Smart Inorganic Nanomaterials for CDR 1 Mesoporous Silica Nanoparticles

ABSTRACT

2. Smart Inorganic Nanomaterials for CDR 1 Mesoporous Silica Nanoparticles

group, polymers have garnered much attention from the beginning, which is going to the present, including hydrogels, capsules, polymersomes, and micelles. In the past couple of decades, inorganic materials have received increasingly interests in the field of CDR, such as mesoporous silica nanomaterials (MSNs), iron oxide nanomaterials (IONMs), and zinc oxide (ZnO). In recent years, some emerging materials are also developed and employed in this fi eld due to their unique properties, e.g., gold nanoparticles (AuNPs), metal-organic frameworks (MOFs), graphene and derivatives, and carbon nanotubes (CNTs). Figure 1 presents an overview of the evolution of CDR based on diverse materials.

2. Smart Inorganic Nanomaterials for CDR

unique advantages. (1) The large surface area. MSNs have highly porous interior structure, which could encapsulate a distinctively high payload of drugs (200–600 mg/g silica), enhancing the chemotherapeutic effi cacy (He et al. 2010). (2) Controllable particle size. MSNs could be easily synthesized by stöber method with the size of diameter from 10 nm to 1000 nm. Endocytosis effi cacy is related with the particle size. Especially, particle dimension of 50–100 nm is optimal for MSNs as nanocarriers with a high effi ciency of cellular uptake. (3) Tunable pore size. By changing surfactants with different chain length and addition of auxiliary organics, the mesopore size could be controlled in the range of 2–10 nm, which could be employed to encapsulate various molecules with different size.

(4) Chemical stability. MSNs are stable in vivo and protect the payloads from bio-erosions, which is important for a carrier to deliver drugs to target sites (Borisova et al. 2011). (5) Facile surface functionalization. MSNs exhibit extensive hydroxyl groups on the surface, which could enable the decoration of functional molecules onto MSNs, and fi nally give rise to smart MSNs vehicles with stimuli-responsive ability. (6) Biocompatibility.

Therefore, MSNs have become one of the most promising smart candidates for CDR. In the past decade, numerous smart MSNs have been designed and investigated in vitro and in vivo with stimuli-responsive ability, including pH, light, temperature, enzyme, glucose, ions, and magnetic fi eld (Fig. 3).

TEOS treatment, calcination

Calcination

MCM-50

MCM-48

MCM-41 1-Liquid

crystal initiated Increasing surfactant

to silica ratio

Surfactant Micelle Micellar Rod

Hexagonal Array

Silicate

Silicate Calcination

2 - Silicate initiated pathway - operating in almost all situations

2.1.2 Recent Advances of Stimuli-Responsive MSNs

(1) pH-Responsive MSNs

pH-responsive MSNs for CDR are of special interests in the past decade.

The development of such smart materials is based on the facts that the pHs are different in the bloodstream (pH 7.4), cancer or infl ammatory tissues (pH 6.5), endosome (pH 5.5–6.0), and lysosome (pH 4.5–5.0). To design such smart vehicles, pH-sensitive components are selected and attached on the outer surface of MSNs, which could be responsive to the change of pH and release the loaded cargo. The mechanisms of triggering the fl ow of cargo can be divided into six main categories, including hydrolysis of chemical bonds (I) (Liu et al. 2010), disassembly of superamolecule (II) (Meng et al.

2010, Zhao et al. 2010), structure conversion (III) (Chen et al. 2011b, Xue and Findenegg 2012), dissociation of coordination bonds (IV) (Xing et al. 2012), dissolution of gate keeper (V) (Muharnmad et al. 2011), and electrostatic interactions of gate keeper (VI) (Yang et al. 2005) (Table 1).

Liu et al. reported a pH-responsive MSNs vehicle by capping AuNPs on the surface through an acid-labile acetal linker. The cargo-loaded MSNs vehicle was stable in basic condition, but allowed the escape of cargo when the pH was changed to acidic condition (e.g., 2.0 and 4.0), which was attributed to the hydrolysis of acetal linker (Liu et al. 2010). Meng et al. have deeply investigated and developed a series of pH-responsive

MSNs vehicles based on the assembly/disassembly of supramolecular machines. For example, they modifi ed aromatic amines (as stalk) on the outer surface of MSNs, and assembled β-cyclodextrin (β-CD, as cap) to block the pores through non-covalent bonds at pH 7.4. Lowering the pH led to the protonation of the aromatic amines, which removed the β-CD caps and allowed the release of cargo. This system was further applied to human differentiated myeloid (THP-1) and squamous carcinoma (KB-31) cell lines, which could automatically release drug in endosomal acidic condition and result in the cell apoptotic (Meng et al. 2010). In recent years, DNA molecules attract considerable attention due to their unparalleled base pairing rule, and are investigated widely in the fi eld of CDR. More information about DNA is introduced in Chapter 2. Chen et al. demonstrated a novel MSNs vehicle by controlling the AuNPs caps through the assembly of DNA nanoswitches.

The reversible structure conversion of DNA strands in alternative acidic

Table 1. The categories of pH-responsive MSNs.

Categories Mechanisms Examples Ref.

I Hydrolysis of chemical bonds

II Disassembly of supramolecule

Meng et al. 2010.

III Structure conversion

Chen et al. 2011b.

IV Dissociation of Coordination

bonds

Xing et al. 2012

V Dissolution of gate keeper

Muharnmad et al. 2011.

VI Electrostatic interaction of

gate keeper

Yang et al. 2005.

and alkaline solution would regulate the opening/closing of pore voids (Chen et al. 2011b).

(2) Light-Responsive MSNs

Light-responsive MSNs was fi rst reported by Mal et al. in 2003. UV light- sensitive coumarin molecules were immobilized on the surface of MSNs, which could storage and release of included organic payloads through the reversible intermolecular dimerization of coumarin derivatives (Mal et al. 2003). Since then, light-responsive MSNs have drawn increasing interests due to their potential applications in cancer therapeutics by light which is a kind of remote, and directional controllable method involving the spatial and temporal guidance (Wen et al. 2012b, Liu et al. 2013, Chen et al. 2014, Zhao et al. 2014).

Chen et al. reported an interesting UV-triggered MSNs vehicle for CDR, which was achieved by controlling the wetting property of MSNs surface coated with spiropyran (SP) and perfl uorodecyltriethoxysilane (PFDTES) (Chen et al. 2014). UV exposure would cause the surface from hydrophobicity to hydrophilicity, resulting in the release of cargo. The further in vitro studies on EA.hy926 cells and Hela cells confi rmed the feasibility of the smart vehicle for CDR triggered by light. However, the UV exposure may cause harm to living tissues and biological samples, which limits the applications of such systems to medicine. In recent years, near-infrared light (NIR) as a new method has been developing (Yang et al. 2012, Yang et al. 2013, Zhao et al. 2014), is much less damaging to normal cells and healthy tissues due to NIR, but has remarkably deeper tissue penetration (Szaciłowski et al.

2005). The generally auxiliary materials with good absorbance in NIR region include AuNPs, and upconverting nanoparticles (UCNPs). In 2012, Yang et al. reported a NIR-triggered MSNs vector fabricated with DNA attached on the outer surface and gold nanorods (GNRs) as the core. Upon NIR light irradiation, the absorbance of GNRs converted the photoenergy to heat, which causes the duplex DNA to dehybridize and unlock the pores. The in vitro study also showed the good feasibility of the new material regulated by NIR stimuli (Fig. 4) (Yang et al. 2012).

(3) Thermo-Responsive MSNs

As the temperature in infl ammatory sites is higher than that in normal tissues, thermo-responsive MSNs for CDR are required to treat such diseases. Poly(N-isopropylacrylamide) (PNIPAM) and its derivatives are the widely investigated thermo-sensitive materials which are featured by the solubility change at the lower critical solution temperature (LCST) and hold potential applications in surface, rheology, and drug delivery. For instance, You et al. reported a thermo-responsive MSNs carrier decorated with PNIPAM on the outer surface for CDR. When the temperature was

changed from 38°C to 25°C (LCST was about 32°C), PNIPAM would undergo from an insoluble state in water to a soluble and expanded state, resulting in the opening of pore voids and release of cargo (You et al. 2008).

Actually, efforts are also devoted to develop novel MSNs vehicles based on other thermo-sensitive molecules in recent years. Aznar et al. found parafi ns assembled on MSNs surface could perform as a thermo-sensitive valve to control the access of pores. The parafi ns performing as a hydrophobic layer to block the pores initially would melt when the temperature increased to the melting point (in the range from 36°C to 38°C), which generated the release of included guests (Aznar et al. 2011). It should be noticed that another kind of thermo-responsive material which can be activated by light, is AuNPs.

The absorbance of AuNPs in NIR could convert the photoenergy to heat, which affects the temperature in the surroundings and thus activates the thermo-sensitive switches (Yang et al. 2012). Recently, the denaturation of DNA molecules in high temperature also inspired the investigation of DNA-based MSNs vehicles (Schlossbauer et al. 2010).

(4) Enzyme-Responsive MSNs

Enzyme is a kind of vital biomolecule in organisms, which could selectively catalyze metabolic chemical reactions. Almost all metabolic chemical reactions in a biological cell need enzymes in order to occur at rates suffi cient for life. Smart MSNs responsive to enzyme are critical to accomplish the delivery and selective release of cargo, which could enhance the effi cacy of chemotherapy and reduce the toxicity. In addition, investigations indicate cancer cells overexpress specifi c receptors on the surface or contain special enzymes in cells, which provide researchers with new ideas to design enzyme-responsive MSNs for CDR (Patel et al. 2008, Bernardos et al. 2009, Chen et al. 2013). For example, hyaluronidase-1 (Hyal-1) is an enzyme major found in tumor cells. MSNs with hyaluronic acid (HA) modifi ed on the surface are responsive to Hyal-1 (Chen et al. 2013). Here, HA acts both as

Figure 4. Scheme of near infrared light (NIR)-responsive MSNs for controlled drug release (Yang et al. 2012).

a capping agent and a targeting molecule which could interact selectively with CD44 receptors overexpressed in solid tumor cells. This MSNs vector can deliver and release the anticancer drug doxorubicin (DOX) selectively inside the cancer cells. The other enzymes overexpressed in tumor/cancer cells are also utilized to design the enzyme-responsive MSNs vehicles, such as decarboxylase which plays a key role in tumor growth and infl ammatory processes (Liu et al. 2011), and α-amylase and lipase which are on abnormal increase in acute pancreatitis (Park et al. 2009).

(5) Glucose-Responsive MSNs

Diabetes is a worldwide disease, which afflicted over 382 million people in 2013. Approximately 90% of them have to take medicine or insulin frequently to control the blood glucose level. This disease is still a challenge for scientists, which requires novel therapies. Glucose- responsive MSNs offer a new approach to treat diabetes instead of frequent insulin injection. The design of glucose-sensitive MSNs is similar to enzyme-responsive MSNs vectors, i.e., the unique interaction between the glucose and glucose oxidase. For example, Aznar et al. attached CD-modifi ed-glucose oxidase (CD-GOx) as a cap to MSNs outer surface through assembly between the cyclodextrins and propylbenzimidazole groups. In the presence of glucose, glucose oxidase would catalyze glucose to gluconic acid, which induced the protonation of propylbenzimidazole, resulting in the removal of CD-GOx and the cargo fl ow (Aznar et al. 2013).

Zhao et al. reported a novel glucose-triggered MSNs vehicle using a different strategy (Zhao et al. 2009). The pore voids were successfully blocked by gluconic acid-modifi ed insulin (G-Ins) through interaction with phenylboronic acid on MSNs surface. In the presence of other saccharides, such as glucose, the stronger interaction of phenylboronic acid groups with glucose would remove G-Ins and open the entrance. In addition, they incorporated cyclic adenosine monophosphate (cAMP), the molecule activating Ca²⁺ channels of cells, in the MSNs vehicle, which was controlled to release by glucose trigger. The smart MSNs vehicle was confi rmed to work in rat pancreatic islet tumor, mouse liver, skin fi broblast, and human cervical cancer cells, which held promise in biological applications.

(6) Multifunctional MSNs

Smart MSNs for CDR have been developing from the initial stage with a simple function (fi rst generation) that cargo escapes from pore voids by diffusion to the present stage with intelligent properties (second generation) that control the release of cargo by stimulus. But it’s far away for the MSNs from applications in clinic because of the complex environment in biological bodies which impose multiple physiological and cellular barriers to foreign objects. In order to improve the effi cacy of chemotherapy and reduce the

adverse toxicity, multifunctional MSNs are highly desired for CDR. In recent years, signifi cant efforts have been devoted to the development in this direction (Casasus et al. 2008, Angelos et al. 2009, Liu et al. 2009, Chen et al. 2011a, Wen et al. 2012a, Wu et al. 2013, Zhang et al. 2013a, Lee et al. 2014, Xiao et al. 2014, Zhou et al. 2014).

Angelos et al. designed a dual-controlled MSNs vehicle using two different types of nanomachines in tandem. The molecular nanomachine azobenzene derivatives responsive to optical signal was modifi ed inside the mesochannels, while pH-switchable nanovalves based on cucurbit[6]

uril (CB[6])/bisammonium assemblies were immobilized on outer surface of MSNs. The open and release of entrapped cargo required the input of both light and pH reduction, which behaved as an AND gate, providing a strategy for accomplishing more sophisticated levels of trigger with more precisely control (Angelos et al. 2009).

In 2013, Zhang et al. developed a multifunctional MSNs vector which could perform both the tracing and release of anticancer drugs in cells upon thermo/pH-coupling stimulus. This novel material was prepared with UCNPs NaYF₄:Yb³⁺/Er³⁺ as the cores, and MSNs as the shells coated by poly[(N-isopropylacrylamide)-co-(methyacrylic acid)] (PNIPMA-co- MAA). Upon exposure to NIR, the cells would be imaged by the bright green fl uorescence from UCNPs, which could be used to trace the position of MSNs. Furthermore, under higher temperature/lower pH condition, anticancer drugs could be released from the hybrid vehicle, causing the death of Hela cells (Zhang et al. 2013b). Recently, Zhang et al. constructed a fi nely programmable MSNs carrier for tumor-triggered drug delivery in cancerous cells. The system was functionalized with β-CD as capping agents via a disulfi de linker, which was subsequently coated with a targeting peptide containing Arginine-glycine-aspartic acid (Arg-Gly-Asp) (RGD) motif, peptide Pro-Leu-Gly-Val-Arg (PLGVR), and polyanion poly(aspartic acid) (PASP) (Fig. 5). The intelligent MSNs carrier could be specifi cally taken up by tumor cells and release encapsulated anticancer drugs because of the removal of β-CD induced by intracellular glutathione (GSH). The “cellular- uptake-shielding” multifunctional MSNs are of clinical importance (Zhang et al. 2013a).

2.1.3 Conclusions

In the past decade, MSNs have been developing quickly towards the application in clinical therapy. Diverse smart MSNs achieve anticancer drugs, genes, proteins and release them under controllable manners.

And more and more multifunctional MSNs are also under increasing development in order to attain high levels of achievement in precise control in complex environment, enhancing chemotherapeutic effi cacy and

reducing the adverse toxicity. But to develop a smart MSNs vehicle capable of delivery and release of anticancer drugs in vivo is still in the early stage.

This task is still challenging as well as hopeful for scientists.

2.2 Iron Oxide Nanomaterials

Magnetic materials include Fe, Cobalt, Nickel, Fe₃O₄ and other metal composites. Below a critical diameter, the magnetic particles display zero coercivity, which is termed superparamagnetic. Superparamagnetic nanoparticles become magnetic in the presence of an external magnetic fi eld, and revert to a nonmagnetic state after the removal of magnetic fi eld. Magnetic nanoparticles are of great interests for research with wide applications in catalysis, biomedicine, magnetic resonance imaging (MRI) and data storage. As one of the most appealing candidates, IONPs have received increasing interests in the past decade, although its application in therapeutics was proposed as far back as 1978 (Senyei et al. 1978). IONPs are biodegradable and the surface could be modifi ed with functional molecules

Figure 5. Multifunctional MSNs for CDR achieved by outer surface modifi cation of β-CD cap, tumor-targeting Arg-Gly-Asp (RGD), matrix metalloproteinase substrate Pro-Leu-Gly-Val-Arg (PLGVR), and polyanion protection layer poly(aspartic acid) (PASP) (Zhang et al. 2013a).

to make it stable in vivo environment. IONPs less than 20 nm become superparamagnetic when each particle consists of a single magnetic domain and thermal energy is high enough to overcome the energy barrier of magnetic fl ipping. IONPs perform in two ways in therapeutics. IONPs act as the vectors with both drugs or genes and functional molecules modifi ed on the surface. The other way is IONPs are used as the core protected by polymer or inorganic shells. Both methods may accomplish the design of smart IONPs with targeting ligands and stimuli-responsive components, which could achieve the precise delivery and release of drugs under the infl uence of stimulus and magnetic fi eld. In MRI, the IONPs nanoparticles generate local inhomogeneity in the magnetic fi eld decreasing the signal, which results in the region in the body that contain SPIONs appear darker in MRI images. This information is useful in tracing the uptake of nanoparticles and monitoring the treatment of cancers.

As a kind of magnetic materials, IONPs could deliver payloads to the target site under the control of applied magnet, which is important for the treatment of diseases. Magnetic nanoparticles offer the possibility of being systematically administered but directed towards a specifi c target in the human body. Rao et al. reported a pH-responsive IONPs vector for transdermal delivery and release epirubicin drugs (EPI) covalently modifi ed to IONPs through a pH-sensitive amide linker (Fig. 6).This nanomaterial is stable at the normal physiological pH with a small amount of release. But in

Figure 6. Superparamagnetic iron oxide nanoparticles (SIONPs) for target transdermal delivery of anticancer drugs triggered by pH (Rao et al. 2015).

pH from 6.7 to 4.5, the magnetic nanomaterial displayed fast release, which was consistent with its behavior in the in vitro cancer-cell experiment. A further investigation of this composite nanomaterial in human abdominal cadaver skin demonstrated the IONPs could penetrate into deeper human skin layer under the applied magnetic fi eld. The results indicated IONPs hold promise in the application of skin cancer treatment (Rao et al. 2015).

In addition, the functionalization of IONPs on the surface brings the materials several advantages, incorporating the MRI imaging, positive targeting property, and stimuli-triggered release. For instance, IONPs were coated with redox-responsive shell of poly(ethylene glycol) (PEG) and chitosan. The materials were further modifi ed with tumor targeting peptide chlorotoxin (CTX) and drug O⁶-benzylguanine (BG) against O⁶- methylguanine-DNA methyltransferase (MGMT). This multifunctional formulation was found to demonstrate redox-responsive release and traffi cking of BG within human glioblastoma multiforme (GBM) cells. The in vivo study also showed its effi cient treatment of GBM xenograft tumors by release drugs under stimulus in target sites (Stephen et al. 2014).

In summary, IONPs have shown broad potential in MRI imaging and drug delivery and release, separation in vitro and in vivo. The critical parameters for designing optimal IONPs applied in clinical applications include the size, shape, and functionalization. The nanotechnology and surface engineering strategies will further promote the development of such smart materials.

2.3 Zinc Oxide Nanostructures

Zinc oxide (ZnO) is a typical semiconductor with a wide bandgap of about 3.4 eV. It possesses good transparency and high electron mobility, which attracts wide interests in electronics. Compared with traditional organic fl uorescence molecules, nanocrystal ZnO possesses advantageous photoluminescence properties, including a broad absorption, a narrow and symmetric emission band, a large Stokes shifts and weak self-adsorption, a tunable emission wavelength based on quantum size effects and high stability against photo-bleaching, which make it a promising candidate in bioimaging. As a cheap nanomaterial with low toxicity, unprotected ZnO quantum dots (QDs) are dissolved at pH 5 aqueous solutions, which make it a pH-responsive candidate for application in biomedicine.

ZnO nanostructured materials were fi rst applied in drug delivery and release in 2010 (Yuan et al. 2010, Barick et al. 2010). Yuan et al.

fabricated a blue-light emitting ZnO QDs with diameter in 2–4 nm by a chemical hydrolysis method. ZnO was combined with biodegradable chitosan (N-acetylglucosamine) conjugated with folic acid for tumor target drug delivery. DOX was trapped between ZnO QDs and polymer

Dalam dokumen and Applications of Smart and (Halaman 101-114)