Inorganic Hybrid

Chapter 9

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CNT-Based and MSN-Based Organic/Inorganic Hybrid Nanocomposites for Biomedical Applications Jiemei Zhou,1 Jiaoyang Li,1 Decheng Wu,2 and Chunyan Hong1,* 1CAS

Key Laboratory of Soft Matter Chemistry, Department of Polymer Science and Engineering, University of Science and Technology of China, Hefei, Anhui, 230026, P. R. China 2Beijing National Laboratory for Molecular Sciences, State Key Laboratory of Polymer Physics and Chemistry, Institute of Chemistry, Chinese Academy of Sciences, Beijing 100190, P. R. China *E-mail: [email protected]

The advancement of nanotechnology opens new and fantastic area of biomaterials for biomedical applications. The organic/inorganic hybrid nanocomposites have attracted growing attention of researchers due to their excellent properties. This review highlights and addresses issues related to recent research on carbon nanotubes (CNTs) based hybrid nanocomposites and mesoporous silica nanoparticles (MSNs) based hybrid nanocomposites for biomedical applications. In this review, the modification of CNTs and applications of CNT-based hybrid nanocomposites in cancer treatment and regenerative medicine are introduced. Then, the functionalization of MSNs and applications of MSN-based hybrid nanocomposites in drug delivery and bio-imaging are described. Prospects of CNT-based and MSN-based hybrid nanocomposites in biomedical field are also envisioned.

Introduction In the past decades, the rapid development of nanotechnology leads to the significant advancement of diverse nanoscale biomaterials, such as polymeric nanoparticles, polymer-protein conjugates, micelles, liposomes, inorganic © 2017 American Chemical Society Ito et al.; Advances in Bioinspired and Biomedical Materials Volume 2 ACS Symposium Series; American Chemical Society: Washington, DC, 2017.


nanoparticles and hyperbranched polymers (1–15), which have aroused wide research interest for biomedical applications. Studies show that traditional drugs fail to meet the promising therapeutics in some cases, usually because of the disadvantages such as poor solubility, rapid clearance from body environments and nonselective treatment of diseased tissues in clinical application. While, the nanoscale drug delivery systems demonstrate higher accumulation in diseased tissues by virtue of better pharmacokinetics and the enhanced permeation and retention (EPR) effect (16, 17). Besides, appropriate surface modification of drug delivery systems with ligands which have specific interaction with diseased tissues can effectively promote the selectivity of treatment (18, 19). Nanobiomaterials have been extensively explored not only in drug/gene delivery systems, but also in lots of other biomedical-related fields, for example probes for diagnosis, contrast agents for bio-imaging, repair materials for tissue engineering, etc. (20–26). Nanomaterials can be roughly divided into three categories: organic, inorganic and organic/inorganic hybrid nanocomposites. The organic materials are relatively mature in clinical translations after decades of development, and several nanotechnology-based organic drug delivery systems (liposomes, virosomes, albumins, etc.) have been used in clinic for tumor chemotherapy, such as DaunoXome, Myocet, Doxil, Abroxane, etc. (27, 28) Polymeric micelles and polymer gels have also been widely investigated with great promise as intercellular delivery carriers as well as cellular imaging platforms (14, 15). However, the disadvantages of organic drug delivery systems, including structural instability and low drug-loading capacity, hinder the development and further clinical translations (29). Inorganic materials, such as MSNs, magnetic nanoparticles, metallic nanoparticles and CNTs, attract increasing attention of researchers, due to the unique properties of physicochemical stability, magnetism, fluorescence, plasma absorption, etc. (30–34). Nevertheless, the inorganic materials themselves can hardly meet the requirement of good dispersion in physiological media, targeted transportation, stimuli-responsive drug release, etc. Hence, the organic/inorganic hybrid nanocomposites were developed to combine the merits of both organic and inorganic nanomaterials for wider applications in biomedical filed (11). There are abundant kinds of organic/inorganic hybrid nanocomposites. MSNs and CNTs are popular to design the hybrid nanomaterials, because lots of reports have demonstrated the safety and biocompatibility of MSNs and CNTs for biomaterial application (35–37). Herein, this review focuses on MSN-based and CNT-based hybrid nanocomposites for the biomedical applications. The applications of CNT-based hybrid nanocomposites in cancer treatment and regenerative medicine are discussed. The applications of MSN-based hybrid nanocomposites in drug delivery and bio-imaging are also reviewed.

CNT-Based Hybrid Nanocomposites as Biomaterials CNTs have attracted great attention in various fields and generated significant influence in the materials research community since the discovery in 1991 by Sumio Iijima (38). As sp2 carbon nanomaterials, CNTs can be described as 170 Ito et al.; Advances in Bioinspired and Biomedical Materials Volume 2 ACS Symposium Series; American Chemical Society: Washington, DC, 2017.


cylindrical tubes by rolling up graphene. Single rolled layer of graphene forms single-walled carbon nanotube (SWNT) with a diameter between 0.4 and 2 nm, while rolled multi-layered graphene forms multi-walled carbon nanotube (MWNT) with a diameter between 2 and 100 nm (39). CNTs possess many unique properties, including high tensile strength, ultralight weight, excellent transport conductivity, physical and chemical stability, high aspect ratio, etc. (40) Owing to the large surface area, CNTs can be functionalized or conjugated with various molecules or polymers. The hollow structure of CNTs can result in excellent drug loading capacity. The small size is likely to facilitate the reaction with living organisms or living cells. All these characteristics make CNTs a promising material in various biomedical applications (41). A wide range of biomedical applications about CNTs have been investigated for therapeutic purposes. For example, cancer diagnosis and treatment, regenerative medicine and implant materials (42–50). It is likely that the CNTs in biological applications would be functionalized-CNTs or CNT-based hybrid composites (34). In the drug or gene delivery systems, CNTs usually serve as a platform to bind with drugs, genes and peptides for the treatment of disease. CNTs are found to work excellently as scaffold materials when they are conjugated to polymeric materials for nerve and bone tissue regeneration (41). Furthermore, the modification with various chemical functional groups can increase the dispersibility, reduce the cytotoxicity of CNTs and add new characteristics. Thus, the functionalization of CNTs can greatly expand their potential fields of application. Modification of CNTs Due to the inherent insolubility in aqueous solvents, pristine CNTs are incompatible with the biological systems. One efficient way to improve the solubility is to modify the surface of CNTs by hydrophilic groups or polymer chains (35, 51). The functionalization methods mainly include covalent attachment and non-covalent attachment. Covalent functionalization may be described as a firmly chemical grafting of molecules onto the surface of CNTs. The versatile reaction is oxidation under strong acid conditions to form carboxyl groups on the walls of CNTs, which can react with alcohol or amine to link CNTs with various molecules (52). Another abundant covalent modification is based on 1,3-dipolar and [4+2] cycloaddition (53, 54). In our study (55), CNTs were modified with thiol-reactive species by the reaction between oxidized CNTs and S-(2-aminoethylthio)-2-thiopyridine. Then, poly(N-isopropylacrylamide) (PNIPAAm) was grafted to CNTs through thiol-coupling reaction. The prepared PNIPAAm-CNT conjugates had temperature-responsive PNIPAAm chain, and disulfide linkages between PNIPAAm and CNTs which were sensitive to bio-stimuli such as glutathione, therefore these polymer-CNT conjugates exhibited dual-responsiveness. You et al. (56) attached hyperbranched poly(amidoamine) (PAMAM) onto the surface of CNTs via a multi-step Michael addition of 1-(2-aminoethyl) piperazine (AEPZ) and N,N′-methylene bisa-crylamide (MBA) via the “grafting from” 171 Ito et al.; Advances in Bioinspired and Biomedical Materials Volume 2 ACS Symposium Series; American Chemical Society: Washington, DC, 2017.


strategy (Scheme 1). The amido and amine units linked on CNTs could facilitate the assembly of CNTs with other functional polymers via hydrogen bonds. The external ultrasound-stimulus was found to induce the assembly of functionalized MWNTs with linear PAMAM into a smart carbon nanotube gel at room temperature. The formed carbon nanotube gels are not only responsive to some mechanical stimuli such as vigorous agitating, but also responsive to some chemical stimuli such as water and acids. The sol-gel switching can be easily realized via heating and ultrasonicating. The new multi-responsive carbon nanotube gels may be useful in sensors and nano-medicine. Giambastiani et al. (57) reported the functionalization of MWNTs by the 1,3-dipolar cycloaddition of a cyclic nitrone. It was found that the diffuse structural defects to the sp2 carbon lattice acted as preferential reactive sites for cycloaddition, and this organic functionalization yielded materials with good solubility in DMF (close to 10 mg per mL of DMF).

Scheme 1. Outline of growing hyperbranched poly(amido amine) from carbon nanotubes. Reproduced from (56). Copyright 2009, Royal Society of Chemistry.

Non-covalent functionalization of CNTs depends on the physical interactions like van der Waals interaction, π-π stacking interaction or electrostatic adsorption. In the work by Jo et al. (58), oligothiophene-terminated poly(ethylene glycol) (TN-PEG) was synthesized and its ability to stabilize aqueous CNT dispersions 172 Ito et al.; Advances in Bioinspired and Biomedical Materials Volume 2 ACS Symposium Series; American Chemical Society: Washington, DC, 2017.


was examined. It was observed that the TN-PEG could be strongly absorbed onto the surface of CNTs via a strong π-π stacking interaction and help to disperse CNTs in aqueous media well. Conveniently, only gentle sonication was needed in this non-covalent coating. Kane and co-workers solubilized SWNTs in water using commercially available proteins through noncovalent interactions. This protein-mediated solubilization of CNTs in water was important for biomedical applications (59). In addition to the above mentioned, Zhang and co-workers (60) proposed the strategy for surface modification of CNTs via combination of mussel inspired chemistry and chain transfer free radical polymerization. Pristine CNTs were coated with polydopamine (PDA), which was formed via self-polymerization of dopamine in alkaline conditions. Due to the strong adhesion of PDA to CNTs and mild reaction condition, this method provided robust surface modification and no damage of CNTs. These PDA functionalized CNTs could be further reacted with amino-terminated polymers through Michael addition reaction. Poly(methacryloxyethyltrimethyl ammonium chloride) (PDMC) terminated with amino-group, which was synthesized via chain transfer free radical polymerization using cysteamine hydrochloride as the chain transfer agent and methacryloxyethyltrimethyl ammonium chloride (DMC) as monomer, was conjugated with surface of functional CNTs with PDA coating.

Application of CNT-Based Hybrid Nanocomposites to Cancer Diagnoses and Treatment Clinical application of CNTs is a very promising field. There are abundant studies about functionalized CNTs used as molecular carriers for applications in cancer treatment. For the early diagnose of cancer, CNTs conjugated to contrast reagent for CT or MRI and antibody with high affinity for cancer cells have been used in highly sensitive detection and imaging of small tumors. The detection of a prostate cancer markers (PSA), colorectal cancer markers (CEA, CA19-9), and a hepatocarcinoma marker (AFP) has been reported (61–64). Furthermore, CNTs have also been used in the photoacoustic imaging of living subjects due to their high photoacoustic signal. For example, SWNTs conjugated with cyclic Arg-GlyAsp (RGD) peptides were used as a contrast agent for photoacoustic imaging of tumor, offering high-resolution images with substantial depth of penetration (65). Drugs delivery systems (DDS) have been vigorously investigated for decades. Among the all kinds of carriers in DDS, CNTs are popular with researchers because of their special characteristics like high surface reactivity, small structure and excellent biocompatibility. Studies show that functionalized-CNTs possess a capacity to be taken up by a wide range of cells and to intracellularly traffic through the different cellular barriers by energy-independent mechanisms. The cylindrical shape and high aspect ratio of functionalized-CNTs can allow their penetration through the plasma membrane (66). CNTs attached with cell-recognizing module can cause the accumulation of drugs within a specific part of the body. The integration of CNTs with biomolecules allows the generation of complex nanostructures with controlled properties and functions (67). 173 Ito et al.; Advances in Bioinspired and Biomedical Materials Volume 2 ACS Symposium Series; American Chemical Society: Washington, DC, 2017.


Figure 1. Synthesis scheme for NPs of FA-MWCNT@Fe, FA-(FITC)MWCNT@Fe and (FITC)MWCNT@Fe, including the oxidization of MWCNT, loading of Fe(NO3)3 onto o-MWCNT, thermal decomposition of Fe(NO3)3, reduction of Fe2O3 NPs, and diimide-activated amidation reaction between o-MWCNT@Fe and the intermediates. Reproduced from (69). Copyright 2011, Elsevier.

Scheinberg et al. (68) reported the tumor-targeting CNT-based hybrid nanocomposites, which were constructed from sidewall-functionalized, water-soluble CNT platforms by covalently attaching multiple copies of tumor-specific monoclonal antibodies, radiometal-ion chelates, and fluorescent probes. These nanoconstructs were found to be specifically reactive with the human cancer cells that they were designed to target. Zou and co-workers synthesized the folate and iron di-functionalized MWNTs by conjugating folate 174 Ito et al.; Advances in Bioinspired and Biomedical Materials Volume 2 ACS Symposium Series; American Chemical Society: Washington, DC, 2017.


and iron nanoparticles with oxidized MWNTs, which were used as a dual-targeted drug nanocarrier to deliver doxorubicin into HeLa cells with the assistance of an external magnetic field (Figure 1). This nanocarrier has a sufficient load capacity and a prolonged release property controlled by near infrared radiation. It also demonstrated both biologically (active) and magnetically (passive) targeting capabilities toward HeLa cells in vitro with ca. 6-fold higher delivery efficiency of doxorubicin than free doxorubicin (69). CNTs exhibit strong optical absorption in the near infrared (NIR) regions and can generate heat to induce the thermal destruction of cancer cells containing sufficient CNT concentrations (42). Thus, targeted functionalized-CNTs can be used for the photo-thermal cancer therapy. Xing et al. (70) explored a therapy model in vivo with mitochondria-targeting SWNTs, which was used to convert 980-nm laser energy into heat and selectively destroy the target mitochondria for cancer treatment. It was found that SWNTs could be efficiently accumulated in the mitochondria of cancer cells, afforded remarkable efficacy in suppressing tumor growth in a breast cancer model, and resulted in complete tumor regression in some cases. A number of other studies about the photo-thermal therapy using CNTs have also been reported (71–73). The application of CNTs to gene therapy has also been studied. Prato et al. (74) functionalized CNTs with polyamidoamine (PAMAM) dendrons on their surface (Figure 2), and the functionalized CNTs formed supramolecular complexes with plasmid DNA through ionic interactions. These complexes penetrated within cells and facilitated higher DNA uptake and gene expression in vitro than that could be achieved with DNA alone. In other studies, linear cationic polymers such as poly(3-aminopropyl methacrylamide)-b-poly(2-lactobionamidoethyl methacrylamide) (PAPMA-b-PLAEMA) and polyethylenimine (PEI) were linked to the surface of CNTs to enhance effect of gene transfection and intracellular trafficking, as well as to induce the endosomal release of genes (75, 76).

Application of CNT-Based Hybrid Nanocomposites to Regenerative Medicine

CNTs have shown good blood compatibility, and they are the suitable scaffold material for repair and regeneration of human body tissues and organs. A study reported a type of guided tissue regeneration (GTR) membrane by electrospinning a suspension consisting of poly(L-lactic acid), MWNTs and hydroxyapatite (PLLA/MWNTs/HA) (77). Cytologic research revealed that the PLLA/MWNTs/HA membrane enhanced the adhesion and proliferation of periodontal ligament cells (PDLCs) by 30% and inhibited the adhesion and proliferation of gingival epithelial cells by 30% also, compared with the control group. CNTs functionalized with biocompatible macromolecules like collagen, polylactic acid or calcium phosphates, have been exploited to promote proliferation of various cells in vitro, such as fibroblasts, osteoblast, vascular endothelial cells, ligament cells and so on (78–82). 175 Ito et al.; Advances in Bioinspired and Biomedical Materials Volume 2 ACS Symposium Series; American Chemical Society: Washington, DC, 2017.


Figure 2. Synthesis of Dendron−MWNTs. Reproduced from (74). Copyright 2009, American Chemical Society.

Saito et al. (83) showed that CNTs promoted bone tissue formation in vivo. The study employed an experimental system that used recombinant bone morphogenetic protein-2 (rhBMP-2) to induce ectopicosteo-genesis in mouse back muscle. Bone formation on a collagen sheet was shown to occur earlier in the presence of rhBMP-2 attached to a scaffold of MWNTs than in the presence of rhBMP-2 alone. The later study (84) reported that CNTs could serve as the seed material for the crystallization of hydroxyapatite, the major component of bone, and that CNTs attracted Ca ions and activated osteoblasts. This activation was accompanied by the deposition of hydroxyapatite around the CNTs, which was catalyzed by alkaline phosphatase (ALP) released from osteoblasts. These findings demonstrated that CNTs, which functioned as a scaffold, could interact 176 Ito et al.; Advances in Bioinspired and Biomedical Materials Volume 2 ACS Symposium Series; American Chemical Society: Washington, DC, 2017.


with the body to promote osteogenesis and thereby the process of bone tissue regeneration. CNTs have been employed in neuroscience research for the design of neuronal interfaces or used as scaffolds favoring neuronal growth and axonal regeneration (85). Studies support the biocompatibility of functionalized-CNT scaffolds when used in vitro to sustain neuronal growth and axonal elongation and branching. Duan et al. (86) reported the investigation of electro-chemically co-deposited polypyrrole/SWNT (PPy/SWNT) films (Figure 3). This study demonstrated the feasibility and advantages of co-deposited PPy/SWNT films on Pt for improving the electro-de-neural tissue interface. The PPy/SWNT microelectrode exhibited a particularly high capacitance and lower electrode impedance (reduced by 95%) at 1 kHz compared to Pt microelectrodes. The SWNT doped conducting polymer film revealed improved mechanical and electrochemical stabilities than pure conducting polymer films. Furthermore, the PPy/SWNT film showed excellent biocompatibility both in vitro and in vivo.

Figure 3. Schematic illustration of the procedures for electrodeposition of polypyrrole with KCl, poly(styrene sulfonic acid) sodium salt (PSSNa), and carboxyl functionalized single-walled carbon nanotubes (SWCNT–COOH). Reproduced from (86). Copyright 2010, Elsevier.

In addition to the above-described applications, CNTs are expected to have biomedical application in a wide variety of therapeutic settings. CNT/polyethylene composite for application in artificial joints and CNT/polyether ether ketone composite for spinal fusion cages used in interbody fusion surgery have been developed by researchers (41). Tissue-compliant neural implants from micro-fabricated CNT multilayer composite have been reported (87). CNTs may also serve as muscle actuators or be directly applied to artificial muscles (88). Studies about CNT-based hybrid nanocomposite as biomaterial will be continued and more breakthroughs for disease therapy are expected. 177 Ito et al.; Advances in Bioinspired and Biomedical Materials Volume 2 ACS Symposium Series; American Chemical Society: Washington, DC, 2017.


MSN-Based Hybrid Nanocomposites as Biomaterials MSNs have been subjected to intense research in recent years for biomedical applications. The MSNs are usually synthesized by a sol-gel method, that is, the hydrolysis of silica precursors (sol) and the condensation on self-assembled surfactant templates (gel), followed by the removal of surfactant templates either by calcination or organic extraction (89). MSNs have the honeycomb-like porous structure with hundreds of empty channels, which lead to the unique properties of high surface area (>900 m2/g) and large pore volume (>0.9 cm3/g). The pore size of MSNs is usually tunable with a narrow distribution (2-10 nm). Combined with the good chemical and thermal stability, MSNs have been explored for various applications, such as catalysis, separation and sensors. Silica materials are known to be biocompatible, and MSNs with defined structures are able to absorb or encapsulate relatively large amounts of bioactive molecules due to the large pore volume. Thus, there are growing reports on the utilization of MSNs as carriers for drug and gene delivery application recently (11). To construct an efficient drug or gene delivery system, the carrier should allow high loading of drug molecules with no leaking of cargo before reaching the destination, possess the cell type or tissue specificity and site directing ability, and control release of drug molecules with a proper rate to achieve an effective local concentration. To meet the requirements, the composite combining MSN and organic molecule or polymer is usually needed for an increased affinity towards targeting molecules, an enhanced control over encapsulated cargoes, or any improved property with regard to application concerns (89).

Functionalization of MSNs Functionalization methods anchored functional groups onto surfaces of mesoporous silica materials generally include co-condensation (one-pot synthesis) and grafting (post-synthesis modification). For the co-condensation approach, functional moiety-containing organoalkoxysilanes are added into reaction solution where template-directed condensation of tetraalkoxysilane occurs. As a result, a direct synthesis of MSNs with functional groups is achieved at the same time as the orderly meso-structures with certain morphology formed. This method is applicable to a wide variety of organoalkoxysilanes, such as thiolate-, carboxylate- and sulfonate-containing organoalkoxysilane (6). The coverage of functional groups is homogeneous, and the loading amount of functional groups is high without affecting the structural ordering of the pores through this method. The grafting is commonly carried out by the reaction between functional moiety and silanol groups on the surface of mesoporous silica materials. Introduction of functional groups to as-made MSNs retains the mesostructure and mesoporosity of parent particles to the largest extent, but the distribution of functional groups on the surfaces of MSNs may be inhomogeneous. The most remarkable feature of the grafting method is that, the functional groups can be selectively modified on the external surfaces of MSNs, when the grafting is conducted before surfactant removal (90). 178 Ito et al.; Advances in Bioinspired and Biomedical Materials Volume 2 ACS Symposium Series; American Chemical Society: Washington, DC, 2017.


Lin et al. (91) fabricated a series of mesoporous silica materials with MCM-41 type of structure containing a homogeneous layer of organic functional groups inside the pores using co-condensation method. This synthetic approach resulted in high surface coverage with several functional groups such as a primary amine, secondary amine, urea, isocyanate, vinyl and nitrile. Our group (92, 93) anchored atom transfer radical polymerization (ATRP) and reversible addition-fragmentation chain transfer (RAFT) functionalities onto the exterior surface of MSNs through the grafting method. MSNs were modified with 3-aminopropyltriethoxysilane (APTES) to get MSN-NH2, then the ATRP agent-functionalized MSNs were prepared by the reaction of amino groups in MSN-NH2 with 2-bromo-2-methylpropionyl bromide, and it can be used to initiate polymerization of 2-(diethylamino)ethyl methacrylate (DEAEMA) to obtain MSN-PDEAEMA (Scheme 2). For the functionalization with RAFT agent, MSNs reacted with (3-glycidyloxypropyl) trimethoxysilane to obtain MSN-OH. The RAFT functionalized MSNs were prepared by the esterification reaction of MSN-OH with S-1-dodecyl-S′-(α,α′-dimethyl-α′′-acetic acid)trithiocarbonate. Polymer chains could be grafted on the surface of MSNs via surface RAFT polymerization of monomers.

Scheme 2. Synthetic route of PDEAEMA-functionalized MSNs (92).

179 Ito et al.; Advances in Bioinspired and Biomedical Materials Volume 2 ACS Symposium Series; American Chemical Society: Washington, DC, 2017.


Application of MSN-Based Hybrid Nanocomposites to Drug Delivery MSN-based controlled release systems have been investigated for years. MSNs work as rigid carriers for drug molecules, which effectively protects the cargo from chemical insults and biological degradation. To meet the targeted and controlled release character, various stimuli-responsive MSN-based drug delivery systems, which are sensitive to external or internal stimuli including temperature, redox, pH value, light, magnetism, enzyme, ultrasound, etc., have been developed (94–97). Lin and coworkers (98) synthesized a 2-(propyldisulfanyl)ethylamine functionalized mesoporous silica nanosphere material with an average particle size of 200.0 nm and an average pore diameter of 2.3 nm, which was used as reservoirs to encapsulate various pharmaceutical molecules and neurotransmitters. The open pores of the drug or neurotransmitter-loaded MSN were capped by acid-derivatized cadmium sulfide (CdS) nanocrystals (the average particle diameter is about 2.0 nm) via the amidation reaction, and the CdS nanocrystals could protect the cargos from escape. The disulfide linkages between the MSNs and the CdS nanoparticles can be cleaved by disulfide-reducing agents, such as dithiothreitol (DTT) and mercaptoethanol (ME), resulting in the release of drugs or neurotransmitters. In this system, CdS nanoparticles worked as “gatekeepers” to regulate the encapsulation and release of drug molecules. Subsequently, a series of nano-caps as gatekeepers for MSNs, which would response to the external stimulation by redox, light or magnetism, were developed, such as Au, Fe3O4, coumarin, diethylenetriamine, PAMAM nanoparticles and [2]-pseudorotaxane (99–101). Zink (96) and Fujiwara (102) designed various MSN-based nanomachines, such as smart supramolecular nano-valves ([2]-pseudorotaxane and [2]rotaxane) and nano-impellers (azobenzene and coumarin), to realize the pH-/light-responsive drug release. We constructed (93, 103) the drug delivery system via coating polymers onto MSNs, such as poly(2-(dimethylamino)ethyl methacrylate-co-3-dimethyl(methacryloyloxyethyl)ammonium propanesulfonate), and cross-linked poly(oligo(ethylene glycol) acrylate-co-N,N′-cystaminebismethacrylamide). The flexible polymers help to stabilize the MSNs, and can realize the controlled release of drugs under external stimulation of pH, temperature or redox. Du et al. reported (104) the controlled release of rhodamine 6G (Rh6G) from novel protein-gated carbohydrate-functionalized MSN nanocontainers. Mercaptoterminated mannose derivatives were synthesized, reacted with alkenyl-terminated silanes using a thiol–ene click reaction, and finally the external surfaces of MSNs were functionalized with mannose epitopes. Subsequent capping with Con A encapsulated the cargo within the pores through the multivalent carbohydrate–protein interactions. The carbohydrate-binding activity is abolished by decreasing the pH value of the buffer or by the competitive binding of glucose at high concentrations, releasing the cargo from MSNs on demand. Cai et al. (105) reported the enzyme-responsive drug delivery system based on MSNs for targeted tumor therapy. MSNs were functionalized with polypeptide, which consists of two components: the cell penetrating peptide 180 Ito et al.; Advances in Bioinspired and Biomedical Materials Volume 2 ACS Symposium Series; American Chemical Society: Washington, DC, 2017.


polyarginine (RRRRRRRRR) and MMP-2 cleavable substrate peptide (PVGLIG). Phenylboronic acid (PBA) was conjugated with human serum albumin (HSA), resulting in PBA-HSA, which was used as the end-capping agent for sealing the mesopores of MSNs. The PSA-HSA was immobilized onto MSNs via the intermediate linker of polypeptides. When the MSN-based drug delivery system reached the tumor site, the over-expressed MMP-2 in the tumor microenvironment could break down the intermediate linker, leading to the release of cargo from MSNs (Scheme 3). Zink et al. (106) designed a light-stimulated, thermally activated system for on-command drug release based on MSNs containing gold nanoparticle cores. Brauchle and co-workers (107) demonstrated a red-light photoactivated drug delivery system by linking the photosensitizer molecules (aluminum phthalocyaninedisulfonate) to the surface of MSNs and encapsulate MSNs with a supported lipid bilayer (SLB) to retain the drug. The activation of the photosensitizer with red light instead of blue light could reduce the phototoxicity and significantly increase the depth of tissue penetration (Scheme 4).

Scheme 3. Schematic illustration of the functionalization routes of an MSN-based drug delivery system and its enzyme mediated biological responses. Reproduced from (105). Copyright 2015, Royal Society of Chemistry.



Scheme 4. Synthesis Pathway of Core (Green) Shell (Red) MSN with Covalently Linked AlPcS2a (Red Star) via PEG Linker (Black Chain) and Surrounded by DOPC/DOTAP Supported Lipid Bilayer with Targeting Ligand (Green Star, TL). Reproduced from (107). Copyright 2013, American Chemical Society.

Application of MSN-Based Hybrid Nanocomposites to Bio-Imaging MSNs intrinsically possess many optical features due to the chemical nature of silica and their unique physical structure. Photoluminescence (PL) spectra of MSNs were determined by many structural characteristics, including specific composition, chemical bonding, defect sites, etc. While the application of MSNs in biological system can’t rely on their intrinsic optical patterns, since the PL quantum yield and the PL intensity of MSNs at a reasonable dosage in biological substances are not good enough to visualize MSNs inside cells, especially compared to those of traditional fluorescent dyes (89). The dye-containing MSNs are much more popular in bio-imaging. The fluorescent dye can be encapsulated into pores of MSNs by physical adsorption, or attached to MSNs by covalent linkage via post-synthetic grafting or co-condensation into the silica framework. Mou and co-workers (108) prepared fluorescein isothiocyanate (FITC) functionalized MSNs via co-condensation and treated FITC-MSNs with 3T3-L1 fibroblasts in vitro. The FITC functionalized MSNs with average diameter of 110 nm were demonstrated to be internalized into 3T3-L1 fibroblast cells and to accumulate in cytoplasm. The MSNs appeared to have no apparent cytotoxic effects on the fibroblast cells, revealing FITC-MSNs a promising material for bio-imaging. Similar investigations were employed in various cell cultures. Lo and co-workers (109) encapsulated indocyanine green (ICG) molecules inside the nanochannels of MSNs to probe the biodistribution of MSNs in anesthetized rats via near-infrared (NIR) microscopy. The high dispersion of ICG molecules in the 182 Ito et al.; Advances in Bioinspired and Biomedical Materials Volume 2 ACS Symposium Series; American Chemical Society: Washington, DC, 2017.


large surface areas of MSNs could efficiently prevent them from aggregation and thus decrease the fluorescence self-quench. In addition, the NIR light source could penetrate centimeters of tissue organic components and minimize the scattering and absorption while traveling through tissues. The fluorescence probe within NIR range was clearly detected after intravenous injection for evaluating particle accumulation inside the liver and kidney and partially in lungs, spleen, and heart. Wiesner et al. (110) reported one-pot synthesis of PEGylated MSNs with sizes around 9 nm that could be labeled with NIR dye Cy5.5, showing promise in future clinical imaging. Zhao’s group (111) loaded NIR dye squaraine inside MSNs, and wrapped the surfaces of MSNs with ultrathin graphene oxide sheets, leading to the formation of a novel hybrid material. The hybrid material exhibited remarkable stability in aqueous solution and could efficiently protect the loaded dye from nucleophilic attack. The in vitro investigation with Hela cells presented significant potential for application in fluorescence imaging (Scheme 5).

Scheme 5. Illustration of enwrapping dye-loaded MSNs with graphene oxide for fluorescence imaging in vitro. Reproduced from (111). Copyright 2012, American Chemical Society.

In addition to the fluorescent imaging, superparamagnetic iron oxide was combined with MSNs to enhance their properties as magnetic resonance imaging (MRI) contrast agents. Qu et al. (112) reported a multistage continuous targeting strategy based on magnetic mesoporous silica nanoparticles (FMSNs) for nuclear drug delivery. In this work, layer of mesoporous silica was coated around the Fe3O4 core and the DNA-toxin anticancer drug camptothecin was loaded into the pores of the silica shell. The nucleus-targeting peptide, trans-activating transcriptional (TAT) activator, was grafted onto the silica surface to enable cellular targeting, and the system was further decorated with a charge-conversional polymer to enhance the stability of FMSNs under physiological conditions. The Fe3O4 nanocore was capable of efficiently accumulating in tumor tissue guided by magnet, and could be simultaneously used as predominant contrast agents for magnetic resonance imaging. Yang and co-workers (113) developed multifunctional theranostic nanoparticles based on mesoporous silica to achieve 183 Ito et al.; Advances in Bioinspired and Biomedical Materials Volume 2 ACS Symposium Series; American Chemical Society: Washington, DC, 2017.


the combination of MRI and near-infrared fluorescence (NIRF) imaging and the target-specific delivery of hydrophobic drugs. The Fe3O4 nanoparticles grafted with hydrophobic poly(tert-butyl acrylate) (PTBA) were employed as the hydrophobic core, while the mesoporous silica modified with transferrin (Tf) and near-infrared fluorescent (NIRF) dye Cy7 acted as the multifunctional shell. The iron oxide core was used as a MRI agent, and the Cy7 fluorescent dye served as a NIRF imaging probe. The modification of Tf proved to be an effective target ligand endows nanoparticles the ability of tumor-targeting delivery. The hydrophobic antitumor drug paclitaxel (PTX) was used as the model drug, and the drug-loaded nanocarrier showed effectiveness of killing cancer cells in cytotoxicity assay. Lin and co-workers (114) grafted gadolinium (Gd) chelate onto MSNs for designing highly efficient MRI contrast agent (Figure 4). MSN-Gd showed no noticeable toxicity to monocyte cells and it was demonstrated to be a highly efficient T1 contrast agent for intravascular MR imaging and an excellent T2 contrast agent for MR imaging of soft tissues when applied at a higher dosage (31 µmol/kg dose). Subsequently, a series of MRI contrast agents by doping Gd into MSNs were developed (89, 115, 116) to improve the magnetic signals and strengthen the biological applicability (Scheme 6). Furthermore, MSN-coated MnO nanocystals were also applied as T1 contrast agents (117, 118). Shi and co-workers (118) reported the synthesis of manganese oxide-based multifunctionalization of hollow mesoporous silica nanoparticles by in situ redox reaction using mesopores as nanoreactors (Figure 5). This manganese-based mesoporous MRI-T1 contrast agent (CA) could release MnII in acidic condition, significantly enhancing the MRI-T1 performance in acidic tumor microenvironment. The relaxation rate of the Mn-based CA was almost two times higher than commercial GdIII-based complex agents. Meanwhile, the hybrid MSNs could encapsulate and deliver anticancer agents (doxorubicin) intracellularly to cancer cells. Liu et al. (119) developed the fluorescent carbon dot (C-dot) nanoclusters by integrating C-dot with hollow silica spheres or PEG-g-hollow silica. Hollow silica spheres worked as a scaffold for the C-dots, and the C-dot nanoclusters showed a redshifted fluorescence emission with an increased excitation wavelength. The in vitro investigation with live HepG2 cells and live MCF-7 cells presented good cytoplasm imaging, and C-dot nanoclusters are more efficient in providing fluorescence imaging than the free C-dots. In addition to the application in drug delivery and bio-imaging fields mentioned above, MSN-based hybrid nanocomposites are also popular in the application of biosensing and biocatalysis by immobilization of various proteins (e.g., enzymes, antibodies) on mesoporous silicas with a variety of mesostructures (120, 121). Compared to free proteins, confined enzymes on inner or outer surfaces of mesochannels possessed an enhanced stability and activity, mainly because MSNs as the host created a protective microenvironment enclosing the guest proteins, sequestering them from external physical or chemical disturbances, such as abrupt changes in pH, ionic strength or temperature. Therefore, sensing or catalytic efficiency and accuracy are much improved.



Figure 4. (a) SEM image of MSN showing the formation of monodisperse, water-dispersible nanoparticles. (b) Schematic showing the Gd-Si-DTTA complexes residing in hexagonally ordered nanochannels of ~2.4 nm in diameter. (c) TGA curves of as-synthesized MSN (black), surfactant-extracted MSN (red), and MSN−Gd (blue). (d) The r1 (solid) and r2 (dashed) relaxivity curves of MSN−Gd at 3 T (black) and 9.4 T (red). Reproduced from (114). Copyright 2008, American Chemical Society.

Scheme 6. Synthesis of NDP2–Gd Complexes within Porous Silica Particles. Reproduced from (115). Copyright 2012, American Chemical Society.



Figure 5. (a) Schematic illustration of the microstructure and structure-related theranostic functions of hybrid mesoporous composite nanocapsules (HMCNs); (b) TEM image of HMCNs (inset: the STEM image with scale bar = 100 nm); (c–f) Element mapping of Si (c), O (d) and Mn (e) In HMCNs (f: the merged image of c, d and e). Reproduced from (118). Copyright 2012, Elsevier.

It is worth noting that MSNs with special structure, such as hollow MSNs and rod-shaped MSNs, have been widely applied in biomedical field like the conventional mesoporous silica. Hollow MSNs possess huge hollow interiors and penetrating pores in the shell that endow them with a sustained release property and a higher drug loading capacity than conventional MSNs, which are ideal as drug delivery system (122). The rod-shaped MSNs with large aspect ratio show some superiorities in biomedical applications. For example, the study of tang and co-workers (123) about the shape effect of MSNs on cellar uptake, biodistribution, and clearance, showed that particles with larger aspect ratios had faster internalization rates and longer circulation times. We have designed a novel nanocarrier by attaching pH-sensitive polymer on the exterior surface of silica nanotube for drug delivery (124). This nanocarrier could encapsulate drug molecules into the hollow interior of silica nanotube and realize controlled release of drug by adjusting the pH of medium. Meanwhile, the in vitro cell viability 186 Ito et al.; Advances in Bioinspired and Biomedical Materials Volume 2 ACS Symposium Series; American Chemical Society: Washington, DC, 2017.

and cellular internalization study presented good biocompatibility and excellent endocytosis property. In general, the quest for intelligent nanomedicine based upon various mesoporous silica materials and the detailed in vitro and in vivo testing is one of the most important areas of biomedical research in recent times as well as in near future.


Conclusion and Perspective Significant and efficient progress has been made employing CNT-based and MSN-based hybrid nanocomposites in various biological applications. The distinguishing properties made them important classes of biologically applicable materials. The number of reports on smart hybrid nanocomposites based on CNTs and MSNs has been increasing. Although these reports have demonstrated the effectiveness of these biomaterials in vitro or in vivo, more effort have to be made to push the hybrid nanocomposites closer to future clinical trials. The prospective studies should focus on two aspects. One is to rationally design and construct nano-platforms, and to study the interactions between such nanoscaled platforms and different biological entities simultaneously. The other is to explore the pharmacokinetics and biocompatibility of these hybrid nanocomposites, and to investigate the toxicity on diseased tissues as well as the side-effect on healthy tissues in vivo. There are still many questions which need to be settled for the practically clinical applications of the hybrid nanomaterials, such as acute and chronic toxicities, genotoxicity, the reproductive toxicity, the long-term in vivo degradation, etc., but we expect that these problems would be solved in the future.

Acknowledgments We thank National Natural Science Foundation of China (No. 21525420 and 21374107) and the Fundamental Research Funds for the Central Universities (WK 2060200012).

References 1. 2. 3. 4. 5. 6. 7. 8.

Greish, K. J. Drug Targeting 2007, 15, 457–464. Khandare, J; Minko, T. Prog. Polym. Sci. 2006, 31, 359–397. Vicent, M. J.; Greco, F.; Nicholson, R. I.; Paul, A.; Griffiths, P. C.; Duncan, R. Angew. Chem., Int. Ed. 2005, 44, 4061–4066. Liu, S.; Maheshwari, R.; Kiick, K. L. Macromolecules 2009, 42, 3–13. Blanazs, A.; Armes, S. P.; Ryan, A. J. Macromol. Rapid Commun. 2009, 30, 267–277. Slowing, I. I; Vivero-Escoto, J. L.; Wu, C. W.; Lin, V. S. Y. Adv. Drug Delivery Rev. 2008, 60, 1278–1288. Xiong, X. B.; Falamarzian, A.; Garg, S. M.; Lavasanifar, A. J. Controlled Release 2011, 155, 248–261. Zhang, Q.; Ko, N. R.; Oh, J. K. Chem. Commun. 2012, 48, 7542–7552. 187 Ito et al.; Advances in Bioinspired and Biomedical Materials Volume 2 ACS Symposium Series; American Chemical Society: Washington, DC, 2017.

9. 10. 11. 12. 13. 14.


15. 16. 17. 18. 19. 20. 21. 22. 23. 24. 25. 26. 27. 28. 29. 30. 31. 32. 33. 34.

Samarajeewa, S.; Shretha, R.; Li, Y.; Wooley, K. L. J. Am. Chem. Soc. 2012, 134, 1235–1242. Wagner, V.; Dullaart, A.; Bock, A. K.; Zweck, A. Nat. Biotechnol. 2006, 24, 1211–1217. Chen, Y.; Chen, H. R.; Shi, J. L. Adv. Mater. 2013, 25, 3144–3176. Arvizo, R. R.; Bhattacharyya, S.; Kudgus, R. A.; Giri, K.; Bhattacharya, R.; Mukherjee, P. Chem. Soc. Rev. 2012, 41, 2943–2970. Robinson, J. T.; Tabakman, S. M.; Liang, Y. Y.; Wang, H. L.; Casalongue, H. S.; Vinh, D.; Dai, H. J. J. Am. Chem. Soc. 2011, 133, 6825–6831. Li, D. W.; Bu, Y. Z.; Zhang, L. N.; Wang, X.; Yang, Y. Y.; Zhuang, Y. P.; Yang, F.; Shen, H.; Wu, D. C. Biomacromolecules 2016, 17, 291–300. Wu, D. C.; Liu, Y.; Jiang, X.; He, C. B.; Goh, S. H.; Leong, K. W. Biomacromolecules 2006, 7, 1879–1883. Lu, J.; Liong, M.; Li, Z.; Zink, J. I.; Tamanoi, F. Small 2010, 6, 1794–1805. Maeda, H.; Wu, J.; Sawa, T.; Matsumura, Y.; Hori, K. J. Controlled Release 2000, 65, 271–284. Rosenholm, J. M.; Meinander, A.; Peuhu, E.; Niemi, R.; Eriksson, J. E.; Sahlgren, C.; Linden, M. ACS Nano 2009, 3, 197–206. Ferris, D. P.; Lu, J.; Gothard, C.; Yanes, R.; Thomas, C. R.; Olsen, J. C.; Stoddart, J. F.; Tamanoi, F.; Zink, J. I. Small 2011, 7, 1816–1826. Vallet-Regi, M.; Balas, F.; Arcos, D. Angew. Chem., Int. Ed. 2007, 46, 754–7558. Kumar, S.; Ahlawat, W.; Kumar, R.; Dilbaghi, N. Biosens. Bioelectron. 2015, 70, 498–503. Koo, H.; Huh, M. S.; Ryu, J. H.; Lee, D. E.; Sun, I. C.; Choi, K.; Kim, K.; Kwon, I. C. Nano Today 2011, 6, 204–220. Son, K. H.; Hong, J. H.; Lee, J. W. Int. J. Nanomed. 2016, 11, 5163–5185. Yang, N.; Chen, X. P.; Ren, T. L.; Zhang, P.; Yang, D. G. Sens. Actuators, B 2015, 207, 690–715. Liong, M.; Lu, J.; Kovochich, M.; Xia, T.; Ruehm, S. G.; Nel, A. E.; Tamanoi, F.; Zink, J. I. ACS Nano 2008, 5, 889–896. Lee, J. E.; Lee, N.; Kim, T.; Kim, J.; Hyeon, T. Acc. Chem. Res. 2011, 44, 893–902. Gabizon, A.; Goren, D.; Cohen, R.; Barenholz, Y. J. Controlled Release 1998, 53, 275–279. Fernandez-Fernandez, A.; Manchanda, R.; McGoron, A. J. Appl. Biochem. Biotechnol. 2011, 165, 1628–1651. Elsabahy, M.; Wooley, K. L. Chem. Soc. Rev. 2012, 41, 2545–2561. Giri, S.; Trewyn, B. G.; Lin, V. S. Nanomedicine 2007, 2, 99–111. Laurent, S.; Forge, D.; Port, M.; Roch, A.; Robic, C.; Elst, L. V.; Muller, R. N. Chem. Rev. 2008, 108, 2064–2110. Skrabalak, S. E.; Chen, J. Y.; Sun, Y. G.; Lu, X. M.; Au, L.; Cobley, C. M.; Xia, Y. N. Acc. Chem. Res. 2008, 41, 1587–1595. Patra, C. R.; Bhattacharya, R.; Mukhopadhyay, D.; Mukherjee, P. Adv. Drug Delivery Rev. 2010, 62, 346–361. Beg, S.; Rizwan, M.; Sheikh, A. M.; Hasnain, M. S.; Anwer, K.; Kohli, K. J. Pharm. Pharmacol. 2011, 63, 141–163. 188 Ito et al.; Advances in Bioinspired and Biomedical Materials Volume 2 ACS Symposium Series; American Chemical Society: Washington, DC, 2017.


35. Lee, Y.; Geckeler, K. E. Adv. Mater. 2010, 22, 4076–4083. 36. Beg, S.; Rizwan, M.; Sheikh, A. M.; Hasnain, M. S.; Anwer, K.; Kohli, K. J. Pharm. Pharmacol. 2011, 63, 141–163. 37. Hudson, S. P.; Padera, R. F.; Langer, R.; Kohane, D. S. Biomaterials 2008, 29, 4045–4055. 38. Iijima, S. Nature 1991, 354, 56–58. 39. Iijima, S. Phys. B: Condens. Matter 2002, 323, 1–5. 40. Liu, Z; Tabakman, S; Welsher, K; Dai, H. Nano Res. 2009, 2, 85–120. 41. Saito, N.; Haniu, H.; Usui, Y.; Aoki, K.; Hara, K.; Takanashi, S.; Shimizu, M.; Narita, N.; Okamoto, M.; Kobayashi, S.; Nomura, H.; Kato, H.; Nishimura, N.; Taruta, S.; Endo, M. Chem. Rev. 2014, 114, 6040–6079. 42. Peretz, S.; Regev, O. Curr. Opin. Colloid Interface Sci. 2012, 17, 360–368. 43. Boncel, S.; Zajac, P.; Koziol, K. K. K. J. Controlled Release 2013, 169, 126–140. 44. Razzazan, A.; Atyabi, F.; Kazemi, B.; Dinarvand, R. Mater. Sci. Eng. C 2016, 62, 614–625. 45. Zhou, M. Y.; Liu, S. H.; Jiang, Y. Q.; Ma, H. R.; Shi, M.; Wang, Q. S.; Zhong, W.; Liao, W. J.; Xing, M. M. Q. Adv. Funct. Mater. 2015, 25, 4730–4739. 46. Kavosi, B.; Salimi, A.; Hallaj, R.; Amani, K. Biosens. Bioelectron. 2014, 52, 20–28. 47. Liu, J. J.; Wang, C.; Wang, X. J.; Wang, X.; Cheng, L.; Li, Y. G.; Liu, Z. Adv. Funct. Mater. 2015, 25, 384–392. 48. Liang, C.; Diao, S.; Wang, C.; Gong, H.; Liu, T.; Hong, G. S.; Shi, X. Z.; Dai, H. J.; Liu, Z. Adv. Mater. 2014, 26, 5646–5652. 49. Menna, F.; Abdelghani, A.; Menaa, B. J. Tissue Eng. Regen. Med. 2015, 9, 1321–1338. 50. Li, X. M.; Yang, Y.; Fan, Y. B.; Feng, Q. L.; Cui, F. Z.; Watari, F. J. Biomed. Mater. Res. A 2014, 102, 1580–1594. 51. Mehra, N. K.; Mishra, V.; Jain, N. K. Biomaterials 2014, 35, 1267–1283. 52. Kim, S. W.; Kim, T.; Kim, Y. S.; Choi, H. S.; Lim, H. J.; Yang, S. J.; Park, C. R. Carbon 2012, 50, 3–33. 53. Kumar, I.; Rana, S.; Rode, C. V.; Cho, J. W. J. Nanosci. Nanotechnol. 2008, 8, 3351–3356. 54. Georgakilas, V.; Kordatos, K.; Prato, M.; Guldi, D. M.; Holzinger, M.; Hirsch, A. J. Am. Chem. Soc. 2002, 124, 760–761. 55. You, Y. Z.; Hong, C. Y.; Pan, C. Y. Adv. Funct. Mater. 2007, 17, 2470–2477. 56. You, Y. Z.; Yan, J. J.; Yu, Z. Q.; Cui, M. M.; Hong, C. Y.; Qu, B. J. J. Mater. Chem. 2009, 19, 7656–7660. 57. Ghini, G.; Luconi, L.; Rossin, A.; Bianchini, C.; Giambastiani, G.; Cicchi, S.; Lascialfari, L.; Brandi, A.; Giannasi, A. Chem. Commun. 2010, 46, 252–254. 58. Lee, J. U.; Huh, J.; Kim, K. H.; Park, C.; Jo, W. H. Carbon 2007, 45, 1051–1057. 59. Karajanagi, S. S.; Yang, H.; Asuri, P.; Sellitto, E.; Dordick, J. S.; Kane, R. S. Langmuir 2006, 22, 1392–1395. 60. Wan, Q.; Tian, J. W.; Liu, M. Y.; Zeng, G. J.; Huang, Q.; Wang, K.; Zhang, Q. S.; Deng, F. J.; Zhang, X. Y.; Wei, Y. Appl. Surf. Sci. 2015, 346, 335–341. 189 Ito et al.; Advances in Bioinspired and Biomedical Materials Volume 2 ACS Symposium Series; American Chemical Society: Washington, DC, 2017.


61. Ding, Y.; Liu, J.; Jin, X.; Lu, H.; Shen, G.; Yu, R. Analyst 2008, 133, 184–190. 62. Kim, J. P.; Lee, B. Y.; Lee, J.; Hong, S.; Sim, S. J. Biosens. Bioelectron. 2009, 24, 3372–3378. 63. Lin, J.; He, C.; Zhang, L.; Zhang, S. Anal. Biochem. 2009, 384, 130–135. 64. Li, Q. F.; Tang, D. P.; Tang, J. A.; Su, B. L.; Huang, J. X.; Chen, G. N. Talanta 2011, 84, 538–546. 65. De la Zerda, A.; Zavaleta, C.; Keren, S.; Vaithilingam, S.; Bodapati, S.; Liu, Z.; Levi, J.; Smith, B. R.; Ma, T. J.; Oralkan, O.; Cheng, Z.; Chen, X.; Dai, H.; Khuri-Yakub, B. T.; Gambhir, S. S. Nat. Nanotechnol. 2008, 3, 557–562. 66. Kostarelos, K.; Lacerda, L.; Pastorin, G.; Wu, W.; Wiecklwshi, S.; Luangsivilay, J.; Godefroy, S.; Pantarotto, D.; Briand, J.; Muller, S.; Prato, M.; Bianco, A. Nat. Nanotechnol. 2007, 2, 108–113. 67. Saito, N.; Usui, Y.; Aoki, K.; Narita, N.; Shimizu, M.; Hara, K.; Ogiwara, N.; Nakamura, K.; Ishigaki, N.; Kato, K.; Taruta, S.; Endo, M. Chem. Soc. Rev. 2009, 38, 1897–1903. 68. McDevitt, M. R.; Chattopadhyay, D.; Kappel, B. J.; Jaggi, J. S.; Schiffman, S. R.; Antczak, C.; Njardarson, J. T.; Brentjens, R.; Scheinberg, D. A. J. Nucl. Med. 2007, 48, 1180. 69. Li, R. B.; Wu, R. A.; Zhao, L.; Hu, Z. Y.; Guo, S. J.; Pan, X. L.; Zou, H. F. Carbon 2011, 49, 1797–1805. 70. Zhou, F. F.; Wu, S. N.; Wu, B. Y.; Chen, W. R.; Xing, D. Small 2011, 7, 2727–2735. 71. Fisher, J. W.; Sarkar, S.; Buchanan, C. F.; Szot, C. S.; Whitney, J.; Hatcher, H. C.; Torti, S. V.; Rylander, C. G.; Rylander, M. N. Cancer Res. 2010, 70, 9855–9864. 72. Marches, R.; Mikoryak, C.; Wang, R. H.; Pantano, P.; Draper, R. K.; Vitetta, E. S. Nanotechnology 2011, 22, 095101. 73. Chen, D. Q.; Wang, C.; Nie, X.; Li, S. M.; Li, R. M.; Guan, M. R.; Liu, Z.; Chen, C. Y.; Wang, C. R.; Shu, C. Y.; Wan, L. J. Adv. Funct. Mater. 2014, 24, 6621–6628. 74. Herrero, M. A.; Toma, F. M.; Al-Jamal, K. T.; Kostarelos, K.; Biano, A.; Ros, T. D.; Bano, F.; Casalis, L.; Scoles, G.; Prato, M. J. Am. Chem. Soc. 2009, 131, 9843–9848. 75. Ahmed, M.; Jiang, X. Z.; Deng, Z. C.; Narain, R. Bioconjugate Chem. 2009, 20, 2017. 76. Wang, L.; Shi, J. J.; Zhang, H. L.; Li, H. X.; Gao, Y.; Wang, Z. Z.; Wang, H. H.; Li, L. L.; Zhang, C. F.; Chen, C. Q.; Zhang, Z. Z.; Zhang, Y. Biomaterials 2013, 34, 262–274. 77. Mei, F.; Zhong, J.; Yang, X.; Ouyang, X.; Zhang, S.; Hu, X.; Ma, Q.; Lu, J.; Ryu, S.; Deng, X. Biomacromolecules 2007, 8, 3729. 78. Han, Z.; Kong, H.; Meng, J.; Wang, C. Y.; Xie, S. S.; Xu, H. Y. J. Nanosci. Nanotechnol. 2009, 9, 1400–1402. 79. Meng, J.; Kong, H.; Han, Z. Z.; Wang, C. Y.; Zhu, G.; Xie, S. S.; Xu, H. Y. J. Biomed. Mater. Res., Part A 2009, 88, 105–116. 80. Zhang, R. J.; Metoki, N.; Sharabani-Yosef, O.; Zhu, H. W.; Eliaz, N. Adv. Funct. Mater. 2016, 26, 7965–7974. 190 Ito et al.; Advances in Bioinspired and Biomedical Materials Volume 2 ACS Symposium Series; American Chemical Society: Washington, DC, 2017.


81. Siqueira, I. A. W. B.; Corat, M. A. F.; Cavalcanti, B. das N.; Neto, W. A. R.; Martin, A. A.; Bretas, R. E. S.; Marciano, F. R.; Lobo, A. O. ACS Appl. Mater. Interfaces 2015, 7, 9385–9398. 82. Mikael, P. E.; Amini, A. R.; Basu, J.; Arellano-Jimenez, M. J.; Laurencin, C. T.; Sanders, M. M.; Carter, C. B.; Nukavarapu, S. P. Biomed. Mater. 2014, 9, 1–13. 83. Usui, Y.; Aoki, K.; Narita, N.; Murakami, N.; Nakamura, I.; Nakamura, K.; Ishigaki, N.; Yamazaki, H.; Horiuchi, H.; Kato, H.; Taruta, S.; Kim, Y. A.; Endo, M.; Saito, N. Small 2008, 4, 240–246. 84. Shimizu, M.; Kobayashi, Y.; Mizoguchi, T.; Nakamura, H.; Kawahara, I.; Narita, N.; Usui, Y.; Aoki, K.; Hara, K.; Haniu, H.; Ogihara, N.; Ishigaki, N.; Nakamura, K.; Kato, H.; Kawakubo, M.; Dohi, Y.; Taruta, S.; Kim, Y. A.; Endo, M.; Ozawa, H.; Udagawa, N.; Takahashi, N.; Saito, N. Adv. Mater. 2012, 24, 2176–2185. 85. Fraczek-Szczypta, A. Mater. Sci. Eng., C 2014, 34, 35–49. 86. Lu, Y.; Li, T.; Zhao, X.; Li, M.; Cao, Y.; Yang, H.; Duan, Y. Y. Biomaterials 2010, 31, 5169–5181. 87. Zhang, H. N.; Petel, P. R.; Xie, Z. X.; Swanson, S. D.; Wang, X. D.; Kotov, N. A. ACS Nano 2013, 7, 7619–7629. 88. Lima, M. D.; Li, N.; Jung de Andrade, M.; Fang, S.; Oh, J.; Spinks, G. M.; Kozlov, M. E.; Haines, C. S.; Suh, D.; Foroughi, J.; Kim, S. J.; Chen, Y.; Ware, T.; Shin, M. K.; Machado, L. D.; Fonseca, A. F.; Madden, J. D.; Voit, W. E.; Galvao, D. S.; Baughman, R. H. Science 2012, 338, 928–932. 89. Tao, Z. M. RSC Adv. 2014, 4, 18961–18980. 90. Titinchi, S. J. J.; Singh, M. P.; Abbo, H. S.; Green, I. R. Adv. Healthcare Mater. 2014, 49–86. 91. Huh, S.; Wiench, J. W.; Yoo, J. C.; Pruski, M.; Lin, V. S. Y. Chem. Mater. 2003, 15, 4247–4256. 92. Sun, J. T.; Hong, C. Y.; Pan, C. Y. J. Phys. Chem. C 2010, 114, 12481–12486. 93. Sun, J. T.; Yu, Z. Q.; Hong, C. Y.; Pan, C. Y. Macromol. Rapid Commun. 2012, 33, 811–818. 94. Sauer, A. M.; Schlossbauer, A.; Ruthardt, N.; Cauda, V.; Bein, T.; Brauchle, C. Nano Lett. 2010, 10, 3684–3691. 95. Cauda, V.; Argyo, C.; Schlossbauer, A.; Bein, T. J. Mater. Chem. 2010, 20, 4305–4311. 96. Meng, H.; Xue, M.; Xia, T.; Zhao, Y. L.; Tamanoi, F.; Stoddart, J. F.; Zink, J. I.; Nel, A. E. J. Am. Chem. Soc. 2010, 132, 12690–12697. 97. Lin, Q. N.; Huang, Q.; Li, C. Y.; Bao, C. Y.; Liu, Z. Z.; Li, F. Y.; Zhu, L. Y. J. Am. Chem. Soc. 2010, 132, 10645–10647. 98. Lai, C. Y.; Trewyn, B. G.; Jeftinija, D. M.; Jeftinija, K.; Xu, S.; Jeftinija, S.; Lin, V. S. Y. J. Am. Chem. Soc. 2003, 125, 4451–4459. 99. Torney, F.; Trewyn, B. G.; Lin, V. S. Y.; Wang, K. Nat. Nanotechnol. 2007, 2, 295–300. 100. Park, C.; Oh, K.; Lee, S. C.; Kim, C. Angew. Chem., Int. Ed. 2007, 46, 1455–1457. 101. Hernandez, R.; Tseng, H. R.; Wong, J. W.; Stoddart, J. F.; Zink, J. I. J. Am. Chem. Soc. 2004, 126, 3370–3371. 191 Ito et al.; Advances in Bioinspired and Biomedical Materials Volume 2 ACS Symposium Series; American Chemical Society: Washington, DC, 2017.


102. Mal, N. K.; Fujiwara, M.; Tanaka, Y. Nature 2003, 421, 350–353. 103. Sun, J. T.; Piao, J. G.; Wang, L. H.; Javed, M.; Hong, C. Y.; Pan, C. Y. Macromol. Rapid Commun. 2013, 34, 1387–1394. 104. Wu, S. S.; Huang, X.; Du, X. Z. Angew. Chem., Int. Ed. 2013, 52, 5580–5584. 105. Liu, J. J.; Zhang, B. L.; Luo, Z.; Ding, X. W.; Li, J. H.; Dai, L. L.; Zhou, J.; Zhao, X. J.; Ye, J. Y.; Cai, K. Y. Nanoscale 2015, 7, 3614–3626. 106. Croissant, J.; Zink, J. I. J. Am. Chem. Soc. 2012, 134, 7628–7631. 107. Mackowiak, S. A.; Schmidt, A.; Weiss, V.; Argyo, C.; Schirnding, C. V.; Bein, T.; Brauchle, C. Nano Lett. 2013, 13, 2576–2583. 108. Lin, Y. S.; Tsai, C. P.; Huang, H. Y.; Kuo, C. T.; Hung, Y.; Huang, D. M.; Chen, C. Y.; Mou, C. Y. Chem. Mater. 2005, 17, 4570–4573. 109. Lee, C. H.; Cheng, S. H.; Wang, Y. J.; Chen, Y. C.; Chen, N. T.; Souris, J.; Chen, C. T.; Mou, C. Y.; Ynag, C. S.; Lo, L. W. Adv. Funct. Mater. 2009, 19, 215–222. 110. Ma, K.; Sai, H.; Wiesner, U. J. Am. Chem. Soc. 2012, 134, 13180–13183. 111. Sreejith, S.; Ma, X.; Zhao, Y. L. J. Am. Chem. Soc. 2012, 134, 17346–17349. 112. Li, Z. H.; Dong, K.; Huang, S.; Ju, E.; Liu, Z.; Yin, M. L.; Ren, J. S.; Qu, X. G. Adv. Funct. Mater. 2014, 24, 3612–3620. 113. Jiao, Y. F.; Sun, Y. F.; Tang, X. L.; Ren, Q. G.; Yang, W. L. Small 2015, 11, 1962–1974. 114. Taylor, K. M. L.; Kim, J. S.; Rieter, W. J.; An, H. Y.; Lin, W. L.; Lin, W. B. J. Am. Chem. Soc. 2008, 130, 2154–2155. 115. Duncan, A. K.; Klemm, P. J.; Raymond, K. N.; Landry, C. C. J. Am. Chem. Soc. 2012, 134, 8046–8049. 116. Huang, W. Y.; Davies, G. L.; Davis, J. J. Chem. Commun. 2013, 49, 60–62. 117. Peng, Y. K.; Lai, C. W.; Liu, C. L.; Chen, H. C.; Hsiao, Y. H.; Liu, W. L.; Tang, K. C.; Chi, Y.; Hsiao, J. K.; Lim, K. E.; Liao, H. E.; Shyue, J. J.; Chou, P. T. ACS Nano 2011, 5, 4177–4187. 118. Chen, Y.; Yin, Q.; Ji, X. F.; Zhang, S. J.; Chen, H. R.; Zheng, Y. Y.; Sun, Y.; Qu, H. Y.; Wang, Z.; Li, Y. P.; Wang, X.; Zhang, K.; Zhang, L. L.; Shi, J. L. Biomaterials 2012, 33, 7126–7137. 119. Wang, G.; Pan, X. Y.; Gu, L. Q.; Ren, W.; Cheng, W. R.; Kumar, J. N.; Liu, Y. Nanotechnology 2014, 25, 375601–375606. 120. Popat, A.; Hartono, S. B.; Stahr, F.; Liu, J.; Qiao, S. Z.; Lu, G. Q. Nanoscale 2011, 3, 2801–2818. 121. Hudson, S.; Cooney, J.; Magner, E. Angew. Chem., Int. Ed. 2008, 47, 8582–8594. 122. Yu, F. Q.; Tang, X. D.; Pei, M. S. Microporous Mesoporous Mater. 2013, 173, 64–69. 123. Huang, X. L.; Teng, X.; Chen, D.; Tang, F. Q.; He, J. Q. Biomaterials 2010, 31, 438–448. 124. Zhou, J. M.; Zhang, W. J.; Hong, C. Y.; Pan, C. Y. ACS Appl. Mater. Interfaces 2015, 7, 3618–3625.


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