Silica‐based organic‐inorganic hybrid nanoparticles and nanoconjugates for improved anticancer drug delivery

Abstract

After the introduction of first generation MSNs for drug delivery with some challenges such as large particle sizes, irregular morphologies and aggregations, second generation provided uniform spherical morphologies, tunable pore/particle sizes and compositions. Henceforth, organic‐inorganic hybrid mesoporous silica nanosystems have grown rapidly and utilized for active and passive targeting of tumorigenic cells especially conjugated with organic polymers followed by third generation counterparts with improved functionalities for cancer therapy. The aim of this review article is to focus on the advancements in mesoporous silica based organic‐inorganic hybrid nanoparticles developed as drug carriers targeting cancer cells. Brief introduction to the state‐of‐the‐art in passive and active targeting methods is presented. Specifically, therapeutic, diagnostic and theranostic applications are discussed with emphases on triggered and ligand conjugated organic‐inorganic hybrid mesoporous silica nanomaterials. Although mesoporous silica nanoparticles perform well in preclinical tests, clinical translation progresses slowly as appropriate doses needs to be evaluated for human use along with biocompatibility and efficiency depending on surface modifications.

Abbreviations

DOX

Doxorubicin

GNPs

Gold nanoparticles

GNRs

Gold nanorods

GSH

Glutathione

ICG

Indocyanine green

MDR

multidrug resistance

mSiO₂

Mesoporous silica structures

MSNs

Mesoporous silica nanoparticles

NIR

Near‐Infrared

PEG

poly(ethylene glycol)

PEI

polyethyleneimine

P‐gp

P‐glycoprotein

p(NIPAm)

poly(N‐isopropylacrylamide)

PVP

Polyvinylpyrrolidone

1. Introduction

The inorganic nanoparticles such as quantum dots (QDs), gold nanoparticles (GNPs), magnetite (Fe₃O₄) nanomaterials have many advantageous features such as luminescent properties with a controllable wavelength, unique surface plasmon resonance properties or high magnetization in the presence of an external magnetic field. Another class of inorganic nanoparticles are silica‐based nanomaterials that can be investigated in two major groups: solid lipid nanoparticles (SNPs) and mesoporous silica nanoparticles (MSNs) 1. Mesoporous silica nanoparticles are widely explored silica based nanomaterials due to large surface areas and specific pore volumes owing to ordered pore structures, which enable drug loading. Furthermore, drug release rates can be regulated by editing the size of mesopores 2, 3. MSNs, such as 2D hexagonal MCM‐41 (Mobile Crystalline Material) and 3D cubic SBA‐15 (Santa Barbara Amorphous) are silica‐based porous materials with hundreds of empty channels, so called mesopores with a narrow size distribution in the range of 2–50 nm. Mesopores are appropriate supports for drug delivery and biomedical applications due to their high chemical and thermal stability 4. Their drug adsorption and release rates mainly depend on the textural and structural properties of the host‐matrix 5 and can be regulated to maximize cellular uptake 6. The approximate drug loading dose of conventional MSNs is about 200–300 mg which accounts for 600 mg drug/g silica 7.

First drug loaded into mesopores was isoprofen packed in MCM‐41 exhibiting a sustained drug release performance with improved loading ratio 8. Thereafter, biomedical studies on MSNs have grown rapidly and their development as a drug carrier has engendered in three generations 9, 10. The first generation was introduced for the sustained release with many challenges such as large particle sizes, irregular morphologies, several aggregations, cell level evaluations and in vivo applications. In conjunction with the fast development of synthetic chemistry, the second generation MSNs were constituted nano‐sized and uniform spherical morphology, tunable pore/particle sizes and compositions. Generation II MSNs have been constructed with various structures and morphologies such as hollow nanostructures, janus MSNs, yolk shell nanorattles (a special kind of core‐shell nanostructure) and organic–inorganic hybrid mesoporous silica. In addition, MSNs integrated with comprehensive functionalities have been presented as generation III, which were designed and fabricated in a more complex manner in regards to surface chemistry and synthesis approaches. The surface modifications are based on the silanol groups (Si‐OH) on the outer or inner mesoporous surfaces with various types of functional groups. The functional groups can be biological recognition ligands, peptides, aptamers, antibodies, nanovalves to control release profiles (e.g., stimuli responsive release, on‐demand release), genes for synergistically overcoming multidrug resistance (MDR) of cancer cells, biocompatible functional polymers/materials for improving blood circulation time and fluorescent agents for bioimaging. Consequently, the latest generation MSNs explore a wide variety of synthetic strategies for functionalization of inorganic nanoparticles with organic molecules and macromolecules.

Although, inorganic nanoparticles are highly stable and multifunctional, their biodegradability and biocompatibility have been disputed. Furthermore, burst release of active ingredients from the matrix is one of the major disadvantages of MSN limiting their use in clinical applications where controlled release is required. On the other hand, organic carriers are known for their high biocompatibility and biodegradability, but low stability and single functionality. The advancements in material science and drug delivery systems catalysed the fabrication of organic‐inorganic hybrid nanoparticles which combine desirable properties of organic and inorganic materials to overcome the weaknesses of MSNs 11, 12, 13, 14. Hybridization of organic and inorganic components can lead to multi‐functionality and enhanced material properties 15. The hybrid nanoparticles have significant properties of both inorganic and organic moieties and in addition they can be modified through the combination of functional elements. Also surface modification with the targeting moieties provides specific targeted imaging and therapeutic properties 1. Hybridized mesoporous nanoparticles can be synthesized via hydrolysis and condensation of organic and inorganic precursors under acidic or basic conditions resulting in monodisperse nanoparticles and tailored for internalization of various drugs 16, 17. These particles may have various morphologies such as stellate 18, ellipsoidal, spherical 19, octopus 20 and walnut kernel‐like 21. It would have been interesting to investigate the effects of these morphologies on drug loading efficiency, release kinetics, cellular uptake, subcellular localization, and cytotoxicity. Hybrid mesoporous materials are reported to act as host matrices for a wide range of drugs via weak interactions 8. The internal surfaces of mesopores can be functionalized to improve drug and carrier interaction. For instance, trimethylsilyl groups were incorporated inside the pore surfaces to enhance loading of hydrophobic drug molecules on to MSNs 18, 22.

This review article focuses on the advancements in mesoporous silica based organic‐inorganic hybrid nanoparticles developed as drug carriers targeting cancer cells. Brief introduction to the state‐of‐the‐art in both passive and active targeting methods are presented. Particularly, therapeutic, diagnostic and theranostic applications are discussed critically with emphases on triggered and ligand conjugated organic‐inorganic hybrid mesoporous silica nanomaterials.

2. Drug targeting to cancer cells

2.1. Passive targeting

Passive targeting is a kind of drug delivery strategy facilitated by nanoparticle fabrication techniques. The change in size, shape, charge and stiffness of the materials to enhance tissue accumulation, adhesion, cellular uptake of nanoparticles and drugs are part of the strategy 23. The polymeric drug carrier particles have more advantages than administration of free drugs like increased circulation time in the body because free drugs can be detected by the reticuloendothelial system (RES) and eliminated. Some anticancer drugs like camptothecin and doxorubicin (DOX) are effective in chemotherapy but the applications in humans were limited due to the poor water solubility of the drug. Therefore, a suitable solution for hydrophobic drug molecules is of prime importance 24. For instance, silicone oxide‐deposited DOX‐loaded stearic acid‐grafted‐chitosan nanoparticles were compared with stearic acid‐g‐chitosan polymeric micelles. The results showed that the nanoparticles have a more rapid drug release rate in vitro than the micelles and they could easily penetrate into the cells due to higher specific surface area obtained by their mesoporous structure 25 which, not only serve as unique drug reservoirs but also have a part in multiphasic release systems. In another study, drug delivery system using DOX loaded mesoporous silica nanoparticle composite nanofibers was fabricated which can release anti‐tumor drugs in two phases (burst release in the early stage and sustained release at a later stage) to reduce local recurrence of breast‐conserving therapy 26. The drug entrapped within MSNs must first be released at a solution state, then from polymeric fibers to the surrounding medium.

Polymeric particles may also be prone to delay or prevent recognition properties due to RES 24. Many types of generation II MSNs were synthesized with various structures and surface morphologies that could be used for targeted drug carrier systems passively through surface modifications with functional polymers. For example, poly(ethylene glycol) (PEG) can significantly enhance the circulation time due to its excellent protein repellent properties 27. The polyethyleneimine‐polyethylene glycol (PEI‐PEG) decoration on the surface of the nanoparticles was reported to decrease RES uptake and resulted in the retention of about 8% of the administered particle dose at tumor site 28. Polyvinylpyrrolidone (PVP) is another type of polymer for functionalization of nanocarriers. In one of the studies, PVP was used as a protecting polymer adsorbed on the surface of silica microspheres and NaOH was employed as an etching agent. Mesopores were created in the silica microspheres owing to the protective nature of PVP and inhomogeneous etching 29. The surface modifications of recent organic‐inorganic silica hybrids with polymers are mostly based on PEG 27, PEI 28 , PVP 29, chitosan 25 and poly‐L‐lactic acid (PLLA) 26 for drug targeting to cancer cell (Table 1).

Table 1.

Passively targeted drug delivery or fluorescent imaging with organic‐inorganic hybrid silica nanosystems

Treated cells/ animals	Drug molecules or imaging agent	Structure/hybrid type	Ref.
Hep‐G2 mice	Docetaxel	PEGylated mesoporous silica nanorattle	27
MCF‐7/MDR mice	DOX and siRNA	Mesoporous silica nanoparticles were functionalized by PEI‐PEG copolymer	28
A549	DOX	Stearic acid‐grafted chitosan (CS‐SA) core and SiO2 shell	25
HeLa	DOX and fluorescein	Fluorescent and cross‐linked organic−inorganic hybrid mesoporous poly‐(cyclotriphosphazene‐co‐fluorescein ) ‘PCTPF’ nanoshells	36
HeLa	Ibuprofen	Fluorescent poly(p‐phenylenevinylene) (PPV)	34
MDA‐MB‐231 mice	DOX	PLLA‐(MSN/DOX)‐DOX composite electrospun nanofibers	26
A549	Rhodamine B	Combined a fluorescent inorganic silica core with a biocompatible polymer shell	24
HeLa	DOX	Luminescent YVO4:Eu3+ nanocrystals integrated mesoporous silica nanoparticles	29

Meng and co‐worker 28 prepared MSNs functionalized with PEI‐PEG copolymer carrier to overcome DOX resistance in the MDR human breast cancer xenograft by co‐delivering DOX and siRNA that targets the P‐glycoproteins (P‐gp) drug exporter. MDR is one of the main obstacles in effective chemotherapeutic treatment of cancer, where pump and non‐pump drug resistances are reported as two major mechanisms. P‐gp and MRP‐1 (MDR‐associated protein‐1) are pump‐related gene products existing at the cellular and the nuclear membranes and pumps anticancer drugs to the extracellular matrix while drug‐induced expression of Bcl‐2 protein is responsible for the activation of anti‐apoptotic cellular defence as major mechanism in nonpump resistance 30, 31. Many studies have shown that co‐delivery of Bcl‐2 siRNA with chemotherapeutic drugs by functionalised MSNs downregulates the Bcl‐2 protein expression, which in turn could induce remarkable cell apoptosis 32, 33.

Co‐delivery of DOX and siRNA by the PEI‐PEG copolymer functionalised MSN nanocarriers resulted in synergistic inhibition of tumor growth in a MDR tumor xenograft model in vivo compared with free DOX and the carrier loaded with either drug or siRNA alone 28. Another approach for functionalization of mesoporous silica nanoparticles is the formation of core‐shell structure. An example for this approach is poly(p‐phenylenevinylene) (PPV) functionalized MSNs which were further coated with a layer of mesoporous silica shell to form the core‐shell structure. The PPV serve as a fluorescent polymer and the developed fluorescence MSNs with or without core‐shell structures were reported to improve the capabilities of drug loading, sustained drug release and cancer cell bioimaging 34.

2.2. Active targeting

During the last decade, surface‐functionalized, end‐capped MSNs have been designed for controlled anticancer drug delivery due to their low toxicity, high surface area and large accessible pore volumes which are suitable for loading drug molecules 35, 36. These systems have the capability of releasing the cargo only at the desired location by responding to certain external stimuli or specific ligand matching which was referred as active targeting 23, 37. Among stimuli response properties, pH changes represent an effective strategy especially for cancer therapy since the extracellular pH in tumour tissue is slightly lower than in normal tissue 35. Consequently, active targeting can not only be achieved by stimuli responsive mesoporous silica nanoparticles that can respond to changes in pH 38, 39, 40, 41, temperature 42, 43, magnetism 44, 45, chemicals 46, enzymes 47, redox 48 or light 38, 49, 50, 51, 52, but also associated with receptor recognition reactions. We discussed these active targeting strategies based on the organic‐inorganic hybrid mesoporous silica nanocarriers for the therapeutic and diagnostic approaches in the next sections.

2.2.1. Therapeutic or diagnostic approach

2.2.1.1. Stimuli responsive organic‐inorganic hybrid silica nanomaterials

Stimuli responsive organic‐inorganic hybrid silica nanocarriers doped with chemotherapeutic drugs or imaging agents for therapeutic or bioimaging purposes are provided in Table 2. The pH sensing functions are of prime importance in MSN‐based triggered‐release nanocarriers. In one of the studies, fluorescent organic/inorganic hybrid MSNs were prepared with controllable redox‐responsive release of rhodamine B as a model drug 53. Indeed, many of hybrid materials prepared for controlled drug release on tumor location were often based on pH or glutathione (GSH) level changes because of acidic pH (5.0) and high GSH concentration levels (2−10 mM) on tumour intracellular environment compared with normal tissues 54. In another study, DOX hydrochloride was released by responding to acidic tumour intracellular environment 55. A dynamic cross‐linked supramolecular network of poly(glycidyl methacrylate)s (PGMAs) derivative chains was constructed on mesoporous silica nanoparticles via disulfide bond and ion‐dipole interactions between cucurbiturils and protonated diamines in the polymer chains, where this network was employed as a pH and GSH dual stimuli‐responsive nanovalve. Disulfide bonds between PGMA chains and MSNs endowed the hybrid material GSH responsiveness.

Table 2.

Stimuli responsive or ligand conjugated organic‐inorganic hybrid silicas for therapeutic or diagnostic purposes

Target cell/animal	Therapy or imaging agent		Nanoparticle/bioconjugate type and triggering factors	Ref.
Stimuli responsive organic‐inorganic hybrid silicas
A549	DOX	–	Organic‐inorganic hybrid mesoporous nanoparticles with pH‐ and GSH‐ responsiveness	55
–		Rhodamine B	Fluorescent pH‐sensing organic/inorganic hybrid mesoporous silica nanoparticles	53
–		Rhodamine 6G	Mesoporous SiO2 films, functionalized with high quantities of azochromophores as photodriven nanoimpellers	52
KB‐V1	DOX and siRNA	–	PEI coated mesoporous silica nanoparticles	30
Ligand conjugated organic‐inorganic hybrid silica nanomaterials
U87 MG HEK 293	DOX		GNPs@RGD peptide‐capped MSNs	59
HCT116 mice	5‐Fluorouracil	‐	MSN‐P(OEGMAa‐co‐ RGD peptide	89
HeLa HEK 293	DiIb and DiOc as model drugs	‐	Folic acid‐conjugated and PEI‐functionalized MSNs	90
HeLa MCF‐7	Camptothecin		Tumor homing and penetrating peptide (tLyP‐1) functionalized MSNs	91

^apoly(oligo(ethylene glycol)monomethyl ether methacrylate).

^b1,1’‐dioctadecyl‐3,3,3’,3’‐tetramethindocarbocyanine perchlorate.

^c3,3‐dioctadecyloxacarbocyanine perchlorate.

Another approach to deliver drugs to specific locations is to control the drug release by light due to its non‐invasive nature. Mesoporous silica nanoparticles have large hollow interiors that serve as large reservoirs for enhanced drug‐loading capacity and demonstrate special structure–property relationships for nanomedicine 56. The first organic–inorganic hybrid hollow mesoporous organosilica‐based nanovehicles (HMOVs) were synthesised as nanocarriers. HMOVs with phenylene‐bridged silsesquioxane frameworks have been employed as excellent nano co‐delivery platforms for efficient intracellular transport of gene‐silencing agent namely the P‐gp and anticancer drugs. The co‐delivery of P‐gp associated short hairpin RNA and DOX enhanced chemotherapeutic efficiency due to higher intracellular DOX concentration 57. Not only the hollow structure of HMOVs was found to be responsible for the high cargo‐loading capacity, but also its phenylene‐bridged framework acted as pH‐responsive drug release.

2.2.1.2. Ligand conjugated organic‐inorganic hybrid silica nanomaterials

Despite the notable success of external and internal stimuli responsive organic‐inorganic hybrid silica nanoparticles, more specific applications were required in cancer therapy such as ligand conjugating strategy as active targeting in order to improve the specificity of nanoparticles towards tumor cells. For instance, traditional MSN drug release systems were not able to distinguish inflammatory tissues, resulting in damage of both inflammatory and healthy tissues 58. Thus, researchers searched for alternatives to improve the delivery efficiency and cancer specific recognition and focused on active targeting ligands, peptides and antibodies that recognize particular receptors in target cells with subsequent uptake through receptor‐mediated endocytosis. An example is functionalized MSNs showing sensitivity to pH by α‐amide‐β‐carboxyl unsaturated bond and further end‐capped with functional RGD peptide‐coated gold nanoparticles (GNPs). Hereby, bioactive surface of the GNPs‐peptide‐capped MSNs facilitated the binding to α _v β ₃ integrin overexpressed U87 MG cancer cells. On the contrary, limited internalization was observed in α _v β ₃ integrin negative HEK 293 cells 59. As majority of the publications related to ligand conjugated organic‐inorganic hybrid silica nanomaterials are designed for both therapeutic and imaging purposes, these will be discussed in the following section.

2.2.2. Theranostic approach

Theranostics describes the co‐delivery of therapeutic and imaging agents in a single formulation 60 where drug delivery can all be integrated into one functionalized nanoparticle 61. There have been many platforms that combine imaging and therapy for optimization of efficacy and safety of therapeutics such as nanocarriers related to light, magnetism, and sound 62.

Ligand‐conjugated organic‐inorganic hybrid silica nanoparticles with triggered mechanisms and stimuli responsive counterparts for theranostic purposes are summarised in Tables 3 and 4, respectively. Various ligands that can specifically bind to receptors overexpressed in cancer cells were utilized for the design of targeted drug delivery systems 63. The differential expressions of receptor proteins, residing in cytosol, organelles or membrane are used as molecular markers. An example is the human epidermal growth factor receptor HER2 which is overexpressed in ∼30 % of breast cancers and used as a marker to target breast cancer cells 64. Overexpressed or specifically expressed receptors in various cancer tissues and cells are reported in literature 65, 66, 67, 68, 69, 70. As receptor‐ligand interactions are highly specific, this mechanism is applied for active targeting of nanocarriers or nanoconjugates 71.

Table 3.

Organic‐inorganic hybrid silicas with target‐ligand interactions for theranostic purposes

Target cell/ animal	Chemo‐therapy agents	Imaging agents	Triggering event	Other therapy responsible agents	Targeting ligand	Target receptor	Nanoparticle/Bioconjugate type	Ref.
Human squamous carcinoma cell spheroids (MCS)	DOX	–	NIR and enzyme dual responsive	Gold nanobipyramids (AuNBs) as a photothermal converter	Azobenzene and α‐cyclodextrin functionalized hyaluronic acid (HA)	CD44 is a major receptor for HA overexpressed in many solid tumor cells	HA(shell)‐MSNs‐AuNBs(core) triple‐layer core‐shell nanocomposites switchable system	85
AsPC‐1 mice	–	Iron oxide as MR contrast agent	NIR light	ICG fluorescent dye as a PTT agent, The gold nanoshells enhance the fluorescence of ICG	antibody (AntiNGAL)	Neutrophil gelatinase‐associated lipocalin (NGAL)	Encapsulated with iron oxide and ICG and then AntiNGAL‐conjugated theranostic triple‐layer‐gold nanoshells (TGNS)	81
U251/Normal human astrocytes, 1800	DOX	–	pH sensitive and NIR stimulative	Graphene nanosheet as a PTT agent	IP peptide	Receptor chain 2 of interleukin 13 (IL‐13Rα2)	A targeting peptide (IP)‐modified mesoporous silica‐coated graphene nanosheet (GSPI)	76
A549 mice	DOX	–	NIR light	GNRs as a PTT agents	RGD peptide	αvβ3 integrin receptor	Conjugated RGD peptides on the terminal groups of PEG on mesoporous silica‐encapsulated GNRs	86
PC‐3 HDFs	–	–	NIR light	Gold shell as a PTT agent	EphrinA1 ligand	EphA2 receptor	Gold‐coated silica nanoshells conjugated to ephrinA1 ligand via PEG linker	82
SK‐BR‐3 HDF	–	–	NIR light	Gold shell as a PTT agent	Human epidermal growth factor (HER)	HER2 receptor	Gold‐coated silica nanoshells conjugated to HER via PEG linker	64
HeLa MCF‐7	Campto‐thecin	Fluorescein isothiocyanate (FITC)	NIR light	Au nanorod core as a PTT agent	tLyP1 tumor‐homing peptide	neuropilin‐1 (NRP1) receptor	tLyP1−Conjugated Mesoporous silica‐coated Au nanorod, (AuNR@SiO2) nanoshell	84
SK‐BR‐3 MCF‐10A	DOX	–	pH and NIR responsive	Mesoporous carbon cores serve as a drug carrier and PTT agent	SP13 ligand	HER2 receptor	SP13 peptide‐conjugated graphitic carbon (core) @ mesoporous silica nanospheres/(MMPSD)	77
SK‐BR‐3 MCF‐10A mice	DOX	FITC	pH and NIR responsive	semi‐graphitized carbon (sGC) on the inner wall can effectively convert NIR light into heat	DNA aptamer (HB5)	HER2 receptor	PEGylated mesoporous silica‐ carbon nanoparticles (MSCN) with HB5 aptamer	63
NCL positive MCF‐7 cancer cells	DOX	Cy5.5 fluorescence	NIR light	Graphene oxide (GO) gatekeeper converted NIR light into heat	Cy5.5 labelled AS1411 aptamer	Nucleolin receptor	Cy5.5‐AS1411 aptamer conjugate graphene oxide nanosheet coated mesoporous silica nanoparticles (MSN@GO)	73
MCF‐7 HEK‐293	DOX Curcumin	–	NIR light	Cu1.8S	Aptamer‐modified GC‐rich DNA helix as gatekeepers and targeting ligand	Nucleolin receptor	DNA‐hybrid‐gated nanocarrier based on mesoporous silica‐coated Cu1.8S nanoparticles	92

Table 4.

Stimuli responsive organic‐inorganic hybrid multifunctional silicas for theranostic purposes

Target cell/animal	Chemo‐therapy agents	Imaging agents	Triggering event	Other stimuli‐responsive agents	Nanoparticle/Bioconjugate type	Ref.
SKOV3	Indomethacin	Gd3+ ions as a T 1‐MR contrast agent	Temperature changes	p(NIPAm‐co‐AAm) was responsive to pH/temperature changes	Luminescent rattle‐type hollow mesoporous silica microspheres with a thermosensitive hydrogel via p(NIPAm‐co‐AAm conjugation	93
HeLa	DOX	Blue‐emitting AIE luminogen	pH responsive	‐	AIE luminogen‐functionalized hollow mesoporous silica nanospheres (FHMSNs) with pH‐ responsiveness	94
A549 mouse	DOX	Y2O3:Yb,Er core	pH/temperature and NIR light	Au25(SR)18 clusters were photodynamic (PDT) and photothermal therapy (PTT) agents.	Core/shell structured Y2O3:Yb,Er(core)@Y2O3:Yb(shell)@mSiO2‐Au25‐P(NIPAm‐MAA) (YSAP) up‐conversion nanoparticles	95
MCF‐7	DOX	Gadolinium(III)‐chelated complexes as MRI contrast agents	NIR laser irradiation	ICG as photothermal agent	Gadolinium(III)‐chelated silica nanospheres loaded with DOX and ICG and then coated PDC (poly(diallyldimethylammonium chloride) (PDC)	96
HeLa	DOX	Cu2‐x‐Se	pH and NIR light	Copper selenide (Cu2‐x‐Se) as a PTT agent	Cu2‐x‐Se nanoparticles core combined with DOX‐loaded MSN shell and then PEGylated	80
HeLa	DOX	CuS	pH and NIR light	CuS nanocrystal cores as PTT agents	CuS crystals @mSiO2‐PEG core–shell nanoparticles	79
HepG2 Chang liver cells	DOX	CuS	NIR laser irradiation	CuS as an efficient PTT agents	PEG‐modified DOX‐loaded/MSN@CuS nanohybrids	78
MCF‐7 mice	DOX	GNRs	pH and NIR light	GNRs as an PTT agents	DOX loaded mesoporous silica‐coated gold nanorods (GNRs@mSiO2‐DOX)	74
HeLa	DOX	GNRs	pH/temperature and NIR light	GNRs as an PTT agents and poly(N‐isopropylacrylamide)‐based N‐butyl imidazolium responsible for thermosensitivity	DOX loaded mesoporous silica shell‐coated GNRs	97

As for stimuli responsive systems, especially Near‐Infrared (NIR) triggered multifunctional organic‐inorganic hybrid silica nanoparticles are commonly used as cancer theranostics. NIR‐triggered organic‐inorganic hybrid silica drug carriers include mainly two components; NIR absorption agents and a drug‐containing silica (mostly mesoporous) moiety, which can enable a synergistic treatment for cancer cells via dual effects of photothermal ablation and chemotherapy 72. Photothermal therapy (PTT) employs near‐infrared (NIR) laser photo‐absorbers to generate heat upon NIR laser irradiation. Indocyanine green (ICG) is one of the fluorescent dyes used for PTT, which absorbs NIR and converts light to heat in order to form localized hyperthermia in the cancerous tissue. Although ultraviolet (UV) and visible (Vis) lights have been used as exogenous stimuli to trigger drug release, concerns about high toxicity to healthy tissues and low penetration depth (∼10 mm) due to strong scattering ability of skin and soft tissues have limited their applications. NIR light triggered drug delivery systems offered some advantages such as deeper penetration, lower scattering and minimal damage 73. Gold nanorods (GNRs) as cores of nanoshells 74, gold layers in core‐shell nanoplatforms, gold nanocages 75, graphene nanosheets 76, graphitic 77 / semi‐graphitic carbon cores 63 and CuS nanoparticles 78, 79 and some other copper compounds 80 are the mostly studied NIR‐absorbing agents in NIR‐triggered hybrid silica nanocarriers.

In an attempt to discuss NIR‐triggered silica nanocarriers in more details, core‐shell structure is regarded as a common denominator and these nanoconjugates are reviewed in two groups. One of the groups is represented with a mesoporous silica core and NIR‐responsive shell (Fig. 1A) is generally required as an additional outer mesoporous silica shell 81 encapsulated with drug, fluorescent agent or photothermal therapy agent. It is worth to mention that surface PEGylation might be required for higher stability and ligand conjugation 64, 82. An example to the first group of nanoconjugates is gold nanoshells (AuNS) with a dielectric core such as silica and a metallic gold layer which shows ~1 million‐fold greater absorption than conventional NIR dye, ICG 83.

Figure 1.

Two types of NIR‐triggered core‐shell type nanoshells; mesoporous silica core encapsulated with drug, fluorescent agent or photothermal therapy agent covered with an NIR responsive shell and an additional outer mesoporous silica shell functionalized for targeted delivery (A), NIR responsive core such as copper, graphene nanosheets and gold derivatives coated with mesoporous silica shell as a drug reservoir and functionalized surface (B).

The other group has a metal core and mesoporous silica shell structure (Fig. 1B) demonstrating many advantages in comparison to carbon derivative or single metal particles 76, 84, 85, 86. As an example for single metal particles, GNRs with nonporous structures exhibit low loading capacities and limited elasticity, restricting their applications in drug delivery 86. But they are still in use due to single‐ and two‐photon induced luminescence and longitudinal plasmonic resonance that can be tuned to near infrared wavelengths 87. Hence, the drug‐loaded mesoporous silica coating on the surface of this type of NIR‐converting agents improved biocompatibility, drug loading and post modification 77. A mesoporous silica‐coated graphene nanosheet (GS) was conjugated with a peptide for glioma targeting. The results showed that peptide conjugation enhanced cellular uptake in human glioma cell line, whereas normal astrocyte cells were not affected, indicating a selective therapeutic effect 76.

Another study focused on mesoporous silica coated graphitic carbon nanospheres conjugated with HER2 receptor specific SP13 peptide for DOX delivery with photothermal effect of NIR responsive graphitic carbon core on the SK‐BR‐3 breast carcinoma cells. The combined effect of nanocarrier system with NIR was remarkable with significantly lower IC₅₀ of DOX (10.05 μg/mL) compared to that of free DOX (124.5 μg/mL) 77. A similar combined chemo‐photothermal therapy was attempted by the design of mesoporous silica encapsulated gold nanorods. A549 human lung adenocarcinoma epithelial cells were incubated with the nanocarrier loaded with DOX and a synergistic effect was reported with lower systematic toxicity 86. The multifunctional hybrid nanocarriers can enhance cancer therapy by providing chemo‐ and photothermal therapies while allowing fluorescence imaging for diagnostic purposes.

3. Concluding remarks

In the mid to late 1970s, the concept of polymer‐drug conjugates or “nano‐therapeutics” have initiated targeted or site‐controlled drug delivery systems in nanoscopic era. The discovery of three key technologies, PEGylation, active targeting to specific cells by ligands or other molecules conjugated to the drug delivery system and passive targeting to solid tumors via the EPR effect stimulated the development of polymeric and nano‐sized carriers as practical clinical applications from late 1980s to the present 88. Although MSNs perform well in preclinical tests, few clinical trials are performed and there are some comprehensible and essential hurdles regarding scale up of its synthesis to required dosage for acceptable pharmacokinetic and pharmacodynamic profiles 2. Herein, just a few of many topics were scrutinized related to silica based mesoporous organic‐inorganic hybrid nanocarrier systems in order to present latest developments in passive and active targeted drug delivery for cancer therapy. As our knowledge of material and biological sciences advances, so our ability to design more complex and multifunctional nano‐structures will continue to grow and MSNs have a promising future for innovative cancer treatments.

Practical application

This review highlights the most recent advances in the use of silica based organic‐inorganic hybrid drug carriers based on cancer therapy with different therapeutic, diagnostic and theranostic applications. Also their novel advantages through drug loading abilities, shape/size modifications and sophisticated functionalization processes were critically discussed in the light of technological developments. Multifunctionalisation techniques such as coating, grafting or capping allow specific responsiveness and homing properties to these nanocarriers. Not only passive or active targeting offer key technologies to tumor homing and penetrating but also photothermal therapy serves as an interesting tool for selective targeting of cancerous tissues.

The authors have declared no conflict of interest.