Bile acids and nanotechnology as emerging platforms for drug delivery

ABSTRACT

Introduction

Drugs are generally classified according to the Biopharmaceutics Classification System (BCS) based on their solubility and intestinal permeability. Group I drugs tend to have higher bioavailability due to their high solubility and permeability. Drugs in group II have low solubility and high permeability, while drugs in group III have high solubility and low permeability. Drugs in group IV have low bioavailability and require various techniques to enhance their delivery due to their low solubility and permeability.

Areas covered

Bile acids are commonly known as biological molecules with surfactant capabilities and continue to be underutilized in enhancing the pharmaceutical profile of drugs. Hence, this review will explore some of the common drug delivery methods and will focus on the use of bile acids and various applications of nanotechnology to enhance drug delivery, including lipid nanotechnology, as well as carbon nanotubes and quantum dots. The authors aim to provide more insights into drug delivery research and contribute to the development of novel drug delivery strategies.

Method

A literature search was conducted using ProQuest and PubMed, covering publications up to 10 years. Older references were included as appropriate.

Plain Language Summary: Improving Drug Delivery With Bile Acids And Nanotechnology

Bile acids are natural molecules produced in the body that can help dissolve and transport substances that dissolve poorly. Despite their useful characteristics, they remained under-researched and underutilized in systems that deliver drugs to the body. This review discusses common and newer methods of drug delivery and highlights the potential of bile acids to improve drug delivery. The review also explores how nanotechnology applications, such as lipid nanocarriers, carbon nanotubes, and quantum dots, can be used as applications in drug delivery. By bringing together current research on bile acids and nanotechnology, this review aims to provide insights that may support the development of more effective drug delivery systems.

GRAPHICAL ABSTRACT

1. Background

For oral medications to have a therapeutic effect, drug dissolution must occur, followed by drug absorption [1,2]. Drug dissolution is commonly defined as the process where drug content is released from its dosage form and dissolves while drug absorption refers to the uptake of these molecules into the systemic circulation [3]. Typically, drugs are classified into four different classes based on the Biopharmaceutics Classification System (BCS), according to the drugs’ solubility and intestinal permeability. This classification continues to be utilized today by regulatory bodies such as the United States Food and Drug Administration (FDA) [1,4–6]. The creation of BCS is intended to ease the classification of different drugs and to correlate their in vitro properties to their in vivo bioavailability, in which the rate and extent of drug absorption are directly related to drug dissolution and gastrointestinal permeability. The aforementioned correlation serves as a basis for predicting the absorption and bioavailability of any drug [1,2,6]. Figure 1 summarizes the different properties of each drug class based on the BCS.

Figure 1.

An illustration of the classification of drugs in the Biopharmaceutical Classification System (BCS).

1.1. Class I drug

Drugs classified as class I have high solubility and high permeability in the gastrointestinal tract, where the drug is well absorbed. In this situation, the rate-limiting step is often either drug dissolution or gastric emptying if dissolution is quick [1]. High solubility of a drug is said to be achieved when its solubility across the whole physiological pH range exceeds the concentration determined by dividing the highest strength of the drug by 250 ml. On the other hand, high permeability is achieved when the absolute bioavailability of the drug is at 90% or higher, or its permeability surpasses its counterpart reference compound in in vitro or in situ assays [7]. As compared to other classes of drugs in the BCS, Class I drugs have fewer formulation challenges and thus, developing them into effective oral medications is easier. Some examples of commonly used drugs that come under class I include paracetamol and diazepam, which are used as a mild to moderate analgesic and anxiolytic, respectively [8].

1.2. Class II drug

Drugs that are classified as class II have properties of low solubility with high permeability. Since drug dissolution will be the limiting step, their dissolution profile, including the media and methods, must be clearly defined and reproducible in order to establish good in vitro and in vivo correlations [1]. Unlike class I drugs, the choice of media is expected to play a very important role in the dissolution of the drug. In the dissolution of a class II drug, factors such as pH, buffer capacity, ionic strength, volume, and the addition of surfactants play an integral role. As such, the media used must closely resemble the physiological characteristics of the upper gastrointestinal tract in order to obtain relevant in vitro and in vivo correlation [9]. Despite the solubility challenges, class II drugs can achieve therapeutic efficacy when appropriate formulation approaches are employed to ensure sufficient drug solubilization in the gastrointestinal tract. An example of a formulation approach would be the use of self-nanoemulsifying drug delivery systems (SNEDDS), which convert into a nanoemulsion with oil and water phases when in contact with water, enhancing the solubility profile of insoluble drugs [10–12]. A commonly used BCS class II drug would be ibuprofen, a propionic acid derivative that is a prototypical nonsteroidal anti-inflammatory agent with analgesic and antipyretic properties used to relieve mild to moderate pain and fever [13]. Ibuprofen has a highly lipophilic structure with low solubility, which results in its low bioavailability. As such, techniques that are utilized to improve ibuprofen’s solubility include the conjugation of molecules to ibuprofen, such as with esters to form salts, thus improving its solubility profile [14,15].

1.3. Class III drug

BCS class III drugs have properties of high solubility with low permeability, where permeability is the rate-controlling step in their drug absorption [1,16]. For drugs in class III, the rate and extent of drug absorption can vary considerably. This variation can be explained by the gastrointestinal content, transit, and membrane permeability, which differ along the gastrointestinal tract, on the assumption that the rate of dissolution is quick [1]. In the United States alone, BCS class III drugs make up about 25% of all marketed drugs [17]. One commonly used class III drug worldwide is Metformin, a biguanide antidiabetic drug commonly prescribed for the treatment of type II diabetes. Metformin works by suppressing hepatic gluconeogenesis to inhibit fatty acid production and oxidation [18]. For class III drugs, drug formulations are usually focused on enhancing the drug’s permeability, often through the use of specialized delivery systems or the addition of permeability enhancers in the formulation [19]. Cefotaxime, a class III cephalosporin antibiotic, was found to display an increase in oral bioavailability up to five times when loaded into nano-sized liposomes with bile salts [20]. Ondansetron, a class III drug commonly used as an antiemetic medication in cancer therapy, is designed as a buccal drug through the hot-melt extrusion technology. Its low bioavailability is attributed to hepatic first-pass metabolism, and thus, by designing it as a buccal drug where absorption occurs in the oral cavity, first-pass metabolism is bypassed, enhancing its bioavailability [21].

1.4. Class IV drug

Effective drug delivery can be a challenge for class IV drugs, which have low solubility and permeability [1,22]. Because of its low bioavailability when orally administered, efforts have been made to improve bioavailability through different techniques, such as particle size reduction, absorption enhancers, conjugations to the drugs themselves, formation of salts or specialized delivery systems [23–27]. A study by Kaneko et al. demonstrated significant improvement in the bioavailability of acetazolamide, a class IV BCS drug, when coated with nano-hydroxyapatite, a highly biocompatible substance that is a main component of mammalian teeth and bone [23]. In another example, the esterification of ciprofloxacin, another class IV drug, resulted in the disruption of the crystal lattice of ciprofloxacin itself, enhancing its solubility [22]. Just like for Class II drugs, self-emulsifying drug delivery systems have also been explored for Class IV drugs such as ritonavir, where solid self-emulsifying granules with ritonavir loaded were designed and shown to result in about a 27 fold increase in apparent solubility and a 20 fold increase in permeability as compared to the bulk drug [11].

1.5. Lipophilicity

Lipophilicity is a term commonly used in the pharmaceutical industry to predict certain properties of drugs, such as solubility, absorption, and distribution. Lipophilicity is commonly represented as Log P and Log D and is defined as a chemical’s affinity or tendency to partition into a nonpolar lipid than an aqueous phase [28,29]. A log P value of greater than 5 in Lipinski’s rule of 5 tool for the prediction of an oral drug compound would suggest that poor absorption or permeation is likely to occur [30,31]. Log P is defined as the log of the partition coefficient of the compound between the nonpolar phase and an aqueous phase, while Log D, on the other hand, is the log of the distribution coefficient of the compound between a nonpolar phase and an aqueous phase. Compounds are all in their neutral form for the calculation of Log P, while for Log D, they can be in either ionic or neutral pH [28]. A high log P value indicates that the compound will likely have poor water solubility, as it is more nonpolar, and likewise, a low Log P value generally means that the compound may experience lower permeability through the lipid bilayer. Hence, a moderate log P value of 1–3 is suggested to ensure that the compound has sufficient water solubility and lipid permeability for optimal bioavailability [30]. Lipophilic drugs commonly fall under class II drugs, where their low solubility has limited their bioavailability.

Due to their limitations in solubility and lipophilicity profile arising from their chemical structure affecting their bioavailability, various administration methods and techniques have to be utilized for drugs in classes II to IV. This review will explore some of the traditional and current modalities to deliver drugs, as well as some of the technologies involved, particularly bile acids and nanotechnology used to overcome poor bioavailability in drug delivery. A literature search was conducted through ProQuest and PubMed, using search terms and keywords related to “bile acids,” “drug delivery,” and “nanotechnology.” Articles or books published within the last 10 years were prioritized to reflect recent advances while older references were included when relevent.

2. Drug administration methods

Traditional drug administration methods, such as oral and parenteral delivery, remain central to clinical practice but are limited by challenges such as poor bioavailability, stability, and lack of targeted delivery. These limitations have driven the development of advanced formulation strategies, including bile acid-based systems and nanotechnology. This section outlines conventional approaches as a foundation for understanding subsequent innovations, while introducing contemporary methods such as transdermal and inhalation delivery to bridge the transition toward modern drug delivery technologies.

2.1. Traditional methods

2.1.1. Oral administration

Due to feasible and affordable manufacturing coupled with ease and accurate dosing for patients, tablets remain one of the most common oral dosage forms, where most of the drugs in the United States are formulated as tablets of various types and sizes [2,32,33]. The compression of powders into solid mass goes back thousands of years, with automated tablet compression only made possible in the 1800s, where 1200 tablets could be made in a minute by the mid-1800s [34]. Tablets can have a variety of shapes, sizes, and surface markings depending on the design and the type of punches and dies used [32,35,36]. Granules or powder blends are compressed in tableting machines to form tablets, and excipients are commonly added to the active ingredient to improve the tablet’s quality or performance profile [32,37–39]. Depending on the biochemical and stability profile of the active drug ingredient in various pH levels and the target site of absorption, tablets can be formulated specifically to overcome the natural barrier of the body, which could otherwise reduce the effectiveness of the active drug [32,37]. A classic example would be enteric-coated tablet formulations, which have a coating to protect the active ingredient from the acidic conditions in the stomach, allowing them to stay insoluble in the stomach and subsequently readily dissolve at the higher pH of the intestine to release the active drug [32,35,37].

Despite their widespread use, conventional tablet formulations do present challenges in delivering drugs with unfavorable physicochemical properties, particularly those in BCS Class III or IV. Nevertheless, drugs such as metformin hydrochloride, a BCS Class III drug, are commonly formulated as immediate and extended-release tablets to optimize their absorption in the gastrointestinal system [40]. Furosemide, a BCS Class IV drug, is still commonly prescribed in oral tablets despite having highly variable bioavailability [41].

Capsules, on the other hand, are dosage forms in which the contents, which can be in powder, semisolid, or liquid form, are enclosed in a soft or hard shell [32,42]. Capsules prepared from gelatin were first patented in France in 1834. They are generally classified into hard or soft capsules, with the material for soft capsules comprising a more flexible and plasticized gelatin as compared to hard capsules [32,35]. Other than the oral route, soft capsules are also commonly used as suppositories, either vaginally or rectally [32,43]. Compared to conventional tablets, the production of disease-specific capsule formulations is made possible with modern capsule technology which allows for the filling of capsules with diverse systems such as granules and semisolids. However, this can also mean higher production costs and more time-consuming production [35]. Because the encapsulation process often entails the capsule content being in a liquid phase for it to be metered into individual capsules, the production reproducibility of soft capsules tends to be higher than hard capsules and tablets [35,44]. Most capsules are completely sealed off, making it challenging to obtain or tamper with the content of the capsule without damaging the capsule itself [42].

Despite capsules having certain formulation advantages over tablets, conventional capsules may still present solubility challenges for drugs that have poor bioavailability. Itraconazole, being a poorly soluble antifungal drug, continues to exhibit variable bioavailability despite formulating as a capsule containing drug-coated pellets with a solubilizing agent to enhance its dissolution [45].

2.1.2. Parenteral administration

The term parenteral drug delivery, which originates from the Greek words meaning ‘beside’ and ‘the intestine,’ refers to the direct administration of the drug into the blood or body tissues rather than through the gastrointestinal tract. In the clinical setting, parenteral drug delivery is more commonly referred to as subcutaneous, intramuscular, and intravenous delivery. Parenteral administration serves as an alternative pathway to deliver drugs into the body when the patient is not conscious, and oral administration is not possible [46]. In emergency situations where an immediate therapeutic effect is desired, parenteral administration would be preferred since the drug is directly administered to the body without having to pass through the gastrointestinal tract [46,47]. However, a major drawback of parenteral administration is that its therapeutic effects are often difficult to reverse once administered, and management strategies are limited. Since the drug enters the tissue or bloodstream directly, sterility must be ensured to prevent infection. Thus, the higher risk of contamination and infection associated with parenteral products, along with higher costs, may reduce patient compliance and health outcome [46].

Parenteral nutrition is a frequently used parenteral application in the clinical setting when food can no longer be delivered through the gastrointestinal route or is not a feasible option anymore [48,49]. To maintain the patient’s normal well-being and bodily functions, parenteral nutrition contains essential components such as amino acids, trace elements such as vitamins, fluid, lipids, and electrolytes, just to name a few [48,50]. Medications can also be added, depending on the patient’s comorbidities and needs. All of these will contribute to the maintenance of essential body functions and organs, including cell renewal and immunity [48]. Another prime example of the use of parenteral administration will be vaccines. Numerous vaccines, including the zoster and measles vaccines, are administered subcutaneously, below the dermis. The loose structure of the subcutaneous tissue allows for larger injectable volume, and due to the connective and adipose tissues within the subcutaneous tissue, a vaccine depot can be formed. Having lesser blood vessels as compared to the dermis allows for lower clearance of the vaccine, and together with the flexibility of the subcutaneous tissue, pain for the patient tends to be more tolerable, allowing for a high compliance level. Depending on the vaccine’s nature and mode of action, vaccines are also administered intravenously or intramuscularly, just to name a few [51].

While parenteral administration is often used to overcome challenges with solubility, variability in bioavailability can still occur. Anticancer drug docitaxel is routinely administered intravenously to achieve its therapeutic levels but often demonstrates variability between patients due to differences in hepatic metabolism and drug clearance [52].

2.2. Contemporary methods

2.2.1. Transdermal drug delivery

Transdermal drug delivery is a noninvasive technique that allows for the sustained release of drug over a prolonged period of time, with or without a stimulus [53]. For transdermal drug delivery to be effective in seeing the desired systemic therapeutic effect, there must be sufficient permeation and accumulation of the delivered drug through the different layers of the skin into the bloodstream [54,55]. Some commonly used drugs that are delivered transdermally include estradiol for hormone replacement, nicotine for smoking cessation, and fentanyl for analgesia [53]. Since the delivery of drugs transdermally allows the drug to avoid the gastrointestinal tract and first-pass metabolism, lower doses of drugs are permitted, possibly reducing side effects [53,56,57]. With controlled and sustained release of drug, longer maintenance of drug concentration in the therapeutic range is made possible, reducing the need for frequent dosing. Most importantly, drug administration can be stopped by simply removing the patch. Drugs used in transdermal delivery are usually no greater than 500 Dalton in size and have both lipophilicity and hydrophilicity, to pass through the stratum corneum and leave the stratum corneum into the bloodstream respectively. However, drugs that are charged or greater than 1000 Daltons would pose a challenge to be delivered transdermally. Hence, enhancement techniques that involve the use of chemical penetration enhancer or disruption of the stratum corneum would have to be utilized to overcome the challenges presented by the stratum corneum [53].

While the transdermal route of administration does provide certain unique advantages over oral or parenteral routes, many drugs still exhibit limited or variable systemic exposure. Fentanyl, for example, when delivered transdermally, can result in interpatient variability in systemic exposure due to differences in skin characteristics between patients [58].

2.2.2. Inhalation

Inhalation is a type of pulmonary route of administration that is noninvasive, quick-acting, and used in a plethora of conditions. When a drug is inhaled, deposition of the drug occurs at the oropharynx or the airway, where it can have both locally and systematically therapeutic effects, through the gastrointestinal route or the airways [59–61]. The use of the lungs as a target for drug delivery is relatively newer as compared to traditional methods, such as tablets, with the commercialization of inhaled drugs only occurring in the late 1940s. With advancements in device design and drug formulations in inhalation that can potentially improve patients’ convenience and compliance, people are preferring inhalation methods over traditional methods such as tablets or parenteral administration [60]. With a large surface area and vast vasculature available for absorption, inhalation delivery methods offer great potential in systemic delivery [59,60].

Dry powder inhalers (DPI) are a type of inhaler that delivers a powdered drug of suitable aerodynamic size, usually less than six microns, for deposition to the lower respiratory tract to exert its therapeutic effect [60,62]. Current DPIs in the market are mostly passive devices, where the activation of the device is dependent on the patient’s inspiratory flow rate to generate enough energy to disperse the drug. Hence, it is ideal to design a device that works at a high level despite the patient not having a high inspiratory rate or is independent of the patient’s inhalation [60]. However, because of the large surface area of powder particles that results in them being highly cohesive, overcoming the cohesion forces can be challenging, resulting in less than 20% of the drug being deposited in the lungs [60–62]. While the use of a DPI does not require much coordination from the patient, the device’s complexity and patient’s dexterity must be considered during prescribing and accompanied by proper education from respective health professionals to ensure patient compliance and device efficacy [60].

While contemporary methods like inhalation and transdermal methods can enhance drug delivery to targeted sites as compared to traditional methods, they do not inherently change the solubility or lipophilicity profile of the drugs delivered. In addition, due to the limitations of these methods, not all drugs are suitable for inhalation and transdermal delivery. These challenges underscore the potential of the use of bile acids and nanotechnology in drug delivery to enhance bioavailability and therapeutic outcomes.

3. Bile acids

Bile acids are produced during the process of cholesterol metabolism in hepatocytes. They are mostly water-soluble and play an important role in the body’s digestion and absorption of fats [63]. Bile acids are characterized into primary and secondary, depending on where they are synthesized, with the conversion of secondary bile acids from primary bile acids by bacteria in the colon [63,64]. Cholic acid and chenodeoxycholic acid are examples of primary bile acids, while deoxycholic acid and lithocholic acid are secondary bile acids, produced when primary bile acids are metabolized by 7α-dehydroxylase of bacteria in the intestine [64]. Bile acids found in bile are usually derived from two different sources, mainly through synthesis or recycling via the enterohepatic circulation pathway [65]. Bile acid synthesis can occur via two different pathways, mainly the classical pathway and the alternative pathway [64,66,67], as illustrated in Figure 2. The 7α-hydroxylation of cholesterol by cholesterol 7α-hydroxylase (CYP7A1) in hepatic microsomes is considered the first and rate-limiting step in the classical pathway, regulated through negative feedback by the enterohepatic circulation of bile acids returning to the liver [64,67–69]. 7α-hydroxycholesterol is subsequently converted to 7α-hydroxy-4-cholesten-3-one by HSD3B7, which is further reduced to 5β-cholestan-3α,7α-diol, a precursor for chenodeoxycholic acid by cytosolic enzymes AKR1D1 and AKR1C4. For cholic acid, 7α-hydroxy-4-cholesten-3-one is hydroxylated by CYP8B1 and subsequently reduced by AKR1D1 and AKR1C4 to 5β-cholestan-3a,7a,12α-triol. Both the precursor 5β-cholestan-3α,7α-diol and 5β-cholestan-3a,7a,12α-triol undergo oxidation at the steroid side chain by mitochondrial sterol 27-hydroxylase, with the products further undergoing side chain cleavage by peroxisomes to form cholic acid and chenodeoxycholic acid [66].

Figure 2.

A simple illustration of the classical and alternate pathways for the biosynthesis of bile acids and the formation of secondary bile acids from primary bile acids.

On the other hand, the alternative pathway starts off with the conversion of cholesterol to 27-hydroxycholesterol by CYP27A1. It then undergoes a reaction regulated by CYP7B1 and CYP27A1 to produce chenodeoxycholic acid [70].

The bile acids found in bile or serum are typically conjugated with taurine or glycine, with a ratio of about 1:3 in humans. Bile acids present in bile and serum are typically conjugated either with taurine or glycine, with a ratio of conjugation to be about 1:3 in a human, and this ratio can vary depending on the type of disease [64,69]. Other than taurine and glycine, bile acids also undergo conjugation with other compounds such as sulfates and glucuronides, including double conjugation, which makes them hydrophilic and can be excreted more easily in urine [64]. Among these conjugated bile acids, glycine-conjugated dihydroxy bile acids will be passively absorbed transcellularly in the duodenum and jejunum as they are protonated. More than 90% of secreted bile acids are instead absorbed through active transport in the ileum. Through the portal vein, the absorbed bile acids will return to the liver, where they will be secreted into bile again [69].

3.1. Physico-chemical properties of bile acids

Unlike other aliphatic surfactants, Bile acids have a unique chemical structure that is derived from cyclopentanoperhydrophenanthrene, a compound also known as the nucleus of a steroid [71,72]. Most bile acids in mammals have a C₂₄ steroid backbone, in which the side chain of the cholesterol is only C₅ as compared to a C₈ for fish and reptiles [73]. The concave α side contains structural components that are hydrophilic, while the convex β side contains structural components that are hydrophobic [72]. The toxicity of bile acids is related to their hydrophobicity. Ursodeoxycholic acid, being the least hydrophobic, will be the least toxic, followed by cholic acid, chenodeoxycholic acid, and deoxycholic acid [74]. Having both hydrophobic and hydrophilic components in its structure, bile acids have the tendency to interact at surfaces and interfaces, forming micelles when the concentration of bile acid reaches CMC, the critical micelle concentration [72,75]. Depending on the type of bile acids, micelles can exist in different forms and structures, with each micelle containing up to 50 bile acid molecules that can be used to solubilize lipophilic drugs or materials [75]. Physicochemical characteristics of common bile acids have been summarized in Table 1.

Table 1.

Physicochemical properties of major bile acids [76–78].

Bile acids	pKa	Approximate critical micelle concentration (mM)	Hydrophobicity	hydrophilic-lipophilic balance (HLB) tendencies	Toxicity Gradient	References
Lithocholic Acid	~5.0	0.9	Very high	Highly lipophilic (Low HLB)	Very High	[76–78]
Deoxycholic Acid	~5.3	3–10	High	Lower HLB due to presence of more lipophilic surface	Moderate-high
Ursodeoxycholic Acid	~5.0	7–19	Low	Reatively hydrophilic due to presence of β-OH configuration	Very low
Chenodeoxycholic Acid	~5.0–5.2	4–9	Moderate	Balanced	Moderate
Cholic Acid	~5.0	11–13	Low-moderate	Hydrophilic due to presence of 3 hydroxyl group	Low-moderate

3.2. Pharmaceutical applications

Traditionally recognized for their role in the digestion and absorption of fats, bile acids have garnered increasing attention in recent years for their potential therapeutic applications in medicine. Research has revealed that bile acids could possibly have a much broader role in biological processes beyond their role in lipid metabolism due to their unique structure. These include acting as signaling molecules for various receptors involved in biological processes such as inflammation and immune response [69,79–82]. This is made possible through various interactions with different receptors through different pathways, including the nuclear receptors farnesoid X receptor, vitamin D receptor, and various G-protein receptors, just to name a few [74,81,83]. Bile acid can play a role in the treatment and management of hypercholesterolemia. Cholestyramine, a common drug used in hypercholesterolemia and cholestatic pruritus, binds to bile acids as a bile sequestrant in the intestine due to its positively charged nature and forms an insoluble complex, which is subsequently excreted. As such, the amount of bile acid in enterohepatic circulation is reduced, and this signals a feedback mechanism to the liver to convert cholesterol to bile acids. When the levels of cholesterol drop in the liver, LDL-receptor expression is increased to uptake more LDL molecules, thus reducing cholesterol levels in the blood [84–86]. Unsurprisingly, bile acids such as cholic acid are also used as replacement therapies for disorders that occur due to the disruption of bile acid synthesis, such as Zellweger spectrum disorder [87–89]. In the management and prevention of cholelithiasis, ursodeoxycholic acid, a secondary bile acid, is the only non-surgical drug treatment approved by FDA [90,91].

4. Nanotechnology

4.1. Background and history

Nanotechnology refers to the branch of science and technology that uses nanoscale units to produce complex macromolecular systems. It encompasses a variety of fields such as biology, physics, and engineering, providing them with an opportunity for collaboration [92,93]. The term nanotechnology only came under the spotlight of people in the 1980s, with the emergence of equipment such as the scanning tunneling microscope in 1981 [94]. The idea of using materials that are of such minute scale can be attributed to pioneers such as Richard Feynman, who envisioned a future where atoms and molecules could be arranged with precision in 1959 [93,95]. Professor Norio Taniguchi of Tokyo University first mentioned the term “nanotechnology” in 1974 to illustrate semiconductor operations that were taking place at the nano level [96]. Nanoparticles generally have sizes between 1 and 100 nm. The properties of nanoparticles tend to differ from molecules of different scales [94,97]. The potential of nanotechnology has since garnered a lot of attention, especially in the field of pharmaceutical and medical science, providing new genetic testing tools and drug delivery systems [93,97,98]. The interaction between nanoparticles and bioactive molecules will serve as a novel approach to deliver the biomolecules to their target, paving the way for the development of new drugs and individualized disease treatment and management [93].

4.2. Bile acid-based nanotechnology

Bile acids combined with nanotechnology remain a novel method in the delivery of active biomolecules. This method could be particularly useful for class III and IV drugs. One possible key mechanism by which bile acid-based carrier systems enhance oral absorption and uptake is transporter-mediated adsorption. In the intestine, transporters known as the apical sodium-dependent bile transporters actively transport conjugated bile acids from the lumen of the intestine into the enterocytes. Basolateral efflux by organic solute transporter α/β subsequently occurs as part of the bile acid enterohepatic recycling [99]. Through the incorporation of bile acids into drug delivery platforms or drugs, these platforms can potentially exploit the high efficiency of the apical sodium-dependent bile transports and organic solute transporter α/β to improve bioavailability [100]. Figure 3 summarizes the mechanisms in which bile acids could possibly enhance membrane permeation in drug delivery.

Figure 3.

Mechanisms in which bile acids can enhance membrane permeation [77,101–103].

Studies by Wagle et al. have shown that the addition of bile acids to the microencapsulation of probucol, a class II drug with limited solubility, has enhanced absorption and permeation through the phospholipid bilayer, making them ideal excipients in various drug delivery systems. The addition of bile acids did not alter the size, shape, or thermostability properties of probucol but increased the mechanical strength of the microcapsules, preventing them from sudden rupture at pH 7.8 [104]. A study by Zhang et al. demonstrated that by incorporating cholic acids onto the surface of nanoparticles containing insulin, the pharmacological bioavailability of insulin in a diabetic mouse model was higher at 475% relative to that of free insulin [105].

Bile acid-drug conjugates have also been shown to improve drug bioavailability and tissue targeting. Agboluaje and team demonstrated that deferoxamine, a drug with limited oral bioavailability used to treat hemochromatosis, when conjugated together with taurocholic acid and hyaluronic acid to form self-assembled nanoparticles, had better permeation in Caco-2 cells, possibly enhancing the oral absorption of deferoxamine [106]. Conjugates of various bile acids, including ursodeoxycholic acid to cytarabine, a drug with poor oral absorption, were found to have enhanced bioavailability of up to 2-fold as compared to the parent compound alone [107]. Zeng et al. demonstrated that the use of cholic acid was not just limited to the targeting of the liver. The team demonstrated that nanoparticles of cholic acid functionalized, star-shaped block copolymer consisting of poly(lactide-co-glycolic acid) loaded with docetaxel and vitamin E had a better pharmacological profile than their linear counterpart. They were associated with higher toxicity against cervical cancer, and there is enhanced drug release and cellular uptake as well [108]. Another study developed a novel hybrid scaffold that had lithocholic acid-derived cationic amphiphiles conjugated to docetaxel demonstrated enhanced anti-cancer efficacy, therapeutic efficacy, and improved solubility and stability of docetaxel [109].

These studies demonstrated that bile acids can be strategically incorporated into drug conjugates and delivery systems to exploit their unique physicochemical properties, including forming micelles and enterohepatic recycling of bile acids. Such properties may possibly enhance the oral absorption and bioavailability of poorly soluble and poorly permeable drugs, particularly those of BCS Class IV, such as docetaxel, highlighting the potential of bile acid-based strategies in next-generation delivery platforms.

4.3. Lipid nanotechnology

Lipid nanoparticles remain as one of the most researched and utilized nanotechnologies in the field of pharmaceutics. Depending on their composition, lipid nanoparticles can exist in various forms and types, with some common ones including solid lipid nanoparticles, nanostructured lipid carriers, lipid drug conjugates, and liposomes [110–112]. Solid nanoparticles, one of the first and most researched lipid nanoparticles, continue to gather interest from scientists. Their advantage of being easy to modify and their flexibility make them excellent novel candidates as drug carriers [110,113,114]. By modifying the surface of solid lipid nanoparticles with N-trimethyl chitosan, a quaternized chitosan derivative, the stability of the nanoparticle containing curcumin at room and refrigerated temperatures was enhanced. Controlled drug release profile was also observed, and there was improved oral bioavailability and distribution to the brain in mice [115]. However, producing solid nanoparticles that are monodisperse is difficult, and this has unfortunately reduce its stability and its therapeutic profile. Nanostructured lipid carriers are modifications of solid nanoparticles, with the addition of a separate, distinct liquid lipid component. Drugs are usually added into the lipid at high temperature where there is only a liquid lipid phase. Because many drugs are more soluble in liquid lipid, the existence of a liquid lipid reduces drug expulsion when the formulation is cooled and the solid lipid solidifies [110]. On the other hand, lipid drug conjugates allow for the incorporation of hydrophilic drugs. This is achieved through the conjugation of a lipid molecule onto a hydrophilic drug through salt formation or covalent linkage, such as esterification, forming an insoluble compound that has enhanced bioavailability in the gastrointestinal tract. Liposomes are one of the most studied lipid nanoparticles due to their biocompatibility with the human body. They are made of phospholipids, which are commonly found in our human body as well, and form micelles due to their amphipathic nature of having hydrophobic tails and hydrophilic heads. These allow for the loading of both hydrophobic and hydrophilic molecules into its structure [111]. In addition, conjugation of polymers to the surface of liposomes can be made to improve specific pharmaceutical profiles [116–118]. The half-life of liposomes and their accumulation at the target site can be enhanced through the conjugation of polyethylene glycol (PEG). The addition of PEG reduces the interaction of liposomes with surrounding proteins in the plasma, thus reducing the likelihood of phagocytosis and subsequent clearing [119].

Lipid nanoparticles have been widely researched in the field of biomedicine, particularly in the treatment and management of cancer [120–122]. A study by Eskiler et al. demonstrated that talazoparib, a highly potent Poly(ADP-ribose) polymerase inhibitor used in triple-negative breast cancer, when loaded into solid lipid nanoparticles, has resulted in an improved therapeutic index, with increased toxicity against HCC1937 breast cancer cells as compared to talazoparib itself [123]. In another study by Valdes et al., it was found that 4-(N)-docosahexaenoyl 2',2'-difluorodeoxycytidine (DHA-dFdC), a novel lipophilic compound with potent and broad-spectrum antitumour activity when incorporated into solid lipid nanoparticles, has enhanced bioavailability when given orally in a mouse model [124]. Thymoquinone, an active compound of black seed that can possibly reduce cancer cells’ proliferation and induce cell apoptosis, has its clinical use severely limited due to its poor bioavailability [125,126]. To overcome this challenge, thymoquinone has been loaded into nanostructured lipid carriers, and it was found that bioavailability had increased as compared to thymoquinone suspension after oral administration in rats [126].

Bilosomes, a novel drug delivery system derived from liposomes with the addition of bile salts, have been demonstrated to have better drug-delivering properties such as permeation and absorption than liposomes alone [127,128]. The addition of bile salts protects the bilosomes from the acidic and alkaline conditions of the gastrointestinal tract, improving the delivery system’s stability and withstanding premature degradation [103]. Progesterone, a BCS class II drug with high lipophilicity, was found to have a higher drug bioavailability of up to 4.287-fold than marketed progesterone capsules and 9.75-fold than the active ingredient itself when incorporated into bilosomes and tested in a rat model [129]. Bilosomes have also been extensively researched in the treatment of cancer, demonstrating enhanced intestinal absorption and a reduced half-maximal inhibitory concentration (IC₅₀), indicating enhanced cytotoxicity profile [130–132]. Table 2 summarizes the key characteristics of the different lipid carriers, including size range, the type of cargo they carry, their release mechanisms, and their scale-up feasibility, providing context for their potential in new drug delivery systems.

Table 2.

Comparative overview of nanocarrier systems: size, drug cargo, release profiles, stability, scale-up, and clinical applications [133–138].

Nanocarrier systems
Parameter	Solid nanoparticles (SLN)	Nanostructured lipid carriers (NLC)	Liposomes	Lipid nanoparticles (LNPs)	Bilosomes
Size Range	50–1000 nm	50–500 nm	50–450 nm	Typically, 50–100 nm depending on formulation and method of manufacturing	5–200 nm
Drug Cargo Type	lipophilic drugs, peptides, genetic material (DNA, RNA, siRNA)	Lipophilic & hydrophilic drugs, genetic materials, plant extracts	Lipophilic, hydrophilic & amphiphilic drugs, nucleic acids, peptides	Nucleic acids (mRNA, siRNA, pDNA, ASOs, saRNA)	Lipophilic & hydrophilic drugs, peptides, antigens, vaccines
Release Mechanisms	biphasic release profile - burst release, followed by sustained release	Rapid initial release, gradual matrix degradation	Triggered release (pH, temperature, light, enzyme, redox, ultrasound), diffusion across phospholipid bilayer	pH triggered endosomal escape	Release occurs following vesicle interaction with intestinal membrane, allowing gradual drug release, transcellular or paracellular pathways
Stability	risk of particle growth, polymorphic transition and gelation)	Superior to SLN; risk of particle growth, drug expulsion over time, gelation	Dependent on lipid composition, sensitive to pH and temperature changes; lyophilization required, risk of leakage	Requires specialised storage conditions (lyophilization or ultra-low temperatures); risk of premature degradation/cargo release	Enhanced stability in gut due to presence of bile salts
Scale-up	High-Pressure Homogenization is the industry-preferred method	High-Pressure Homogenization (HPH) and High-Shear Homogenization (HSH) preferred methods	key strategies employ high- throughput techniques like microfluidics and inline homogenization	Scaled using parallel microfluidics, impingement jet mixing. Size uniformity and batch reproducibility can be challenging.	Hot homogenization is the preferred scalable method, but scaling up still under researched
Real World Approvals	Lymphoseek as an imaging agent (FDA approved); mainly cosmetic and academic use	Primarily utilized in cosmetic industry; emerging as pharmaceutical carrier system	~20 liposome-based formulations approved by FDA/EMA; oncology dominance, vaccine adjuvants	mRNA vaccines: Covid-19 vaccines); siRNA (Patisiran)	No FDA/EMa-approved products; ongoing pre-clinical, experimental and clinical stages
References	[133,134]	[133,135]	[134,136–138]	[139]	[127,140]

5. Carbon nanotubes

Carbon nanotubes (CNT) are long, cylindrical carbon tubes in molecular size with a small diameter in the nanoscale [141]. Japanese scientist Sumio Lijima was the first to identify it as one of the many allotropes of carbon back in 1991 during the process of fullerene synthesis. CNTs can exist as either single-walled or multi-walled, each having different properties and used in different areas [142]. In recent advancements in biomedical technology, the use of carbon nanotubes in medical devices such as biosensors has become more prominent [141,143]. Not only that, carbon nanotubes have been explored as supporting structures for the regeneration and proliferation of osteoblast, neuronal, and ligament tissues in the field of regenerative medicine [141,144]. CNTs also show promising potential in the field of drug delivery, possibly acting as novel drug carrier systems that can efficiently transport and deliver drugs with low bioavailability [141,145]. However, due to their poor solubility in both organic and aqueous media, the use of nanotubes in photonic or electrical devices can be a problem. Poor solubility of CNTs can be overcome with the conjugation of chemical groups onto CNTs, such as the addition of surfactants or the formation of salt [142].

5.1. Applications of carbon nanotubes

The unique structure and physico-chemical properties of CNTs make them ideal complementary materials in scaffoldings that support tissue engineering in the field of regenerative medicine. In one example, the addition of single-walled CNTs into propylene fumarate has enhanced its mechanical profile as a linear biodegradable polyester for the regrowth of tissue [141]. The larger surface reactive area of CNTs serves as a potential for binding and modifications that allow for more specific biomolecule detection at the nanolevel [142,146,147]. In the field of drug delivery, unlike conventional therapy such as surgery and chemotherapy, carbon nanotubes offer the advantage of being able to deliver drugs to highly specific cancer cells without causing damage to the surrounding healthy tissues [142,148]. Depending on the area of application, drugs and other therapeutic molecules can be incorporated either on the surface or in the cavity of CNTS, making them highly adaptable and flexible [141,149]. Furthermore, it has been demonstrated that CNTs are capable of crossing over the cell membranes of mammals, showcasing their ability to transport various biomolecules or drugs to targeted cells, expanding the possibilities of personalized care and therapy [141,150,151].

Unlike lipid-based carriers that have well-established clinical safety research, clinical translation for CNTs can be challenging due to the existing problem of poor solubility in various media, concerns of long-term safety profile as well as potential immunogenicity. Advantages of CNTs over liposomes are observed when the stability of drug carrier system is a concern or when membrane-penetrating properties of CNTs enable more efficient delivery (i.e., cancer cells) and are preferred over lipid-based systems.

6. Quantum dots

Quantum dots (QD) are semiconductor crystals that are nanosized and possess a metalloid crystalline core with physical dimensions smaller than the exciton Bohr radius, and depending on their composition and size, will determine the type of fluorescence they emit [152–154]. Quantum dots of different cores can exist, with the more common ones made up of cadmium-selenium, cadmium-tellurium, or indium-phosphate, just to name a few. The core is usually coated with a semiconductor shell of zinc sulfide material to stabilize the core and enhance its profile in various aspects, including optical and bioavailability [152]. Other than zinc oxide, other polymers can be added as well to further enhance certain properties such as solubility. A common example would be the addition of polyethylene glycol to the surface of quantum dots [152,155].

6.1. Applications of quantum dots

Due to their unique fluorescence, optical, and electrical properties that can be further modified, quantum dots have been widely utilized in the development of biological applications such as real-time imaging and diagnostics [152,156]. As compared to traditional dyes, quantum dots offer numerous advantages that include easier detection as they are much brighter, and a wider excitation spectra confers them high versatility, just to name a few. These properties that is dependent on the size of the quantum dot makes quantum dots very attractive assets in biomedical applications, as it allows for specificity and prevent the overlapping of detection, which is critical in efficient imaging and detection [156]. Other than the pharmaceutical industry, QDs have been extensively used in the lighting and display industry, with QDs found in QD films for liquid crystal display (LCDs) panels and other various lighting applications [157–159].

6.2. Quantum dots as drug carriers

The large surface area of quantum dots confers it the ability for many compounds, such as drugs and imaging agents to attach to, making it highly modifiable [152]. Combined with its optical profile, quantum dots hold significant potential to improve current modalities and approaches toward drug delivery, imaging as well as disease detection and treatment of cancer [152,160,161]. Chen and team have designed a cadmium/tellurium quantum dot conjugated with multiple components, including a polyethylene glycol shell to increase circulation time in vivo, folic acid to target cancer cells, glutathione as a stabilizer and loaded with doxorubicin. They found that their design has successfully delivered doxorubicin to targeted cancer cells and showed higher cytotoxicity [162].

Clinical translation, however, remains limited for many QDs, especially for QDs with a cadmium core due to cytotoxicity concerns. Being reactive in its ionic stage, cadmium-selenium or cadmium-tellurium QDs may be cytotoxic at certain concentrations when exacerbated by the presence of oxygen, UV exposure, and the large surface area of quantum dots, limiting them to in vitro and ex vivo diagnostics and imaging applications, where systemic toxicity is not of concern [152,163]. When being compared to lipid-based carriers such as liposomes, cadmium-based QDs offer optical properties and surface modifications that can be highly modified, which are advantageous for targeted labeling or real-time tracking of therapeutic targets. However, for pure drug delivery purposes where fluorescence or optical properties are not necessary, lipid-based carriers offer a safer option.

The penetration of quantum dots into the cell and nucleus can be a double-edged sword. While it allows for the delivery of therapeutic materials, it also brings toxicity to the cell, including the alteration of membrane fluidity as well as the binding of cadmium ions to the DNA, preventing the repair mechanism from working [164]. To overcome these toxicity problems, carbon quantum dots, a variation of quantum dots without a metallic core, have been explored. Graphene, a variation of carbon quantum dots when modified with folic acid ligands and loaded with the anti-cancer drug doxorubicin, allows for the real-time monitoring of drug delivery and cell labeling to take place [165,166]. Similarly, a study by Zeng et al. has successfully demonstrated that carbon dots, when conjugated with doxorubicin via non-covalent bonding, have localized drug delivery for liver cancer in their in vivo experiment [167]. Yang and his team functionized carbon dots with a nuclear localization signal pepide, and when coupled with doxorubicin, exhibited a higher tumor inhibition level than free doxorubicin, showing enhanced antitumor activity [168].

Therefore, current realistic clinical applications of QDs can be summarized as using cadmium-containing QDs for highly effective real-time imaging and tracking while carbon or graphene QDs are reserved when long-term safety is prioritized due to their low toxicity.

7. Summary

In conclusion, this review has discussed the classification of drugs, routes of administration, and the emerging role of bile acids and nanotechnology in drug delivery. Together, these strategies present opportunities to improve drug solubility, permeability, and overall bioavailability, particularly for compounds with poor physicochemical properties.

Bile acids represent an important class of endogenous molecules that can be incorporated into drug delivery platforms due to their unique amphiphilic structure and interactions with various biological membranes and transport systems. These properties make them attractive functional components for advanced drug delivery systems, where they may enhance drug stability and facilitate absorption and therapeutic performance.

However, several challenges must be addressed before bile acid containing carriers can be translated to clinical applications. Their potential cytotoxicity at high concentrations, formulation stability, and safety when incorporated into other drug carrier platforms would all have to be evaluated. Continued research addressing these limitations will be essential to further support the development of bile acid-based drug delivery systems.

8. Future perspective

In the next 5 to 10 years, advances in drug delivery and nanotechnology are expected to further expand the therapeutic potential of bile acid-based drug delivery system. A deeper understanding on the transporter system of bile acids may enable the design of more targeted delivery systems with bile acids incorporated in them, including bilosomes and lipid nanoparticles and even hybrid nanosystems such as carbon nanotubes and quantum dots.

Another promising direction is the potential synergistic integration of bile acid-based delivery with modulation of bile acid signaling pathways that allows for the drug delivery system to not only deliver the drug but also influence relevant metabolic pathway beneficial for the patient. However, in order to achieve successful clinical translation, research would first be required to focused on optimizing formulation design and system stability before following on to safety, manufacturing and reproducibility. Addressing these challenges will be essential to move bile acid-based delivery systems to clinical success.

Funding Statement

This paper was not funded.

Article highlights

• While current drug delivery methods and technological advancements have proven to be effective, many drugs still suffer from low bioavailability, limiting their therapeutic potential.

• Applications of nanotechnology such as quantum dots and nanotubes are increasingly being researched as novel drug delivery systems with their unique chemical and biological profile.

• Endogenous molecules like bile acids are extensively researched as solubility or permeation enhancers given their high versatility.

• The addition of bile acids to various drug delivery systems has demonstrated improved drug delivery and pharmacological profile, showing promise in optimizing the bioavailability and safety profile of drugs.

CRediT authorship contributions statement

Abril Mena Balborin: Writing – review & editing, Visualization, Validation, Software. Armin Mooranian: Writing – review & editing, Writing – original draft, Visualization, Validation, Supervision, Software, Resources, Project administration, Methodology, Investigation, Data curation, Conceptualization. Bozica Kovacevic: Writing – review & editing, Visualization, Validation, Software, Data curation, Conceptualization. Hani Al-Salami: Writing – review & editing, Writing – original draft, Visualization, Validation, Supervision, Software, Resources, Project administration, Methodology, Investigation, Data curation, Conceptualization. Le Yang Sen: Writing – review & editing, Writing – original draft, Visualization, Validation, Software, Methodology, Investigation, Formal analysis, Data curation, Conceptualization. Mengistie Diress: Writing – review & editing, Visualization, Validation, Formal analysis. Mikhaela Lorenzo: Writing – review & editing, Visualization, Validation, Formal analysis, Methodology. Susbin Raj Wagle: Writing – review & editing, Visualization, Validation.

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