hence, the obstacle related to the premature thiol oxidation could be overcome. Disulfide bonds are redox-sensitive linkages that can be reduced in a reducing environment, such as glutathione, leading to hydrogel network degradation. This formulation can be chosen as the feature for stimuli-responsive or on-demand drug delivery and tissue engineering scaffold by controlling the rate of cargo release(Naeimipour et al., 2023).

In another study by Bu et al., a redox-responsive alginate-SS-ibuprofen as a self-assembled micelle was developed to release doxorubicin in a controlled manner in the tumor. They aimed to increase drug loading, enhance tumor targeting, and trigger controlled release in response to glutathione. Firstly, alginate was degraded to a low molecular weight one to promote conjugation and self-assembly. Secondly, cystamine was grafted to the alginate backbone to introduce a disulfide linker. Thirdly, ibuprofen, as the hydrophobic part, was covalently attached via the SS linkage to provide an amphiphilic chain. Remarkably, low molecular weight alginate-SS-ibuprofen spontaneously formed micelles. In simulating a tumor environment, glutathione-containing PBS, cumulative doxorubicin release reached 67 % in 12 h, while this was much slower in PBS without glutathione (Bu et al., 2024).

4.1.4.2. Polymer-drug conjugate systems

The pendant delivery system will be developed when the medicine is chemically linked with the polymer, either by covalent attachment or grafting(Soma, 2015). While in polymer-drug dispersion systems, the drug is physically dispersed. The linkage provides a pharmacokinetic alteration and promotes biodistribution of the medicine. A high loading of drugs, controlled release, and unwanted drug leakage are the superiorities of covalent conjugation. Furthermore, enhancing the solubility of poorly soluble drugs and extended circulation time are other advantages of this system. The release mechanism of the medicine in a pendant system via cleavable linkers can depend on pH hydrolysis (like the tumor microenvironment), enzymes (like matrix metalloproteases), and reduction reactions (mostly the amount of glutathione)(Sagita et al., 2018).

In alginate-based delivery systems, the alginate backbone can be modified with cleavable linkers, such as carbodiimide(Growney et al., 2020), or stimuli-responsive spacers(Gao et al., 2017). In an investigation, ethylenediamine-modified sodium alginate polymer was created to develop a polymer-drug conjugate material. Carbodiimide chemistry was used to chemically modify sodium alginate, and phenolic bioactives were covalently attached to the amine groups on the chemically modified alginate. Actually, the free amine groups on the modified alginate backbone can react with carboxyl groups on medicines to form stable amide bonds. Notably, modification with ethylenediamine changed the gel mechanics, as Ca2+ gelling sensitivity decreased (Torlopov et al., 2025). The release mechanism of the introduced platform would be expected to be sustained and dependent on degradation or hydrolysis of the linker in biological environments or enzymes.

4.1.5. Ion exchange-based systems

In these controlled release systems, a water-insoluble polymer cross-linked with plenty of ionized groups adjusts the release of ionic drugs. Ionic medicine that is electrostatically attached to ionic groups of the resin exchanges with resembling charged ions in the medium and leads to the release of the medicine. Ionic strength, pH of the surrounding medium, the charge density and molecular weight of medicine and resin, and the amount of cross-linking in resin are the factors controlling the release rate(Adelli et al., 2017; Huynh and Lee, 2014). Generally, a medium with a high concentration of salts will influence this type of system, and a sustained release is not appropriate for this medium(Park et al., 2022).

Nicorette®, Delsym®, and Betoptic S® are marketed products for an ion exchange delivery system(Adelli et al., 2017).

Alginate, as a polyanionic polymer, is capable of entrapping cationic drugs through ionic interaction and releasing them via ion exchange (Teixeira et al., 2014). While unmodified alginate may poorly control the release of medicines, some of the modifications, such as sulfation or blending with ionic polymers, might have an effective role in strengthening ionic capacity for binding with ionic drugs.

To the best of our knowledge, there is no alginate-based system with the controlled release of its cargo based on an ion exchange system.

Overall, in novel alginate-based delivery systems, not one mechanism governs the release profile; usually, it is complicated and is controlled by several mechanisms mentioned. For example, a novel composite hydrogel system based on octyl succinic anhydride-modified chitosan and oxidized sodium alginate was developed to deliver cyclodextrin-loaded hydrophobic terbinafine. The Schiff base linkage formed between modified chitosan and oxidized sodium alginate made it sensitive to acidic pH; the linkages underwent hydrolysis and broke down more rapidly in infected tissue conditions, the matrix swelled, and the encapsulated drug-cyclodextrin complex diffused out more rapidly(Liu et al., 2025).

4.2. Applications of modified alginates in controlled-release systems

Novel DDSs are not limited to just one dosage form; they usually develop in combination with each other. When two or more materials in different physical or chemical phases come together, composites are formed(Ziaei et al., 2023). Alginate bio-composites are comprised of synthetic polymers, natural polymers, and inorganic compounds to promote the alginate properties. Among these characteristics is fluidity improvement(Lakkakula et al., 2022). The classification below is based on the alginate form.

4.2.1. Hydrogels

Alginate, which possesses pendant carboxylic acid groups, forms a gel through ionotropic gelation when exposed to multivalent cations, and other molecules like proteins, cells, genes, and drugs can be encapsulated(Chaturvedi et al., 2019). One of the important disadvantages of the physical crosslinks is the lack of stability in the physiological medium in contact with monovalent ions. On the other hand, covalent crosslinks lead to irreversible and promoted mechanical strength, which covers the mentioned defect(Venkatesan et al., 2017a).

A triple crosslinked hydrogel was developed as a trigger-responsive material with improved mechanical strength, responsive to hydrogen peroxide in the tumor environment. In this novel formulation, modified gelatin was crosslinked to alginate dialdehyde via two kinds of bonds: imine and boronate ester. The amine groups of gelatine reacted with aldehydes of the alginate dialdehyde, which was produced as a result of alginate oxidation; these bonds are Schiff base linkages and sensitive to acidic pH. In acidic conditions, the hydrogel network contracted and allowed down cargo release. Besides that, chemically modified gelatin, which had extra phenylboronic acid groups, reacted with the alginate dialdehyde diol groups and formed boronate ester bonds; they are cleavable upon exposure to H₂O₂. Finally, the third crosslink (calcium-carboxylate) was organized by adding calcium ions. To check the hydrogel response in the presence of hydrogen peroxide and at different pH, the cumulative release of the BSA, congo red, and doxorubicin was assessed. Hydrogen peroxide oxidized the boronate ester bonds, broke them down, and ruptured the hydrogel network. Therefore, the drug release would be facilitated as a consequence of hydrogel dissociation(Shen et al., 2023). Hence, the controlled release capability of hydeogel showed that the encapsulated cargo can be rapidly released in response to H₂O₂ (a representative ROS) via chemically-triggered release, while the release rate can be slowed down at acidic pH by decreasing the swelling and the rate of diffusion.

4.2.2. Bioprinting techniques

3D-bioprinting is a cutting-edge technology with vast utilization in regenerative medicine and tissue engineering. Bioink (printable materials) has to demonstrate the appropriate properties such as biocompatibility, stiffness, porosity, viscosity, and shear-thinning. Alginate, as a biocompatible natural polymer with tunable mechanical properties, has been applied in a broad laboratory and marketed as a bioink product(Piras and Smith, 2020).

Sulfation, oxidation, and grafting are the common alginate chemical modifications in bioprinting formulations. Oxidation facilitates the degradation of alginate and promotes its rheological characteristics by decreasing the molecular weight. Sulfated modification imitates the sulfated glycosaminoglycan (sGAG) in the extracellular matrix (ECM). This molecule has an important role in adjusting the proliferation, differentiation, and migration of the cells by attaching to the growth factors. RGD and PEG are two widely used grafts, which increase cellular attachment and hydrogel viscoelastic properties, respectively(Wei et al., 2023).

A novel alginate patch was designed with the aim of prolonged release of vascular endothelial growth factor (VEGF) in wound healing. The patch was double-crosslinked with both physical and chemical crosslinks: calcium ions and methacryloyl groups-induced ultraviolet (UV) irradiation, respectively, were applied for better mechanical strength. Chondroitin sulfate as an sGAG was bound to photo-cross-linkable methacryloyl, followed by printing. Besides this, VEGF was modified with an acrylate group and covalently attached to the scaffold using the same method. The Cell Counting Kit-8 (CCK-8) assay demonstrated that there was no significant difference between the modified alginate/chondroitin sulfate methacrylol patch and the unmodified one in cell growth. As a release marker, BSA was labeled with fluorescein isothiocyanate, modified with acrylate, and crosslinked with the patch. The intensity of the fluorescence gradually reduced, indicating sustained release. The main release mechanism is a polymer-drug conjugate system, as the VEGF was covalently crosslinked with the hydrogel matrix and its release was dependent on the degradation of covalent bonds; the cargo diffused from the matrix as the network degraded(Liao et al., 2023).

4.2.3. Nanofiber-based delivery systems

NFs, nanomaterials with a cross-sectional diameter of 10–100 nm, are usually made using the electrospinning method(Askari et al., 2024b; Tayebi-Khorrami et al., 2024; Tayebi-Khorrami et al., 2025). It is not possible for alginate, a hydrophilic polymer, to become NF with this method. Therefore, its spinnability will be increased by adding synthetic polymers, mostly polyethylene oxide and polyvinyl alcohol. Additionally, modifying alginate with the chemical reaction leads to a decrease in the hydrogen bonding in the alginate and promotes spinnability(Chen et al., 2015; Karim et al., 2022).

For example, Chen et al. synthesized a hydrophobically spinnable nano-fiber to increase the encapsulation and prolong the release of ibuprofen as a lipophilic drug. To achieve this goal, alginate was first oxidized and subsequently subjected to reductive amination to form a reductive amination of oxidized alginate derivative (RAOA). In the end, PVA as a cosolvent was blended with the modified alginate solution to simplify the electrospinning. Due to the results, by increasing the volume of the RAOA concerning PVA volume, the encapsulation efficiency was enhanced. The formulation sustained the release of ibuprofen for 810 min, compared to the unmodified alginate/PVA combination, which achieved full release in about 150 min(Chen et al., 2022). The release of the drug was the result of absorption of water, swelling, and diffusion through the fiber matrix.

4.2.4. In-situ gelling systems

A maintained solution or suspension comprising the dispersed medicine along with a gelling agent is the primary component of the in-situ gelling system. The gelling-trigger factor might be multivalent ions, physiological temperature and pH, enzyme, etc. This type of drug delivery system enhances the presence of medicine at the target site, and interval administration and decreases systemic absorption(Neha and Nirmala, 2014).

The in-situ gelation of the alginate is commonly performed by divalent ions. Calcium ions diffuse into the solution of the alginate from an environmental medium or an external source. Alternatively, the inactive reservoir of the calcium ions can be within the alginate solution, and an inducer factor causes them to be released(Essa et al., 2021).

Chemically crosslinked in situ alginate gel also has a wide range of applications in controlled-release drug delivery systems. A novel 3D in situ hydrogel was designed based on oxidized alginate and gelatin to prolong the release of doxorubicin for breast cancer therapy. The medicine was encapsulated within AuNPs that were covered by chitosan to reduce the attachment affinity of proteins to the NPs' surface. Due to the high potential of the AuNPs in absorbing X-rays, the hydrogel exhibited theranostic properties. An anionic crosslinker, beta glycerophosphate (β-GP), was used in the formulation for rapid gelation. In addition, a Schiff-base reaction occurred between gelatin and oxidized alginate to form a gel. The release of doxorubicin was enhanced at acidic pH as a consequence of a greater swelling ratio and higher solubility of the medicine(Rahmanian-Devin et al., 2021; Ziaei et al., 2023). This formulation offered sustained and pH-triggered drug release as a result of the formed linkages, leading to enhanced swelling and gradual diffusion of the medicine from the hydrogel matrix.

4.2.5. Nanoparticle delivery systems

Ionic gelation, complexation (mostly by chitosan), covalent crosslinking, self-assembly, and emulsion are the common methods for alginate NP preparation. The application of alginate NPs is usually focused on insulin delivery, cancer treatment, gene delivery, and antibiotic transfer in bacterial infection(Lakkakula et al., 2022; Venkatesan et al., 2017b).

In a novel investigation, an inactivated vaccine against pseudorabies virus was developed based on synthesizing an adjuvant consisting of zeolitic imidazolate frameworks (ZIF) NPs coated with alginate. At first, ZIF NPs with amine groups were prepared, and subsequently, oxidized alginate with dialdehyde groups was coated on the NPs through a Schiff base reaction. According to the pH-sensitive characteristic of the ZIF and its porous structure, along with the higher solubility of the alginate coating, it demonstrated a similar preventive impact compared to the marketed ISA201. The results indicated that the antigen was released from NPs in acidic pH after two hours, and by enhancing the pH, the release rate decreased. Acidic environment destabilized the coating layer, bonds cleaved, and the antigen slowly diffused from MOF pores and possibly through the alginate coating(Yin et al., 2024).

Razmjooei et al. developed modified-alginate NPs for oral insulin delivery. To achieve this goal, alginate was chemically modified via carbodiimide chemistry with ethylenediamine and subsequently conjugated with deoxycholic acid, enhancing intestinal absorption via the apical sodium-dependent bile acid transporter. Insulin was loaded into NPs using an immersion-like method. The release profile of the insulin was simulated using the gastrointestinal route, gastric, intestinal, and body fluids with pH levels of 1.2, 6.8, and 7.4, respectively. In the first step, 5 % of insulin was released during 2 h in a gastric condition. Subsequently, by changing the medium to a higher pH, the percentage of released insulin reached 25 % approximately over a period of 6 h. Finally, in simulated body fluid, progressively 94 % of insulin was released within 48 h. The pH-sensitive swelling behavior of alginate contributed to a sustained release, which was governed by insulin diffusion from the polymer matrix(Razmjooei et al., 2024). Despite these promising preclinical findings, it is important to acknowledge the substantial challenges that have historically hindered the clinical translation of oral insulin delivery systems. Numerous candidates have failed in advanced development stages due to poor bioavailability, variability in absorption, safety concerns such as hypoglycemia from unpredictable release, and high manufacturing costs. The oral route exposes insulin to enzymatic degradation and variable pH environments, leading to insufficient systemic uptake. Additionally, long-term safety data remain scarce, and some carriers or chemical modifications used to enhance permeability have raised toxicity or immunogenicity concerns in vivo(Drucker, 2020; Morishita and Peppas, 2006). As a result, the field of oral insulin has become known as a “commercial graveyard” where even major pharmaceutical companies have withdrawn after investing heavily in development programs that failed to meet efficacy or economic viability thresholds. Therefore, while novel delivery systems such as modified alginate nanoparticles offer renewed hope, addressing these long-standing clinical and translational barriers remains critical for future success.

5. Targeted drug delivery systems

5.1. Mechanisms of targeting

Researchers employ various systems and methods to target specific tissues and enhance the effectiveness of treatment. These methods can be generally divided into two parts: active or passive targeted drug delivery.

5.1.1. Passive targeting

Micro and nano systems based on alginate demonstrate notable drug-loading capacity and controlled-release characteristics. These systems can be easily modified through chemical changes. Various targeted drug delivery systems utilizing alginates have been developed, incorporating passive targeting, active targeting, and stimuli-responsive release mechanisms. This has led to the development of a broad range of drug-delivery systems that can precisely deliver medications to specific sites in the body(Iravani and Varma, 2022).

Inflammation and hypoxia are prevalent in tumors, causing the endothelium of blood vessels to become more permeable compared to its healthy state. In response to hypoxia, tumors can either generate new blood vessels or incorporate existing ones. The newly formed permeable blood vessels in tumors facilitate the targeted and enhanced delivery of large macromolecules and nano systems into the tumor's extracellular matrix. However, in different tumors and patients, this effect varies significantly, limiting its predictability and reproducibility. Additionally, the lack of regular lymphatic drainage in tumors contributes to the retention of NPs within the tumor. However, this unique feature is ineffective for small-molecule drugs, as they have a short circulation time and are quickly eliminated from the tumor. Therefore, by encapsulating small-molecule drugs in nanosized drug carriers, their pharmacokinetics can be improved, resulting in prolonged systemic circulation. This approach also offers some level of selectivity for targeting tumors and helps to reduce side effects associated with the drugs. This type of targeting, which is called passive targeting, does not depend on a specific ligand or binding to a particular tissue and organ and depends on the size and duration of the carrier circulation in the blood and the biological characteristics of the tumor, such as vascularity and permeability(Attia et al., 2019). It has been reported that even active and stimuli-responsive targeting strategies often rely on the initial passive accumulation of drug carriers via the EPR effect. This highlights the essential role of passive targeting in nanoscale drug delivery systems (He et al., 2020b). As mentioned above, gaps created in blood vessels and disruption of impaired lymphatic drainage in tumor tissues can trap nanoparticles inside the tumor. This is the EPR effect or passive tumor targeting(Chen et al., 2023b). Polymer micelles have recently gained significant attention as Nanocarriers specifically designed to deliver drugs to tumors. These micelles encapsulate anti-cancer drugs to enhance their water solubility and bioavailability. Utilizing the EPR effect, they can passively target tumor tissues. This approach not only minimizes toxic side effects on healthy tissues and organs but also facilitates drug accumulation at tumor sites, thereby boosting the anti-cancer efficacy of the encapsulated drugs(Biswas et al., 2016; Maeda, H.J.A.i.e.r., 2001). Although this approach increases drug accumulation and therapeutic efficacy, as discussed above, it still suffers from interpatient variability and inconsistent tumor uptake, which limits its clinical reliability compared to more controlled and specific targeting strategies. Fig. 6 illustrates the suggested pathways for drug nanocarriers to penetrate the tumor(Sharifi et al., 2022).

Fig. 6.

(A) Paracellular process: Drug nanocarriers enter the extracellular space of solid tumors passively through intercellular gaps up to 2000 nm in size, which are critical for the EPR effect. (B) Transcellular process: Drug nanocarriers in mature vessels lacking gaps actively infiltrate the extracellular space of solid tumors through vesicles (endocytosis-exocytosis) and pores. Reprinted from(Sharifi et al., 2022).

5.1.2. Active targeting

5.1.2.1. Ligand-conjugated alginate

One type of active targeting is the conjugation of ligand-receptor, antigen-antibody, and other types of molecular recognition onto drug delivery systems (DDSs) to achieve targeted delivery to particular cells, tissues, or organs(He et al., 2020a).

One common use of ligand-conjugated targeted delivery is folic acid receptor-based targeting. Folic acid is a stable, low-cost, immunogenic, low molecular weight (441 Da) molecule that has a strong affinity for the folic acid receptor (FR). Moreover, the surface of numerous human malignant cell types has overexpression of FR, whereas the majority of healthy cells have negligible or no FR expression at all(He et al., 2020a). According to Lee et al., (Lee and Lee, 2020), 5-aminolevulinic acid was encapsulated using a water-in-oil (W/O) emulsion technique after alginate and folic acid were attached to create unique alginate-conjugated folic acid nanoparticles. The obtained fluorescent precursors were precisely and accurately delivered to cancer cells for cancer-specific fluorescence imaging, and neither enzymes nor other external factors were able to degrade them before they reached the cancer cells. Another example of ligand-conjugated targeted delivery is epidermal growth factor receptor (EGFR)-based targeting. The EGFR tyrosine kinase family's high levels of expression in many epithelial malignancies produce large changes in the number of receptor molecules on the surface of malignant and healthy cells(Yewale et al., 2013). Wang et al. (Wang et al., 2014) created EGF-modified cisplatin alginate conjugate liposomes (CS-EGF-Lip). When CS-EGF-Lip was administered instead of free cisplatin, it improved the delivery of cisplatin into ovarian tumor tissues, improving antitumor efficacy and lowering nephrotoxicity and body weight loss in mice.

Looking at the big picture, using receptor-based targeting as a strategy of active targeting has several key advantages, such as being inexpensive and non-immunogenic. Furthermore, this method has the ability to distinguish between cancerous and healthy cells. Among different ligands, such as asialoglycoprotein, glycyrrhetinic Acid, glycyrrhizin, epidermal growth factor Receptor, folic acid is more suitable for conjugation with alginate due to its cheaper price, expression on the surface of many types of human cancerous cells, and more straightforward (He et al., 2020b).

5.1.2.2. Stimuli-responsive systems

Novel drug delivery systems are required for the best possible cancer therapy because anticancer medications are toxic and have major adverse effects. When a cancer cell's microenvironment changes, such as when the pH, temperature, or an ion is present, stimuli-responsive DDSs typically undergo a phase transition(Zhou et al., 2018). On the other hand, non-invasive physical triggering signals from the outside, such as heat, magnetic fields, light, and ultrasound, may cause drug release(Do et al., 2019). This review discusses some of the most important stimulus-responsive DDSs, including pH-responsive DDSs. It is commonly known that pH levels can range greatly between various tissues or organs, including the stomach and colon, as well as between disease states, including infection, inflammation, and cancer(Liu et al., 2014). A pH-sensitive polymeric carrier was created by Abdelrahman et al. (Rezk et al., 2019)to deliver the anticancer medication bortezomib (BTZ) to cancer cells locally. Alginate-conjugated polydopamine served as their polymer-building component. They discovered that the release mechanism was non-fickian, with diffusion acting as the main mechanism and a minor contribution from erosion. Targeted cancer cells' release of BTZ is regulated by a pH-sensitive mechanism. They explained that an in vitro cell culture test showed high biocompatibility for Alg and dopamine-modified alginate (AlgPD), while AlgPD-BTZ enhanced cytotoxicity against colon and squamous cancer cells. Moreover, for colon cancer cells, FACS analysis identified cell apoptosis as defined by loss of cell viability. Targeting based on physical stimuli from the outside. Magnetic fields are one example of an “external stimulus,” which are characteristics outside the body that might cause the regulated release of drug delivery systems that target cancer. Contrary to internal stimuli-responsive systems, external stimuli-responsive systems can naturally incorporate or introduce contrast agents to image the assemblage of nanoparticles within targeted tissues, cells, or organelles. and after that activate the nanocarriers out of the body by light or other triggers at the suitable moment. As a result, the release of loaded medicines is better regulated by external triggers than by internal factors inside the cancer microenvironment(Yao et al., 2016).

5.1.2.3. Targeting using a magnetic field response

Additionally, magnetic field-responsive DDSs have become a popular therapeutic option for the detection and management of malignancy. A magnetic field frequency below 400 Hz can be remotely directed to the appropriate tissue and is generally not absorbed by the body(Prijic et al., 2012). Magnetic nanoparticles with a core layer of doxorubicin-gelatin (DG) and a shell layer of iron tetroxide (Fe₃O₄)-alginate (FA) were created by Huang et al. (Huang et al., 2020)to serve as specific anticancer drug delivery vehicles. Targeting the medicine to the tumor tissue and enabling regulated drug release are two benefits of the outer magnetic layer. Higher drug encapsulation rates are provided by the gelatin core, and drug delivery is improved, and the cytotoxicity of DG/FA NPs is reduced when they pass through healthy tissues by the alginate magnetic layer. In the presence of an external magnetic field, experiments demonstrated that the appropriate physicochemical features of DG/FA NPs boosted cellular absorption into tumor cells and subsequently induced cell death. Similar to the results obtained with 4 μM free DOX, DG/FA NPs loaded with 2 μM DOX reduced the cell viability of MCF-7 breast cancer cells by 48 % in the in vitro cytotoxicity assay. Chemotherapeutic DOX may be effectively delivered by DG/FA NPs to MCF-7 cell nuclei, where it would kill cancerous cells.

In conclusion, stimuli-responsive systems increase the efficacy and reduce the side effects of anticancer drugs due to their ability to release encapsulated drugs in the proper place at the proper time. Moreover, these systems are a good option when controlling the release rates of encapsulated drugs is needed (He et al., 2020b).

5.1.2.4. Multifunctional targeting strategies

Different strategies can be combined in active medication delivery. Using Ligand-conjugated with any kind of stimulus-responsive technique, for example, or combining various stimulus-responsive methods. pH values were employed as a single parameter in several active medication delivery techniques in the majority of the studies. A dual stimuli-responsive drug carrier was created by Gao et al. (Gao et al., 2020)for the delivery of cancer drugs. It was decided to use DOX as a model drug and hydrophobic modified alginate (HMA). α-L-fucosidase significantly increased the release rate of DOX from DOX-HMA micelles, as demonstrated by the enzyme- and pH-triggered release behavior of the drug. The release of DOX was also accelerated in acidic media. Comparing DOX-HMA micelles to free DOX, in vitro cellular tests showed that the former was more successful at internalizing cells, whereas the latter demonstrated strong, targeted antitumor efficacy against malignant cells. In contrast to free DOX, DOX-HMA micelles could be released consistently and gradually. A thermo/pH/magnetic-triple sensitive nanogel was created by Bardajee et al.(Bardajee and Hooshyar, 2018) for the delivery of anticancer drugs. The medication utilized was DOX, and it was discovered that their release rates increased with temperature, decreased with pH, and increased with a magnet present.

Generally speaking, using different mechanisms of active targeting is more effective. As different studies demonstrate that this approach is more successful in preventing encapsulated drugs from leaking or degrading before reaching the active site, so that multifunctional targeting carriers are a good candidate as anticancer drug carriers(Bardajee and Hooshyar, 2018; Lee and Lee, 2020).

5.2. Applications in disease-specific targeting

5.2.1. Cancer therapy

One of the most serious illnesses with a high death and morbidity rate is cancer. It is among the leading causes of death in the world. Anticancer medications often cause undesirable side effects and low treatment efficacy since they are harmful to both cancerous and healthy cells. It is critical to differentiate cancer cells from normal cells with extreme precision to selectively target and eliminate cancer cells. One way to do this is by using intelligent drug delivery systems. It is necessary to select appropriate polymers in order to build such smart platforms(He et al., 2020b). Even though the majority of the chemotherapy medications used today—including paclitaxel and doxorubicin—are hydrophobic and have poor solubility in water(Pourjavadi et al., 2018), they are all efficient in killing cancer cells. Anticancer medications themselves, since their concentrations in a site of targeting are too low to be both effective and lethal for cancer cells(Inoue et al., 2006). Biodegradable polymers have demonstrated the most promise in recent decades for the construction of DDSs for anticancer medications. Because of their biodegradability and biocompatibility, natural polymers—especially those derived from marine organisms—are typically regarded as being far safer than synthetic polymers(He et al., 2020b). The most common marine biopolymer in the world, alginate, is typically used to create DDSs that target cancer. Amazing biodegradability, low toxicity, non-antigenicity, chemical adaptability, crosslinking ability, pH sensitivity, mechanical stiffness, cell attachment ability, and the ability to bind or release bioactive molecules upon alterations are some of the alginate's qualities. Alginate is a perfect material to create multitasking DDSs for cancer imaging and therapy because it is easily changed to yield derivatives with various structures, characteristics, functionalities, and applications(Park et al., 2017).

Alginate-based DDSs' drug loading and controlled release capabilities are readily tunable through chemical modification or production methods(Zhou et al., 2018). Since alginate is modifiable, it has been employed in numerous studies to create targeted drug delivery systems. As previously said, the majority of anticancer medications are hydrophobic. Therefore, modifying alginate to form an amphiphilic copolymer is a suitable alteration for alginate as a promising agent for cancer therapy. Using dodecyl glycidyl ether as a hydrophobic group, Gao et al. (Gao et al., 2020) created a dual stimuli-responsive drug carrier based on hydrophobic modified alginate (HMA) that could form self-assembled micelles in aqueous solution above the threshold micelle concentration. The model drug, doxorubicin (DOX), was effectively loaded into HMA micelles. Using fluorescence measurement, the percentage of drug loading effectiveness of the HMA was found to be 65.4 %. Alpha-L-fucosidase significantly increased the release rate of DOX from DOX-HMA micelles, as demonstrated by the enzyme- and pH-triggered release behavior of the drug. The release of DOX was also accelerated in acidic media such as the tumor extracellular environment, the endosome, and the lysosome. In the presence of AFU at pH 5.5 of lysosome, it was discovered that over 80 % of the DOX was released from the DOX-HMA micelles as a result of cleaving glycosidic groups. In contrast to free DOX, DOX-HMA micelles could release consistently and gradually. Furthermore, in vitro drug release experiments demonstrated that DOX-HMA micelles can pass across the cell biological membrane by endocytosis, enabling cancer cells to efficiently uptake DOX-HMA compared to free DOX. It has been demonstrated that the drug-loaded micelles exhibited significant toxicity towards the cancer cells, whereas the blank micelles exhibited low toxicity (Fig. 7).

Fig. 7.

Diagram illustrating the production and stimuli-responsive release of DOX-HMA micelles: (A) alginate modified by dodecyl glycidyl ether; (B) DOX contained within HMA micelles; (C) DOX-loaded HMA micelles accumulated within tumor cells; and (D) intracellular stimuli-responsive breakdown and drug release. Reprinted from(Gao et al., 2020).

As previously stated, alginate's sensitivity to pH is one of its desired qualities. Drug release techniques utilize alginate's ability to undergo acid-catalyzed hydrolysis in an acidic environment(Lee and Lee, 2020). This property of alginate has seen extensive application in the delivery of anti-cancer medications in recent years. Researchers looked at the combined effects of various factors, like higher enzyme levels and promoting a low pH environment in cancer cells, in the majority of these investigations. Because it is known that cancer cells overexpress folic acid receptors in their epithelium, conjugation with folic acid has also been employed(Gao et al., 2020; Lee and Lee, 2020). The alginate-based microcapsules for curcumin's targeted, controlled release were created by Meng et al.(Meng et al., 2024). Folic acid led to wall modifications in microcapsules. According to in vivo tests, microcapsules are able to sustain a high degree of stability within the typical human milieu, hence mitigating the side effects of loaded medications on healthy tissues. Another option in which cancer DDSs were found is external physical stimuli-responsive targeting. Researchers are interested in systems that respond to external physical inputs, such as magnetic impulses. Drug-loaded magnetic nanoparticles (MNPs), which offer targeted drug delivery and may lessen the side effects of chemotherapy medications, have drawn special attention in the context of cancer therapy. This method involves attaching or encasing medications within MNPs, which are then moved to the desired location by an external magnetic field. It can minimize the harmful effects on healthy tissues and optimize the dosage of the medication(Huang et al., 2020). A novel magnetic nanobiocomposite was devised and synthesized by Radinekiyan et al.(Radinekiyan et al., 2024), utilizing CaCl₂ as a cross-linker agent to produce an Alg hydrogel. Tests for hemolysis and in vitro cytotoxicity demonstrated the substance's compatibility with erythroid cells, anticarcinogenicity, and biocompatibility. This novel magnetic nanobiocomposite's characteristics. Using both internal and external physical stimuli is an intriguing additional technique for the administration of cancer drugs. Curcumin-loaded hybrid magnetic nanoparticles (HMNPs) were created by Amani et al. (Amani et al., 2019) by adding Fe²⁺ and Fe³⁺ ions to alginate in an alkaline environment. Under acidic conditions, the curcumin-loaded HMNPs released curcumin under control. The final nanoparticles' positive charge may contribute to better treatment outcomes, longer release times, proper attachment of the particles to the intestinal mucus layers' negative surface, and prevention of self-aggregation.

The latest studies on drug delivery systems based on modified alginates in cancer treatment are summarized in Table 3.

Table 3.

Summary of studies on modified alginate drug delivery systems in targeted cancer therapy.

Type of modification	Cargo	Type of Drug Delivery System	Application	Specific ligand	In- vitro	In- vivo	In-vivo outcome	Special Functionality	Ref
Glycyrrhetinic acid (GA)-modified Alginate(ALG)	Doxorubicin	Nanoparticles	Liver cancer		HepG2 cells	H22 liver tumor-induced Kunming mice	Tumor growth inhibition rate reached 76.6 % after treatment with DOX-GA-ALG nanoparticles, compared with 52.6 % in DOX.HCl group, 22.8 % in GA-ALG NPs group, and 14.4 % in the saline control group	Active targeting	(Zhang et al., 2012)
Poly(ethylene glycol) oligomer (mOEG)-modified sodium alginate (ALG–mOEG)	Doxorubicin	Nanoparticles	Liver cancer		HepG2 cells	H22 liver tumor-induced Kunming mice	DOX–ALG–mOEG nanoparticles showed significantly higher antitumor activity compared to DOX–ALG nanoparticles (75.6 % vs. 62.7 % inhibition, based on tumor weight) after 16 days of treatment (*P < 0.05)	Increasing the duration of action	(Guo et al., 2013)
The mannose (MAN) modified Alginate (MAN-ALG)		Nanoparticles	Cancer immunotherapy	Ovalbumin (OVA)	Mouse bone marrow dendritic cells (BMDCs)	BALB/c mice	facilitated antigen uptake of BMDCs, cytosolic antigen release, and Significant up-regulation of cytokine secretion.	-“easy-to-adopt” vaccine delivery - Dendritic cells targeting - pH sensitivity -Active lymphatic targeting	(Zhang et al., 2017)
Alginate- beta Cyclodextrin (β- CD)	5-fluorouracil	Nanogels	Colon cancer delivery		HT-29 cell line		No data reported	Pressure-sensitive	(Hosseinifar et al., 2018)
PEGylate-modified oxidized Alginate	rhodamine B	Nanogels	Theranostic (both therapeutic and diagnostic applications)	Folic acid (FA)	HepG2 cells		No data reported	-Active targeting -pH-responsive	(Pei et al., 2018)
Ligand-modified Alginate	Indocyanine green	Nanogels	Diagnosing and inhibiting lung metastasis by assisting orthotopic tumor therapy	Anti-programmed cell death 1 ligand 1 antibody (anti-PD-L1)			Tumor recurrence and metastasis inhibition	- An effective strategy for postoperative adjuvant immunotherapy	(Zhang et al., 2021)
Carboxymethylated Alginate	Cisplatin	Nanomicelles	Gastric cancer immunotherapy				Enhanced DC activation, e cytotoxic T lymphocytes infiltration, tumor burden reduction, and prolonged survival in the gastric cancer animal model.	- Reverse the immunosuppressive tumor microenvironment - Synergistically enhance the chemotherapy - Immunotherapy for gastric cancer	(Chen et al., 2023a)
Folic acid (FA)-functionalized and alginate (Alg)-modified poly lactic-co-glycolic acid (PLGA)	Doxorubicin	Nanocomposite	Liver cancer delivery	Folic acid (FA)	HepG2 and Huh7 liver cancer cells	–	No data reported	- pH-sensitive and controlled release behavior of the nanocarrier - Fewer side effects and high biocompatibility	(Hoseinzadeh et al., 2023)
(amine-modified ZnO)-oxidized alginate-PEG ((ZnO-N)-OAl-PEG)	Doxorubicin	Polymeric assemblies	Cancer therapy	–	MCF-7 cells	Mice with MCF-7 tumors	Significant antitumor efficacy with negligible side effects, dual pH responsiveness enabled targeted DOX release and tumor suppression in vivo.	- pH-responsiveness and maintains stability under physiological conditions	(Feng et al., 2024)
Oxidized sodium alginate (OSA) and carboxymethyl chitosan (CMC)	Metal-organic framework material (MOF) with porphyrin core and doped with Cu2+ and surface-modified with polydopamine (PDA)	Nanocomposite hydrogel	Synergistic and precise cancer therapy		4 T1 cells (mouse breast cancer cells)	BALB/c nude mice (female, 4 weeks old)	The hydrogel showed effective tumor inhibition in vivo (4 T1 model), consistent with in vitro photothermal results	- Non-chemotherapeutic systems to achieve precise and efficient tumor treatment	(Zhang and Yuan, 2024)

5.2.2. Treatment of inflammatory diseases

Alginate is highly regarded for its biomedical applications due to its biocompatibility, biodegradability, and non-toxic nature. Additionally, it has immunomodulatory properties, making it an excellent choice for various medical uses(Zhang et al., 2023a). Alginate has been demonstrated to influence human macrophages by deactivating the pro-inflammatory cascade, which aids in resolving inflammation during the healing process. Sodium alginate stimulates natural immune responses by activating the NF-kappaB transcription factor associated with the innate immune system. This factor regulates DNA transcription, cytokine production, and cell survival, following a pathway similar to pathogen recognition. Moreover, alginate oligomers with specific chemical structures exhibit cytokine-inducing activities, structure-dependently(Gimmestad et al., 2009). The anti-inflammatory properties of various alginate-containing compounds have been examined in many studies. Here are a few examples that have been briefly reviewed.

Alginate chitosan nanoparticles have numerous applications as oral drug carriers. One notable use, studied by Oshi et al., is the targeted treatment of ulcerative colitis. This research developed oral core-shell nanoparticles containing curcumin nanocrystals in the core and chitosan/ alginate multilayers in the shell. A unique feature of this formulation is its ability to alter the surface charge in response to pH changes. Due to the polyelectrolytes in the shell, this pH-dependent surface charge modification affects the formulation's interaction with mucin. It increases the accumulation of curcumin nanocrystals in the inflamed tissues of the colon(Oshi et al., 2020). In another study, the effects of chlorogenic acid (CA) alone and in combination with sodium alginate were examined. Chlorogenic acid, a polyphenol with multiple functions, including anti-inflammatory and antioxidant properties, has demonstrated therapeutic benefits in treating various diseases, such as ulcerative colitis. Similarly, sodium alginate also possesses anti-inflammatory properties, protects the digestive system's mucosal lining, and can treat small intestine mucositis. The study's results indicated that using Chlorogenic acid and sodium alginate together is more effective due to their enhanced ability to regulate pro-inflammatory and anti-inflammatory cytokines, protect the colon mucosa, and modulate the intestinal flora(Niu et al., 2022). Alginate oligosaccharides (AOS) can be produced through acidolysis and enzymatic hydrolysis of alginate. These production methods lead to variations in the structure and physiological functions of the resulting oligosaccharides. Alginate oligosaccharides have been shown to protect against intestinal damage by modulating gut microbiota, boosting immune responses, reducing endotoxemia, and alleviating gut inflammation. The specific roles of AOS in intestinal inflammation are not fully understood. However, previous studies suggest that AOS may enhance the intestinal inflammation network by modulating T helper and regulatory T cells, along with their secreted cytokines. These cytokines include essential protein-protein interaction hub genes such as interleukin-1 beta (IL-1β), IL-2, IL-4, IL-6, IL-10, and tumor necrosis factor-alpha (TNF-α), potentially through the regulation of probiotics(Zhang et al., 2023b).

Liver diseases are linked to various factors, including medication and alcohol use, and have become a worldwide issue. These diseases are often accompanied by inflammatory complications, which could serve as a potential target for treatment. Alginate oligosaccharides have been proven to have numerous beneficial effects, with a notable emphasis on their anti-inflammatory properties. They achieve these anti-inflammatory effects by downregulating the expression of pro-inflammatory cytokines, reducing macrophage infiltration, and upregulating the expression of anti-inflammatory cytokines. In this study, busulfan, an effective anti-cancer drug known for its numerous side effects on various organs, including the liver, was used. Liver damage was induced in mouse models using busulfan, and AOS was administered as a treatment. The findings revealed that AOS at a dose of 10 mg/kg improved liver function damaged by busulfan. This research highlights AOS as a potential treatment for inflammatory liver diseases(Hao et al., 2023). In another study by Sugihara et al., alginate oligosaccharide was utilized. The research focused on the Maillard reaction involving the myofibrillar protein of salmon fish, where lysine residues, digested by pepsin and trypsin, were conjugated with alginate oligosaccharide groups. This conjugation inhibited the production of inflammatory cytokines, specifically tumor necrosis factor-α, and IL-6, in lipopolysaccharide-stimulated mouse macrophages. The anti-inflammatory effects increased with the amount of conjugates containing AOS. The study concluded that these anti-inflammatory effects were independent of changes in the peptide patterns of the digested proteins. Additionally, it was demonstrated that the anti-inflammatory effect was enhanced by accelerating the Maillard reaction under high relative humidity conditions. AOS-conjugated peptides, identified as the main anti-inflammatory agents, were effectively isolated using auto-focusing (isoelectric focusing without carrier ampholytes). These peptides were concentrated in acidic fractions, aided by the negative charge of the AOS carboxyl groups. Therefore, combining AOS conjugation with autofocusing presents a valuable method for generating new anti-inflammatory peptides from salmon myofibrillar protein(Sugihara et al., 2021).

5.2.3. Targeting infectious diseases

Antibiotics are a type of medication used to combat bacterial infections. A significant issue in modern healthcare is the rise of bacterial infections that are resistant to many existing antibiotics. Despite antibiotics being highly effective against bacterial infections, the discovery of new antibiotics has slowed. At the same time, antibiotic-resistant bacteria are becoming more prevalent. This situation underscores the urgent need for alternative treatment methods that utilize innovative and targeted formulations(Banin et al., 2017; Laxminarayan et al., 2024). One of the innovative therapeutic strategies in managing infectious diseases, particularly those caused by opportunistic pathogens, is the application of AOS. These oligosaccharides exhibit a unique mucolytic activity and can alter the biofilm produced by bacteria during colonization. Additionally, AOS can modify the biofilm's surface charge and porosity, hindering pathogen growth and compromising their cell membranes. Moreover, research has demonstrated that AOS enhances the antifungal efficacy of standard medications against Aspergillus and Candida strains. AOS also positively influences the growth of Bifidobacterium species, making them potential probiotic and prebiotic agents(Szekalska et al., 2016; Wang et al., 2021a). Another study explored the effectiveness of combining AOS with nystatin against Candida species. The findings demonstrated that AOS not only inhibits the growth of Candida species but also enhances the efficacy of antifungal agents like fluconazole and nystatin. This therapeutic combination is extensively used for preventing and topically treating Candida biofilm infections, helping to overcome the inherent resistance of biofilm structures to antifungal treatments (Powell et al., 2023).

One of the common challenges in drug delivery is the low solubility of certain medications, including some antibiotics. This poor solubility can lead to reduced bioavailability, which diminishes the effectiveness of antibacterial drugs, contributing to the development of bacterial resistance. Nanotechnologies offer a solution to the issue of low drug solubility in water. Natural polymers are commonly utilized in creating polymeric nanoparticle systems due to their biodegradability, which reduces the risk of toxicity in the body. Chitosan and alginate are among the preferred biodegradable polymers because of their water solubility and simple production process. Despite their many advantages, natural polymers have inherent limitations, with stability being a significant issue in polysaccharide applications. Chitosan, in particular, tends to aggregate due to its ionic instability. This problem can be addressed by combining chitosan with other polysaccharides. Alginate is an ideal partner due to its contrasting anionic properties, complementing chitosan's polycationic nature. Alginate and chitosan-based nanoparticles enhance antibiotic performance through four primary mechanisms: 1) they reduce drug particle size, enhancing solubility and absorption; 2) they protect the drug until it reaches the target site, thereby increasing bioavailability; 3) the ionic interaction between chitosan's positive charge and the bacterial cell surface's negative charge increases drug selectivity; and 4) they enable sustained drug release, maintaining bactericidal effects over an extended period(Wathoni et al., 2024).

The use of alginates in various infectious diseases has been researched extensively, yielding promising outcomes. Tuberculosis serves as a notable example of such research. Tuberculosis (TB) is a widespread and serious infectious disease caused by Mycobacterium tuberculosis. In recent years, improved medical care has decreased TB cases in developed countries. However, before the COVID-19 pandemic, TB was the leading cause of death worldwide. The rise of drug-resistant TB strains underscores the urgent need for a robust and effective strategy to combat this disease. Sodium alginate-enhanced anti-TB agents in nanoparticle form have shown notable effectiveness, offering several benefits, such as enhanced drug bioavailability and decreased dosing frequency. Additionally, due to their efficacy and biocompatibility, sodium alginate nanomaterials provide a solid foundation for managing tuberculosis, making treatment regimens more practical and cost-effective(Patel et al., 2023).

5.2.4. Wound healing

A “wound” is the result of damage to the skin from external sources, often leading to tissue destruction and impairment of the skin's structure. Managing chronic and infected wounds over an extended period places significant financial and psychological stress on patients. Another benefit of alginate is its application in wound care products because it can absorb exudates(Bakil et al., 2020; You et al., 2024). In short, we examine several examples demonstrating how alginate compounds are used in this field.

In a study by Zhu et al., using chitosan and alginate nanoparticles to encapsulate Esculentoside A (EsA) significantly improved EsA sustainability and effectiveness for anti-inflammatory purposes and the treatment of burn injuries. Chitosan/alginate nanoparticles were developed to enhance stability and minimize toxicity. These nanoparticles were then incorporated into a collagen/chitosan scaffold. It was shown that a 5 μg dose of the hybrid scaffold reduced the secretion of inflammatory cytokines, inhibited M1 macrophages, promoted the release of anti-inflammatory cytokines, and activated M2 macrophages. This dual action ultimately led to faster and higher-quality healing of wounds. The findings showed that EsA in nanoparticles played a crucial role in enhancing the healing of burn wounds by maintaining long-lasting, gentle anti-inflammatory effects and consistently regulating the polarization of macrophages (Zhu et al., 2023). In a study by You et al., a composite sponge dressing was created by combining the fermentation liquid of a specific strain of Lactobacillus plantarum with zinc oxide (LFL-ZnO), PVA, and SA using a freeze-thaw cycle and freeze-drying molding process. The findings highlighted the impressive properties of this sponge composite in terms of swelling, hydration, and mechanical strength. Additionally, the porous structure of this dressing exhibited notable effectiveness in inhibiting Staphylococcus aureus and methicillin-resistant Staphylococcus aureus(You et al., 2024). Fig. 8 illustrates the summary of the preparation method for this sponge composite.

Fig. 8.

Preparation method of A: LFL-ZnO; (B) sponges. (The sponges created with varying levels of nano‑zinc oxide are SP, SPZ0.5, SPZ1, and SPZ2.). Reprinted from(You et al., 2024).

In a study conducted by Bakil et al., antibacterial films were created using SA and zinc oxide nanoparticles through a solvent-casting method. The antibacterial effectiveness of these films was tested against Gram-negative bacteria (Escherichia coli) and Gram-positive bacteria (Staphylococcus aureus). The findings revealed that the sodium alginate and zinc oxide combination exhibited slightly higher antibacterial activity against Staphylococcus aureus than Escherichia coli. This combination can be a promising therapeutic option for wound treatment.

5.3. Types of alginate-based targeted drug delivery systems

5.3.1. Nanoparticle-based drug delivery systems

Nanoparticles have a specialized surface area and unique size that give them various features not seen in materials of a typical size. The use of NPs in medicine is common(Chang et al., 2021). Over the years, a multitude of nanoparticle types have been produced and are currently frequently used because of their optimized surface modification and capacity to transport different therapeutic components(Pratiwi et al., 2019). One kind of hybrid nanomaterial that is widely used in cutting-edge medication delivery systems is MNPs. The in-situ precipitation of iron ions in a bio-based matrix can be used to create MNPs(Saikia et al., 2015). Le et al. created an alginate-based Fe₃O₄ nanoparticle that was loaded with DOX for chemotherapy and cancer hyperthermia (Le et al., 2018). Exceedingly paramagnetic Co-precipitation was used to develop Fe₃O₄ nanoparticles (MNPs), which were then coated with sodium alginate. Additionally, these MNPs may produce heat within a specific temperature range, which would destroy cancer cells.

5.3.2. Hydrogel-based drug delivery platforms

Hydrogel is a soft material featuring a three-dimensional cross-linked network structure known for its excellent biocompatibility, biodegradability, hydrophilicity, and mechanical properties. Consequently, it is promising for research and clinical applications in various fields. Hydrogels can be categorized into synthetic and natural types based on their sources. Due to their safety, cost-effectiveness, ability to regulate physiological activities of cells and tissues, and adjustable properties for drug release or tissue adhesion, there has recently been a growing interest in using natural polymers such as alginate for hydrogel preparation. Alginate hydrogels can be produced through two primary methods: noncovalent (physical) cross-linking, which prevents the hydrogel matrix from dissolving, and covalent (chemical) cross-linking, which uses various chemical reagents as cross-linking agents for stabilization. These biodegradable gels are typically nanoporous and encapsulate many substances, from small-molecule drugs to macromolecules. Compared to traditional drug delivery systems, alginate-based hydrogels offer several advantages, including high encapsulation efficiency, low toxicity, and excellent patient compliance. Their unique biological and physicochemical properties make them attractive as drug carriers(Chen et al., 2024; Shinde et al., 2023; Tan et al., 2023). Recently, there have been a significant number of studies utilizing alginate hydrogels for drug delivery. Here, we highlight several of these investigations.

Chen et al. conducted a 2024 study focused on creating an appropriate new medication for treating bladder cancer. Traditional treatment methods often cause numerous side effects for patients. Hydrogels made with sodium chitosan alginate have advantages such as excellent biodegradability and biocompatibility, making them effective slow-release carriers for drugs needed to treat bladder cancer. However, conventional hydrogels have drawbacks, including insufficient adhesion and poor targeting in drug delivery. In this study, a chitosan/dialdehyde sodium alginate/magnetic dopamine hydrogel was utilized. The hydrogel, named GelDA, was synthesized from chitosan by cross-linking with sodium dialdehyde alginate and dopamine. Increasing the dopamine content enhanced the adhesion between the hydrogel and the bladder tissue mucosa, with this adhesion being correlated to the catechol group content. Thus, the dopamine content can be regarded as a critical factor in the formulation. Moreover, Fe₃O₄NPs were incorporated to enhance the hydrogel's targeting efficiency. In physiological conditions, the hydrogel's gelation time was about 5–10 min. The hydrogel can achieve directional movement and self-adhesion on the porcine bladder wall when subjected to an applied magnetic field. The findings of this study demonstrated that GelDA can serve as a more effective drug carrier with a drug release duration exceeding 25 h and tissue adhesion lasting over 12 h, effectively addressing common issues in bladder drug delivery(Chen et al., 2024).

In another 2022 study, researchers investigated a flexible drug delivery system for methylene blue (MB) in treating traumatic optic neuropathy (TON). One of the contributing factors to damage is the uncontrolled production of reactive oxygen species (ROS), which traditional treatments cannot effectively manage. Methylene blue serves as a strong remover of ROS and functions as a neuroprotective agent that can penetrate the blood-brain barrier. The study's findings demonstrated sustained release of MB over time and the formation of an in situ gel. The sustained release in this formulation is attributed to the electrostatic interaction between the cationic MB and the anionic alginate polymers. Internally cross-linked alginate hydrogels were synthesized with uniformly distributed insoluble calcium carbonate (CaCO₃) and D-glucono-lactone (GDL). This approach decreases the gelation time to 10 to 50 min. Adjusting the ratio of CaCO₃ to GDL impacts hydrogel swelling, mechanical properties, and the release of MB. Increasing their concentration in the formulation enhances the potential to treat TON damage and other diseases associated with the accumulation of active species(Maxwell et al., 2022).

In another study, researchers created double-network hydrogels using SA and PVA. Through hydrogen bonding, SA and PVA formed miscible solutions and blends. Crosslinking of SA was facilitated by replacing sodium ions with calcium ions using calcium chloride in the SA/PVA solution, forming the first hydrogel network. The second network was established by introducing physical crosslinks in PVA through the freeze-thaw process. Increasing the amount of PVA is directly related to strengthening these double-network hydrogels. Ciprofloxacin was used as a model drug and incorporated into hydroxyapatite (HAP) nanoparticles. These nanoparticles were blended with SA/PVA solutions to form SA/PVA/ciprofloxacin-loaded HAP microspheres. The microspheres obtained were subjected to a freeze-thaw process following their separation. Subsequently, these microspheres were incorporated into an aqueous agar solution. This agar solution formed gels that could reversibly form a hydrogel at physiological temperatures. This system was developed to enable the sustained release of antibiotics and promote the reconstruction of infected bones. Ultimately, the results demonstrated the efficacy of these drug-loaded hydrogels against E. coli bacteria(Ghazagh and Frounchi, 2024).

6. Biological safety and immunogenicity

Concerning general toxicity, alginate is known as a biocompatible substance(Hariyadi and Islam, 2020), acute cytotoxicity investigations generally find modified alginates nontoxic, as long as reagents are removed. For instance, alginate-PNIPAAm formulations in the form of IPC and grafting were non-toxic in vitro(Cheaburu-Yilmaz et al., 2019). Similarly, cells encapsulated in oxidized alginate remained viable(Volpatti et al., 2023). Notably, developed polymer should be differentiated from residual chemicals; incomplete purification, partial existence of solvent or reagent residue can cause inflammation(Mutch et al., 2024; Veiseh and Vegas, 2019). In general, modified alginate largely retains the biocompatibility of the native polymer, but its safety must be validated.

When it comes to the immunogenicity, it is widely known that alginate, like many other implanted biomaterials, evokes a foreign body reaction characterized by macrophage recruitment(Bray, 2016). Chemical modifications can modulate this reaction. For instance, optimizing the net charge of alginate hydrogel with poly(ethylene imine) in the neutral range can mitigate the foreign body reaction(Zhang et al., 2018).

There are some considerations based on the route of administration for different alginate delivery systems. Firstly, in oral delivery, alginate is generally safe by mouth, as it is used as a food additive(Bi et al., 2022). Modified alginate beads or tablets primarily transit the gastrointestinal tract without absorption; hence, there might be little concern about systemic immune response since absorption is minimal. Additionally, oral modified alginate formulations, which served as the vaccine, showed no adverse effects(Hashemi et al., 2024; Jazayeri et al., 2021).

Secondly, injected alginate particles or hydrogels with a typical size of microns do not have the ability to enter into lymphatic or vascular circulation, which generally occurs with nanoparticles smaller than 100 nm(He et al., 2023; Hoshyar et al., 2016). Therefore, local safety concerns with microspheres generally should focus on inflammation rather than systemic effects; degradability-based design can prevent the accumulation of polymer fragments. While sub-micron alginate particles must pass sterility, endotoxin-free assessments, and safety considerations, as these particles may exhibit different biodistribution patterns upon entering the lymph or blood circulation.

Finally, large alginate implants have the highest foreign body response and are surrounded by fibrotic tissue(Veiseh and Vegas, 2019). Hence, some modifications can mitigate their chronic immunogenic profile, as mentioned above.

7. Challenges and future directions

7.1. Current challenges in modified alginate drug delivery

Modified alginates hold immense promise for precision drug delivery, yet several challenges and limitations must be addressed to realize their full potential. This paper provides a detailed examination of these issues alongside prospects. Alginates, known for their biocompatibility and tunable properties, require significant chemical modifications, such as ionic crosslinking, cyclodextrin-linking, and functional group modifications (e.g., esterification, sulfation, and copolymerization), to meet the specific demands of controlled-release and targeted delivery systems(Askari et al., 2024c). While these modifications enhance alginate's mechanical strength, degradation rates, and drug-loading efficiency, challenges like the reproducibility of modifications, scalability of production, and maintaining structural stability under physiological conditions persist.

While the safety and efficacy of alginates for oral and topical use have been thoroughly investigated in clinical studies, the parenteral use of alginates is less well established. The clinical studies in which alginate-based materials were utilized parenterally in human subjects did not concern drug administration(Thomas et al., 2006). As alginates are derived from natural sources, they may contain impurities(Tam et al., 2006; Tønnesen and Karlsen, 2002; Torres et al., 2019). These impurities present a significant challenge in the application of drug delivery, as they have the potential to induce adverse effects and compromise the efficacy of the material. Research has demonstrated that the purification process can markedly enhance the hydrophilicity and solution viscosity of alginate, both of which are pivotal factors for its pharmaceutical properties(Tam et al., 2006). Furthermore, unpurified alginates have been associated with increased immune responses, fibrotic tissue formation in vivo, and reduced cell viability and differentiation in vitro(Klöck et al., 1997; Torres et al., 2019). These challenges underscore the necessity for rigorous purification to ensure safety and efficacy in pharmaceutical applications. Furthermore, modifications can pose their own set of challenges. For instance, sulfated alginates have been associated with increased anticoagulant activity and an elevated risk of bleeding(Xue et al., 2016). Moreover, the byproducts and residues of modification reactions have the potential to pose a considerable threat to human safety.

Modified alginates enable diverse mechanisms in controlled-release drug delivery systems, including dissolution, diffusion, water penetration, chemical reactions, and ion exchange. Despite these advancements, fine-tuning drug release profiles remains problematic, particularly for therapeutic agents that require highly specific release kinetics. Physiological conditions, including pH variability, enzymatic degradation, and varied vascular access, have the potential to exert a substantial influence on the release profile of the drug delivery system. These factors must be addressed to ensure the optimal performance of the system. Applications such as hydrogels, in-situ gelling systems, and nanoparticle-based delivery have shown promise, yet scaling up these technologies while maintaining consistent performance remains a formidable hurdle. At the same time, innovative bioprinting techniques and nanofiber-based delivery systems suffer from technical challenges related to production efficiency and material compatibility. Achieving precise control over drug release profiles, particularly for complex therapeutic agents like proteins and nucleic acids, remains a technical hurdle. Furthermore, while applications in oral, transdermal, and injectable systems are promising, the need to overcome rapid clearance and immune responses limits their efficacy.

In targeted drug delivery, modified alginates offer both passive and active targeting mechanisms, enabling disease-specific interventions in areas such as cancer therapy, inflammatory diseases, infectious diseases, and wound healing. However, passive targeting often suffers from nonspecific accumulation in non-target tissues, reducing therapeutic efficacy and increasing side effects. Active targeting strategies rely on ligand-conjugated alginates and face issues related to ligand stability, retention, and cost-effective production. Moreover, the heterogeneity of disease tissues and barriers like the blood-brain barrier complicate efficient drug targeting.

7.2. Translational and commercialization barriers

Regulatory and commercialization barriers further complicate the adoption of modified alginate systems. Maintaining the natural alginate source with reduced property variability and accounting for environmental factors could impact the reproducibility of the process during commercialization. The lack of standardized protocols for synthesis and characterization impedes reproducibility, while the high costs of functionalization processes limit their accessibility for large-scale manufacturing. Furthermore, regulatory concerns obligate manufacturers to validate each process and furnish extensive documentation, which results in costly delays in commercialization. Biocompatibility concerns, particularly for chemically modified alginates, necessitate rigorous in vivo testing to ensure safety and efficacy, which adds time and expense to product development(Askari et al., 2024b).

7.3. Future directions and emerging innovations

Looking ahead, innovations in alginate chemistry, such as the development of bioorthogonal modification techniques, promise to improve the precision and efficiency of chemical functionalization. Dynamic control over drug release and targeting may be made possible by developments in materials science, such as the incorporation of alginates with smart materials and stimuli-responsive systems: multifunctional nanocomposites and other applications of nanotechnology promise to resolve issues with heterogeneity and scalability. Addressing the biological and technical issues related to modified alginates will require interdisciplinary cooperation. Alginate-based drug delivery systems can be predicted and optimized for particular therapeutic needs by researchers through the combination of computational modeling and experimental design. The utilization of artificial intelligence (AI) models holds great promise for expediting the prediction of the properties of modified alginates and their cost-effective optimization(Das et al., 2023). Moreover, it is important to note that these models can also have an incredible impact on the commercialization of alginates for personalized therapeutic applications. Furthermore, the integration of AI models facilitates real-time quality control and expedites the implementation of corrective actions. Additionally, standardizing procedures and expediting regulatory approval processes will require collaborations between academic institutions, businesses, and regulatory bodies.

To sum up, modified alginates are a revolutionary method of precise drug administration that may be used in a variety of therapeutic domains. Despite their difficulties, promising answers are provided by ongoing research and technological advancements. In order to overcome present constraints and realize the full promise of alginate-based systems in developing precision medicine, this study emphasizes the necessity of sustained investment in research, innovation, and cooperation.

8. Conclusion

Modified alginates combine different modifications in the chemistry field with several release mechanisms in pharmaceutical science to provide advanced functionalities for addressing the limitations in modern medicine. These numerous modifications, such as ionic crosslinking, cyclodextrin-linking, and carboxyl and hydroxyl group modifications, are highlighted in this review to explain how important their role is in providing various delivery systems with release kinetics. Such altered alginates in forms of controlled-release systems, including hydrogels, bioprinting, nanofibers, in-situ gelling, and nanoparticles, offer custom-made therapeutic profiles and better patient compliance. They offer the advantage of being susceptible to passive and active targeting strategies in targeted drug delivery, thus showing their potential in the therapy of complex diseases.

Applications ranging from cancer therapy and inflammatory disease therapy to infectious disease targeting and wound healing demonstrate their broad-spectrum utility. Nanoparticles and hydrogels represent some of the platforms that also demonstrate the scalability and flexibility of these systems in application-specific diseases. Despite these developments, there are still obstacles relating to maintaining reproducibility, large-scale synthesis, and long-term biocompatibility. Additionally, further investigations are necessary to understand their interactions with biological systems. Development of multi-functional alginate-based systems, AI-driven design in formulation and release mechanism prediction, and the optimization of green manufacturing processes are the attractive opportunities in the future. In conclusion, modified alginates play an essential role in the progression of precision drug delivery. They can be known as the state of the art in addressing modern medical issues and promoting development in controlled-release and targeted therapeutic platforms by integrating chemical modifications with biological occurrence.

Artificial Intelligence (AI) use

The authors confirm that no paper mills and no artificial intelligence were used.

CRediT authorship contribution statement

Sara Masoumi Shahrbabak: Writing – review & editing, Writing – original draft, Investigation. Seyede Melika Jalali: Writing – review & editing, Writing – original draft, Visualization, Investigation. Maryam Fadaei Fathabadi: Writing – review & editing, Writing – original draft, Visualization, Investigation. Vahid Tayebi-Khorrami: Writing – review & editing, Writing – original draft, Visualization, Investigation. Mostafa Amirinejad: Writing – review & editing, Writing – original draft, Visualization, Investigation. Soheil Forootan: Writing – review & editing, Writing – original draft, Visualization. Mahsa Saberifar: Writing – review & editing, Writing – original draft, Visualization, Investigation. Mohammad Reza Fadaei: Writing – review & editing, Writing – original draft, Visualization, Validation, Methodology, Investigation. Zohre Najafi: Writing – review & editing, Writing – original draft, Visualization, Investigation. Vahid Reza Askari: Writing – review & editing, Writing – original draft, Visualization, Validation, Supervision, Methodology, Investigation, Conceptualization.

Ethics approval and consent to participate

Not applicable.

Human and animal rights

No animals/humans were used for studies that are the basis of this research.

Funding

None.

Declaration of competing interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Data availability

No data was used to support the findings of this study.