pH-responsive drug-delivery systems.

DOI: 10.1002/asia.201402715

Focus Review

Drug Delivery

pH-Responsive Drug-Delivery Systems Ying-Jie Zhu* and Feng Chen[a]

Chem. Asian J. 2014, 9, 1 – 23

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2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

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Focus Review Abstract: In many biomedical applications, drugs need to be delivered in response to the pH value in the body. In fact, it is desirable if the drugs can be administered in a controlled manner that precisely matches physiological needs at targeted sites and at predetermined release rates for predefined periods of time. Different organs, tissues, and cellular compartments have different pH values, which makes the pH value a suitable stimulus for controlled drug release. pH-Responsive drug-delivery systems have attracted more and more interest as “smart” drug-delivery systems for overcom-

ing the shortcomings of conventional drug formulations because they are able to deliver drugs in a controlled manner at a specific site and time, which results in high therapeutic efficacy. This focus review is not intended to offer a comprehensive review on the research devoted to pH-responsive drug-delivery systems; instead, it presents some recent progress obtained for pH-responsive drug-delivery systems and future perspectives. There are a large number of publications available on this topic, but only a selection of examples will be discussed.

1. Introduction

2. pH-Responsive Drug-delivery Systems 2.1. Organic-Materials-Based pH-Responsive Drug-Delivery Systems

The pH values in various segments of the gastrointestinal tract, different organs, tissues, and cellular compartments are different. For example, the pH values vary in a wide range from the stomach (pH 1.5–3.5) and small intestine (pH 5.5–6.8) to the colon (6.4–7.0).[1] The pH values in tumors and inflammatory tissues are lower than those in blood and normal tissues ( 7.4), and the acidic cellular environments exhibit even lower pH values (e.g., endosomes (pH 5.5–6.0) and lysosomes (pH ~ 4.5–5.0).[2] The difference in the pH value of different organs, tissues and cellular compartments may provide a suitable physiological stimulus for pH-responsive drug delivery. The strongly pH-dependent drug release profile of the drug-delivery system is an ideal platform for targeted drug delivery because the drug release is inhibited during systemic circulation at the physiological pH value of 7.4 and the drug is released only in the acidic environment of cancer cells. There have been many reports of organic-polymer-based pH-responsive drug-delivery systems in the literature; however, more and more papers have been published in recent years regarding inorganic, and in particular inorganic/organic composite, pH-responsive drug-delivery systems owing to their advantages in terms of biocompatibility, thermal stability, variety, and control of morphology, size, and structure. Herein, we divide the discussion into four sections according to the type of drug carrier: 1) organic-materials-based pH-responsive drugdelivery systems; 2) inorganic-nanostructured-materials-based pH-responsive drug-delivery systems; 3) inorganic/inorganicnanocomposites-based pH-responsive drug-delivery systems; 4) inorganic/organic-composite pH-responsive drug-delivery systems. Finally, we will present some future perspectives in this rapidly developing research field.

There are a large number of papers published regarding pH-responsive drug-delivery systems that use various organic materials as drug carriers. In 2006, Schmaljohann[3] reviewed the research progress in stimuli-responsive (including pH-responsive) polymers in drug delivery, discussed how polymers can be used in a smart fashion that potentially led to multiple responses at the desired site of action, and described the physical basis behind these effects. A selection of examples in drug delivery was given and a brief outlook of future aspects was provided. Balamuralidhara et al.[1] published a review article on pH-sensitive drug-delivery systems and discussed several pHsensitive drug-delivery systems, including pH-sensitive hydrogels and pH-sensitive liposomes. One important strategy for realizing pH-responsive drug delivery is the formation of pH-sensitive linkages between the drug molecules and the drug carrier, such as the hydrazone linkage that exhibits excellent pH sensitivity. Another strategy is to use polymers that contain weakly acidic or basic groups in the polymer backbone; variation in the pH value of the solution will cause swelling or deswelling of the polymer and in this way the drug release from these polymers will exhibit release rates that are pH-sensitive.[1] Hydrogels are an important kind of material with many applications in various biomedical fields. Gupta et al.[4] reviewed the applications of hydrogels in stimuli-responsive and, in particular, pH-responsive drug delivery. Compared with other synthetic biomaterials, the physical properties of hydrogels resemble living tissues closely because of their relatively high water content and soft and rubbery consistency. Hydrogels show little tendency to adsorb proteins from body fluids because of their low interfacial tension. More importantly, the ability of drug molecules with different sizes to diffuse into and out of hydrogels allows the possible use of dry or swollen polymeric networks as drug-delivery systems. Hydrogels can perceive and respond the stimuli by changing their physical or chemical behavior, which results in the controlled release of loaded drugs. Readers are recommended to refer to reference [4] for more detailed information on the applications of hydrogels in drug delivery. Berger et al.[5] published a review article to present

[a] Prof. Dr. Y.-J. Zhu, F. Chen State Key Laboratory of High Performance Ceramics and Superfine Microstructure Shanghai Institute of Ceramics Chinese Academy of Sciences Shanghai 200050 (P. R. China) Fax: (+ 86) 21-52413122 E-mail: [email protected]

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Focus Review region compared with day 0, whereas saline/bFGF or polymeronly had no effect. By responding to local changes in pH and temperature in an animal model of ischemia, this hydrogel system provided sustained local delivery of bFGF, improved angiogenesis, and therapeutic effects in regional blood flow and cardiac function. A new type of redox/pH dual-stimuli-responsive poly(methacrylic acid)-based hydrogels was reported.[10] The hydrogels could be degraded into individual linear short chains in the presence of 10 mm dithiothreitol (DTT) or glutathione (GSH). Doxorubicin (DOX; a model anticancer drug) was very efficiently loaded into the hydrogels (up to 42.3 wt %) due to the strong electrostatic interactions between the amine group in DOX and the carboxyl groups in the hydrogel at physiological pH. The cumulative release profile of the DOX-loaded hydrogel showed a low level of drug release (less than 15 wt % in 24 h) at pH 7.4 and was significantly accelerated at a lower pH (5.0) and reducing environment (over 91 wt % in 5 h), exhibiting an obvious pH/redox dual-stimulus-responsive controlled drug release capability. The drug release was very different in the presence of GSH and DTT and at different pH values; the loaded DOX could be quickly released in the presence of GSH, but not with DTT. The DOX-loaded hydrogels could be taken up quickly by human glioma through endocytosis and then bi-

a critical analysis of covalently and ionically crosslinked chitosan hydrogels for medical and pharmaceutical applications. Covalent crosslinking leads to the formation of hydrogels with a permanent network structure, and this type of linkage allows absorption of water and/or bioactive compounds without dissolution and permits drug release by diffusion. Ionically crosslinked hydrogels are generally considered to be biocompatible and well tolerated with a non-permanent network, and ionically crosslinked chitosan hydrogels exhibit a higher swelling sensitivity to pH changes compared with covalently crosslinked chitosan hydrogels. Vashist et al.[6] highlighted the diverse applications of hydrogels in revolutionizing the research on drugdelivery systems and summarized the role of hydrogels as drug-delivery vehicles used in various disorders related to the brain and other distinct parts of the human body; the clinical applications and toxicological aspects of hydrogels were also discussed. In addition, the limitations and future perspectives in the development of biopolymeric hydrogels were discussed. Some selected hydrogel examples are given below to demonstrate their applications in pH-responsive drug delivery. Basak et al.[7] prepared hydrogels of poly(vinyl alcohol) by crosslinking with maleic acid; they found that the swelling of the hydrogels was highest in intestinal fluid (pH 7.5) and lowest in simulated gastric fluid (pH 1.2); hydrogels loaded with vitamin B12 and salicylic acid exhibited colon-specific drug release behavior with a higher drug release in intestinal fluid (pH 7.5) than that in simulated gastric fluid (pH 1.2). Bastings et al.[8] reported a pH-switchable supramolecular hydrogel by using fourfold hydrogen-bonding supramolecular ureidopyrimidinone (UPy) units coupled with alkyl urea spacers to poly(ethylene glycol) (PEG) chains. These UPy-modified PEG hydrogels formed fibers in aqueous solution that could cross-link to form transient supramolecular networks, and these unique UPy-transient networks were pH-responsive, which enabled a sol-to-gel switch in a subtle pH range. The hydrogel could be switched into a liquid at pH > 8.5, with a viscosity low enough to enable passage through a 1 m long catheter, whereas it rapidly forms a hydrogel in contact with the tissue. The hydrogel exhibited self-healing properties, which countered adjustments to the injection site. Growth factors were delivered from the hydrogel and showed a reduction in infarct scar in a pig myocardial infarction model. The catheter-injected hydrogel solution transformed into a locally controlled drug release reservoir by immediate gelation upon contact with the heart tissue. Garbern et al.[9] prepared a pH- and temperature-responsive, injectable hydrogel to take advantage of the acidic microenvironment of ischemic myocardium, and this system could improve therapeutic angiogenesis by providing spatiotemporal control of angiogenic growth factor delivery. The pH- and temperature-responsive random copolymer poly(N-isopropylacrylamide-co-propylacrylic acid-co-butyl acrylate) was a liquid at pH 7.4 and 37 8C but formed a physical gel at pH 6.8 and 37 8C. Retention of biotinylated basic fibroblast growth factor (bFGF) between 0 and 7 d after injection into infarcted rat myocardium was tenfold higher with hydrogel delivery versus saline. Treatment with bFGF-loaded polymer for 28 d resulted in a twofold improvement in relative blood flow to the infarct Chem. Asian J. 2014, 9, 1 – 23

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Feng Chen was born in 1981 in Anhui, China. He received his B.S. in Biology from Anhui Normal University in 2005, and received his M.S. in Chemistry under the supervision of Prof. Xiu-Mei Mo from Donghua University in 2008. He then joined the research group of Professor Ying-Jie Zhu at Shanghai Institute of Ceramics, Chinese Academy of Sciences. His current research interest focuses on the microwaveassisted synthesis, properties and applications of nanostructured materials.

Ying-Jie Zhu is a full Professor at Shanghai Institute of Ceramics, Chinese Academy of Sciences (CAS). He received his Master degree and Ph. D. at the University of Science and Technology of China (USTC) in 1992 and 1994, respectively; he worked as Assistant Professor and Associate Professor at USTC from 1994 to 1997. Then, he worked as a Visiting Professor at University of Western Ontario, Canada from 1997 to 1998. He worked as Alexander von Humboldt Research Fellow at Fritz-Haber Institut der Max-Planck-Gesellschaft, Germany from 1998 to 1999. Then, he worked as a Postdoctoral Fellow at University of Utah and University of Delaware, USA from 1999 to 2002. In 2002, he was selected by the Chinese Academy of Sciences under the Program for Recruiting Overseas Outstanding Talents (Hundred Talents Program), and started to work as a full Professor and a group leader at Shanghai Institute of Ceramics, CAS. He has published more than 240 peer-reviewed journal papers, and has more than 20 granted patents. His current main research interests involve nanostructured biomaterials and microwave-assisted preparation of nanostructured materials.

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Focus Review odegraded to release the loaded drug, which led to a good antitumor efficacy.[10] Kozlovskaya et al.[11] reported on a novel type of hydrogel microparticle that underwent large, rapid, and reversible volume changes in response to the pH value. They prepared cubic hydrogels as interconnected poly(methacrylic acid) network replicas of mesoporous manganese oxide templates by sequential infiltration of poly(methacrylic acid) and poly(N-vinylpyrrolidone), followed by crosslinking of poly(methacrylic acid) and template dissolution. These hydrogel cubes exhibited a reversible twofold change in size, while maintaining their shape in response to pH variations. The swelling behavior of cubic and spherical hydrogel particles could be adjusted by changing the poly(methacrylic acid) molecular weight. They also showed pH-triggered loading and release of the drug DOX to and from cubic hydrogels. The pH-triggered DOX release from cubic hydrogels was observed to start at pH 5 and reach complete disappearance of DOX from the cubes at pH 3. As a result of DOX release, the network size increased due to the breakage of electrostatic interaction between poly(methacrylic acid) hydrogel and DOX. After exposure of DOX-loaded cubes to pH values of 7.4 and 5 for 24 h, the drug release was only (4.4 0.1) % and (7.2 0.1) %, respectively. In contrast, (80 1) % of the loaded DOX was released from the cubes within 1 h on exposure to pH 3. These results demonstrate that DOX can be released from poly(methacrylic acid) cubic hydrogel particles in an acidic endosomal/lyzosomal environment following the uptake of the particles by the cells. The viability of A549 and HeLa cancer cells was significantly decreased upon interaction with DOX-loaded cubic hydrogels.[11] Anirudhan et al.[12] prepared a gelatin-based pH-responsive composite hydrogel by grafting b-cyclodextrin (b-CD) to gelatin (Gel) and crosslinking with oxidized dextran (OX-Dex), and the as-prepared pH-sensitive b-CD-grafted Gel crosslinked with OX-Dex (b-CD-g-Gel/OX-Dex) or composite hydrogel (CHG) was used to investigate the colon delivery of the anticancer drug 5-fluorouracil (5-FLU). They found that the grafting of b-CD enhanced the drug encapsulation capacity and that the drug release profile followed the Higuchi model. Degradation and swelling of the hydrogel were found to contribute to the drug release. Release profiles of 5-FLU were studied both at gastric pH 1.2 and intestinal pH 7.4, and the results showed that the drug release was very low at pH 1.2 and high at pH 7.4. The drug-loaded b-CD-g-Gel/OX-Dex (CHG) showed enhanced colon cancer cell inhibition compared with the free drug. Gao et al.[13] prepared biodegradable and pH-responsive carboxymethyl cellulose/poly(acrylic acid) hybrid hydrogels, which deswelled in acidic artificial gastric fluid but rapidly swelled in neutral artificial intestinal fluid, and exhibited selective enzymatic degradation of the gels and accelerated drug release from insulin-loaded hydrogels in artificial intestinal fluid. Oral administration of insulin-loaded hydrogels to streptozotocin-induced diabetic rats led to a continuous decline in the fasting blood glucose level within 6 h post-administration, and the relative pharmacological availability increased more than 10 times compared with oral administration of a solution of free insulin. Chen et al.[14] reported a drug-delivery microdevice that &

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integrated pH-responsive hydrogel nanoparticles that acted as intelligent valves; they prepared pH-responsive hydrogel nanoparticles that were embedded into a composite membrane and the resulting pH-responsive composite membranes were integrated with polydimethylsiloxane microreservoirs through a room-temperature transfer bonding technique to form the proof-of-concept microdevice. They found that the release rate of vitamin B12 as a model drug increased dramatically when the local pH value was decreased from 7.4 to 4. Block copolymers are potential organic drug carriers for pHresponsive drug delivery. Bae et al.[15] reviewed their recent research efforts on the design and preparation of intelligent polymeric micelles from poly(ethylene glycol)-poly(amino acid) block copolymer with a spherical core-shell structure loaded with the anticancer drug. The poly(ethylene glycol)–poly(amino acid) with a hydrazone linkage allows the polymeric micelles to release the drug selectively at acidic pH values (pH 4–6). The attachment of folic acid on the micelle surface could enhance cancer-cell-specific drug-delivery efficiency along with pH-controlled drug release. They pointed out that the Schiff base, or azomethine, is considered the most facile and appropriate linkage to design pH-sensitive drug release systems, and the imine bond is stable at pH 7.4 but cleavable at pH values below 6, but it is reversible even at pH 7.4. In contrast, the hydrazone bond exhibits excellent pH sensitivity and is more stable than the imine bond, and the hydrolysis rate of the hydrazone linkage can be adjusted depending on the environment, which thus leads o the controlled drug release. Bae et al.[16] reported a pH-sensitive polymeric micelle drug carrier prepared from self-assembly of an amphiphilic block copolymer, poly(ethylene glycol)-poly(aspartate hydrazone adriamycin), in which the anticancer drug, adriamycin, was conjugated to the hydrophobic segments through acid-sensitive hydrazone linkers; this drug-delivery system could preserve the drug under physiological conditions (pH 7.4) and selectively release the drug by sensing the intracellular pH decrease in endosomes and lysosomes. Wang et al.[17] reported a poly(amino acid)-based amphiphilic copolymer drug-delivery system that exhibited a pH-dependent drug release profile in vitro; they found that the cumulative release of DOX was much faster at pH 5.0 than that at pH 7.4, and the DOX-loaded drug-delivery system had higher antitumor activity compared with that of free DOX. Liu et al.[18] prepared poly(d,l-lactide)-block-poly(2methacryloyloxyethyl phosphorylcholine) block copolymer and investigated the anticancer drug loading and release by using DOX and doxorubicin hydrochloride (DOX·HCl), and they found that the release of DOX and DOX·HCl from the block copolymer was highly pH-dependent, that is, the drug release was significantly faster at mildly acidic pH 5.0 compared with that at physiological pH 7.4. Furthermore, the DOX·HCl-loaded block copolymer exhibited faster drug release than the DOXloaded block copolymer under the same pH conditions. The as-prepared block copolymer drug-delivery system could enter HepG2 cells, localize in the endosomes/lysosomes with an acidic pH environment and display enhanced intracellular drug release into the cytosol.

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Focus Review Oh et al.[19] reported pH-responsive flower-like block copolymer micelles as the drug carrier for pH-triggered drug release. The micelles, with particle sizes of 165 nm, were constructed from poly(Ne-(3-diethylamino)propyl isothiocyanato-l-lysine)-bpoly(ethylene glycol)-b-poly(l-lactide). As the pH value was decreased to slightly acidic levels (< 7.0), the hydrophobicity of the micellar core of the flower-like polymeric micelles changed. The protonation of poly(Ne-(3-diethylamino)propyl isothiocyanato-l-lysine) changed the physical property of the polymer from hydrophobic to hydrophilic, which resulted in disintegration of the micellar core. The co-presence of the pH-insensitive poly(l-lactide) block in the micellar core affected the protonation of poly(Ne-(3-diethylamino)propyl isothiocyanato-l-lysine), which allowed the micelle to be stable at pH 7.0–7.4. The release of DOX from the micelles was accelerated in response to the tumor pH value. Figure 1 shows the pH-dependent cumulative DOX release from poly(Ne-(3-diethylamino)propyl isothiocyanato-l-lysine) (10K)-b-poly(ethylene glycol) (2K)-b-poly(l-lactide) (1K) micelles and poly(ethylene glycol) (2K)-b-poly(l-lactide) (1K) micelles (as a control) over a release time of 24 h.[19] Both DOX-loaded micelles exhibited approximately 35 % drug release at pH 7.4. The DOX release from pH-sensitive poly(Ne(3-diethylamino)propyl isothiocyanato-l-lysine)-b-poly(ethylene

glycol))-b-poly(l-lactide) micelles gradually increased when the pH was decreased, and 90 % of the drug was released at pH 6.0. However, the release rate of DOX from pH-insensitive poly(ethylene glycol)-b-poly(l-lactide) micelles did not change obviously at any pH value. The kinetic profiles of DOX release from poly(Ne-(3-diethylamino)propyl isothiocyanato-l-lysine)-bpoly(ethylene glycol))-b-poly(l-lactide) micelles indicated that the differences in DOX release in regard to the pH value were remarkable (Figure 1b); 20–30 wt % DOX release from the micelles was observed at all pH values for 1 h; however, the drug release from the micelles increased to 35 % for 24 h at pH 7.4, and the DOX release was accelerated at pH values lower than 7.0 within 4 h, and reached approximately 80 % of the plateau in 24 h. It is interesting that these micelles responded to small pH differences between 7.0 and 6.8, which indicated that the micelles constructed from poly(Ne-(3-diethylamino)propyl isothiocyanato-l-lysine)-b-poly(ethylene glycol))-b-poly(l-lactide) were more sensitive to a small change in the tumor pH value compared with physiological pH.[19] Oh et al.[20] reported surface-charge-switched polymeric micelles ( 85 nm) with a pH signal as the drug carrier for tumor targeting; the micelles were constructed from poly(l-lactic acid)-b-poly(ethylene glycol)-b-poly(l-lysine-Ne-(2,3-dimethyl maleic acid)), formed by self-assembly in an aqueous solution at pH 7.4, and consisted of a hydrophobic core (poly(l-lactic acid) and two hydrophilic shells (poly(ethylene glycol) and poly(l-lysine-Ne-(2,3-dimethyl maleic acid)). An anionic charge could be built on the surface of the micelle at physiological pH 7.4 due to 2,3-dimethyl maleic acid. However, 2,3-dimethyl maleic acid was chemically dissociated from the micelle under mild acidic conditions (pH 6.5–7.0), which led to the formation of a cationic surface due to the poly(l-lysine). The pH-triggered switch of the surface charge may enhance cellular uptake of micelles to solid tumors through an adsorptive endocytosis pathway due to the electrostatic interaction between micelles and cells. Chitosan can also be used as a pH-responsive drug carrier. Chitosan is a polysaccharide derived from the partial deacetylation of chitin, primarily from crustacean and insect shells, and it consists of repeating units of glucosamine and N-acetyl-glucosamine. Chitosan is insoluble at neutral pH but is soluble and positively charged at acidic pH values in aqueous solution. Chitosan is promising as a drug carrier due to its intrinsic features, such as biodegradability, biocompatibility, nontoxicity, and antibacterial properties.[21] Vivek et al.[21] reported a pH-responsive drug-delivery system based on chitosan nanoparticles for the controlled release and enhanced chemotherapeutic efficiency of tamoxifen. Tamoxifen was loaded onto chitosan nanoparticles by forming complexes, and was released from the drug-delivery system much more rapidly at pH 4.0 and 6.0 than at pH 7.4, which is a desirable characteristic for tumor-targeted drug delivery. Fan et al.[22] used micellar nanoparticles self-assembled from folate–chitosan as the carrier to co-deliver pyrrolidine dithiocarbamate and DOX for targeted delivery with a pH-responsive drug release. The DOX release at neutral or alkalescent pH values was slow; however, it was much faster in the weakly acidic environment, with approximately 75 to 95 % of the loaded drug released within the first 2 h. DOX re-

Figure 1. a) pH-dependent DOX release from poly(Ne-(3-diethylamino)propyl isothiocyanato-l-lysine) (10K)-b-poly(ethylene glycol) (2K)-b-poly(l-lactide) (1K) micelles (*) and poly(ethylene glycol) (2K)-b-poly(l-lactide) (1K) micelles (~; n = 3) after 24 h. b) Time-dependent DOX release from poly(Ne-(3-diethylamino)propyl isothiocyanato-l-lysine) (10K)-b-poly(ethylene glycol) (2K)-bpoly(l-lactide) (1K) micelles at each pH value after incubation for 1 (*), 2 (&), 4 (~), 6 ( ! ), and 24 h (^) (n = 3). Reprinted from reference [19]. Copyright 2009 Elsevier B.V. Chem. Asian J. 2014, 9, 1 – 23

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Focus Review leased from folate–chitosan micelles was pH-sensitive, which led to intracellular targeting, and folate–chitosan micelles greatly enhanced the cellular uptake efficiency. Cui et al.[23] prepared pH-responsive polymer-drug conjugates in mussel-inspired polydopamine capsules for intracellular drug delivery. They conjugated anticancer drug DOX to thiolated poly(methacrylic acid) with the pH-cleavable hydrazone bond and then immobilized it in polydopamine capsules by using robust thiol–catechol reactions between the polymer–drug conjugate and the capsule walls. They found that the loaded DOX showed limited release at physiological pH but significant release (over 85 %) at endosomal/lysosomal pH. The DOX-loaded polydopamine capsules showed enhanced anticancer efficacy for HeLa cancer cells compared with free drug under the same assay conditions. Yang et al.[24] reported pH-dependent gradient-release drug-delivery systems for poorly water-soluble nitrendipine with a solid dispersed matrix structure. The drug-delivery systems involved three types of pH-dependent microspheres, which were fabricated by using acrylic resins Eudragit E-100 (EuE-100), hydroxypropylmethylcellulose phthalate (HP-55), and hydroxypropylmethylcellulose acetate succinate (ASH). They found that the drug release rate from the drug-delivery systems increased with an increasing amount of pH-dependent polymers. In these drug-delivery systems, the drug was incorporated in pH-dependent polymers and was present in a solid dispersion state in the microspheres, and the release rate of the drug from the microspheres was dependent on the dissolution rate of the polymers, which was mainly influenced by the pH value of the drug-release medium. The drug-release behavior of the system under simulated gastrointestinal tract conditions exhibited obvious gradient-release characteristics, which showed that the release rate of the drug could be controlled efficiently before the microspheres reached the appropriate region of the gut. A folate–bovine serum albumin (BSA)-cis-aconitic anhydride– doxorubicin (FA-BSA-CAD) prodrug was reported by Du et al.[25] A tumor-targeting agent, folic acid, was linked to BSA to increase the selective targeting ability of the conjugate; BSA provided a large number of reactive sites for drug molecules and improved the water solubility of the prodrug; DOX was attached to the BSA by a pH-sensitive linker, cis-aconitic anhydride, which could hydrolyze in the acidic lysosomal environment to allow pH-responsive release of DOX. This drug-delivery system exhibited a pH-responsive drug-release behavior under different pH conditions. The prodrug could selectively target tumor cells and tissues and the therapeutic efficacy of the prodrug for folate-positive tumors increased compared with the non-conjugated DOX, as shown in Figure 2. The in vivo antitumor activity was evaluated in the nude mice model of heterotopic implanted tumor by using a human hepatocellular carcinoma cell line (BEL-7402). The changes in tumor volume and body weight are shown in Figure 2. Figure 2A shows that both free DOX and FA-BSA-CAD had an efficient inhibitory effect on the tumor, and the inhibition ratio of the FA-BSA-CAD group was 77 %, which is higher than that of the free DOX group (66 %). Figure 2B shows the body weight changes of animals treated with NaCl, free DOX, and FA-BSA-CAD. The decrease in &

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Figure 2. In vivo antitumor activity of FA-BSA-CAD, free DOX, and NaCl (n = 6). A) Tumor volumes of BEL-7402-bearing mice as a function of time. B) Animal weights of BEL-7402-bearing mice as a function of time. Reprinted from reference [25]. Copyright 2013 Elsevier Ltd.

the body weight in the group treated with free DOX was up to 28.6 % of the original weight, which indicated the severe side effects of free DOX on normal tissues. In contrast, the body weight loss of the FA-BSA-CAD group was only 9.5 % of the original weight, which is much lower than that of the NaCl group (24.5 % of original weight) or the free DOX group (28.6 % of the original weight). These results indicate that folic acid and BSA can effectively reduce the side effects and toxicity induced by free DOX.[25] Chen et al.[26] reported a multifunctional nanocomposite drug-delivery system capable of selective targeting, in situ imaging, and anticancer therapy. The nanocomposite consisted of luminescent Au nanoparticle diagnostic probes conjugated to a folic acid-modified pH-responsive amphiphilic polymer in a core-satellite structure, which encapsulated the hydrophobic drug and released it in mildly acidic endosomal/lysosomal compartments by the action of the pH-labile linkage in the polymer. The Au nanoparticles provided positioning information and the hydrophobic drug provided the therapeutic action at the targeted cells. The rate of hydrolysis and consequently the rate of drug release from the nanocomposite were strongly pH-dependent; the hydrolysis of the polymeric nanocarrier over a 12 h period was negligible at physiological pH 7.4, which indicates that the nanocomposite was stable in the physiological environment. However, fast hydrolysis occurred at pH 5.0, which resulted in the decomposition of approximately 90 % of the nanocomposite in 12 h. Consequently, the release of paclitaxel was negligible over 24 h at pH 7.4. However, most of the drug was released within 12 h at pH 5.0, and 95 % of the drug was released in 24 h. In vivo studies demonstrated the selective accumulation of the folic acid-con6



Focus Review mediated targeted complexes facilitated the in vivo accumulation of Cy5.5-siRNA within tumors. Second, the distribution of the PEI/3-maleimidopropionic acid hydrazide/PPF/Cy5.5-siRNA complexes was studied at different time points after intravenous injection in the tumor-bearing mice. Following systemic injection through the tail vein, there was obvious intratumoral accumulation of Cy5.5-siRNA after 1 h, which peaked after 6 h (Figure 3B). The extracted tumor tissues showed strong fluorescence after 24 h (Figure 3C), whereas the hearts, lungs, spleens, and livers showed only background-to-moderate signals, due to nonspecific electrostatic interactions between complexes and negatively charged plasma membranes of capillary endothelial cells. Of the isolated organs, the renal fluorescence intensity at 24 h after a single injection was higher than other organs (Figure 3C).[27] Other examples of organic-materials-based pH-responsive drug-delivery systems have also been reported, including poly(b-l-malic acid),[28] poly(ethyleneimine)-poly(ethylene [29] P(2-(methacryloyloxy)-ethyl phosphorylcholine)-bglycol), P(2-methoxy-2-oxoethyl methacrylate),[30] linear dendritic block copolymers composed of polyamidoamine dendrimer and poly(ethylene glycol) with or without galactose,[31] amphiphilic diblock copolymer that consists of a hydrophilic poly(ethylene glycol) block and a hydrophobic polymethacrylate block with acid-labile ortho ester sidechains,[32] block ionomer complexes of poly(ethylene glycol)-block-poly(4-vinylbenzylphosphonate) and cationic surfactants,[33] poly(ethylene glycol)-b-poly(l-histidine)-b-poly(l-lactic acid)-b-poly(ethylene glycol),[34] carboxymethyl dextran-coated liposomes,[35] chitosan oligosaccharide/ arachidic acid-based nanoparticles,[36] chitosan salts coated with stearic acid,[37] amphiphilic carboxymethyl-hexanoyl chitosan/poly(acrylic acid) hybrid macromolecules,[38] comb-like amphiphilic copolymers with an acetal-functionalized backbone based on poly[(2,4,6-trimethoxybenzylidene-1,1,1-tris(hydroxymethyl) ethane methacrylateco-poly(ethylene glycol) methyl ether methacrylate],[39] PEGylation of aliphatic dendritic polyester by forming acetal linkages,[40] mixed micelles of poly[(d,l-lactide)-co-glycolide)]poly(ethylene glycol)-folate and poly(b-amino ester)-poly(ethylene glycol)-folate,[41] unimolecular micelles formed by dendritic amphiphilic block copolymers poly(amidoamine)-poly(l-lactide)-b-poly(ethylene glycol) conjugated with anti-CD105 monoclonal antibody (TRC105) Figure 3. Targeted accumulation of siRNA in xenograft tumors (right axilla) after intravenous administration of the complexes. A) The targeted accumulation of Cy5.5-siRNA complexes in the tumor by fluorescence quantification and 1,4,7-triazacyclononaneof extracted tumor tissues of mice 7 h post-injection. B) Distribution of PHD/PPF/Cy5.5-siRNA complexes in mice N,N’,N-triacetic acid (NOTA, as detected by using a whole-animal imaging system. C) Representative images from extracted tumor tissues and a macrocyclic chelator for organs of mice at 24 h after the intravenous injection of PHD/PPF/Cy5.5-siRNA complexes. The control was saline. 64 Cu),[42] composite microparticle Reprinted from reference [27]. Copyright 2013 Elsevier Ltd. jugated nanocomposite in tumor tissues by folate-receptormediated endocytosis. Dong et al.[27] reported multifunctional PHD/PPF/siRNA complexes by using a one-step assembly of prefunctionalized polymers PEI-HZ-DOX (PHD) and PEI-PEG-folate (PPF) with siRNA. PHD was a conjugate of PEI (polyethylenimine) with DOX by a pH-responsive hydrazone linkage with the ability of pH-controlled drug release. PPF was a tumor-targeting folate ligand conjugated to PEI by using poly(ethylene glycol) (PEG) as a linker, which enabled immune evasion and cell-specific targeting. The complexes were capable of delivering siRNA and DOX to cancer cells and synchronous release in the cells in an acid-triggered manner, that is, hydrazone-bond cleavage and endosome/lysosome escape. The PHD/PPF/siRNA complexes increased DOX and siRNA accumulation in cancer cells and decreased the nonspecific distribution in normal tissues. They used a near-infrared dye (Cy5.5)-labeled siRNA to investigate the in vivo distribution of siRNA formulated in complexes. First, mice were administrated saline, free Cy5.5-siRNA, PEI/3-maleimidopropionic acid hydrazide/Cy5.5-siRNA, or PEI/3-maleimidopropionic acid hydrazide/PPF/Cy5.5-siRNA by tail vein injection. The targeting accumulation of siRNA complexes in the tumor was detected by fluorescence quantification of extracted tumor tissues 7 h post-injection. As shown in Figure 3A, the fluorescence intensity in the tumors was 2.4-fold higher in mice treated with PEI/3-maleimidopropionic acid hydrazide/ PPF/Cy5.5-siRNA compared with mice treated with free Cy5.5siRNA and 1.7-fold higher compared with mice treated with PEI/3-maleimidopropionic acid hydrazide/Cy5.5-siRNA. In comparison, the mice injected with saline did not show visible fluorescence in the tumor. These results indicate that the folate-

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Focus Review drug-delivery systems based on chitosan, alginate, and pectin,[43] dendronized heparin,[44] polypeptide-based block ionomer complex formed by anionic methoxy poly(ethylene glycol)-b-poly(l-glutamic acid),[45] polyphosphazene backbone with poly(ethylene glycol) branches and pH-sensitive N,N-diisopropylethylenediamine,[46] mixed polymeric micelles based on three grafted copolymers (poly(ethylene glycol)-1,2-distearoylsn-glycero-3-phosphoethanolamine, poly(histidine), and poly(ethylene glycol)),[47] poly(ethylene glycol)-poly(e-caprolactone)/ folic acid/DOX,[48] and poly(d,l-lactide-co-glycolide)/poly(ethylenimine).[49] In summary, various polymeric materials have been investigated for applications in pH-responsive drug delivery. Although significant progress has been made in past decades, there are still some issues and challenges that are to be solved. The intellectualized polymeric materials can realize pHresponsive drug delivery through the breaking of pH-sensitive linkages, degradation, and structural transformation of the polymers. Therefore, close attention should be paid to investigating the interactions between various polymeric drug carriers and drug molecules and to enhancing the drug loading capacity and stability of the carriers. However, the biological properties of the polymer carriers should be considered in the design and preparation of pH-responsive drug-delivery systems to achieve high biocompatibility and to avoid the toxicity of drug carriers. It is desirable to evaluate and improve the distribution and biodegradability of polymer-based pH-responsive drug-delivery systems in vivo. The ideal polymeric drug carriers should maintain good stability and high biocompatibility, effectively enter into the pathologically changed tissues through circulation around the body, and deliver drugs before being discharged out of the body by the degradation and metabolic pathways. In addition, to achieve multifunctional properties of the polymer-based pH-responsive drug-delivery systems is an important future research direction in the field. Much effort should be devoted to achieving these goals.

search be conducted on calcium phosphate- and calcium silicate-based nanostructured materials as pH-responsive drug carriers in the future. Gu et al.[50] reported a drug-delivery system based on singlewalled carbon nanotubes loaded with DOX by using a hydrazone bond. The single-walled carbon nanotubes were first stabilized with polyoxyethylene bis(amine), and then hydrazinobenzoic acid was covalently attached to the carbon nanotubes by using carbodiimide-activated coupling to form hydrazinemodified carbon nanotubes. DOX was conjugated to the hydrazinobenzoic acid segment of carbon nanotubes by using hydrazine as the linker. The resulting hydrazone bonds formed between the DOX molecules and the hydrazinobenzoic acid segment of the carbon nanotubes were acid cleavable, which thereby allowed pH-responsive drug release. The DOX-loaded carbon nanotubes could be efficiently taken up by HepG2 tumor cells and release DOX intracellularly. Compared with the DOX-loaded carbon nanotubes, the carbon nanotubes/hydrazinobenzoic acid/DOX drug-delivery system had higher DOX loading and prolonged DOX release. Zhu et al.[51] reported mesoporous carbon nanospheres ( 90 nm) as a drug carrier for pH-dependent DOX release. By effective passive and active targeting, mesoporous carbon nanospheres could be internalized into HeLa cells, in which the carried DOX could be efficiently released in the acidic microenvironment of the tumors. Aryal et al.[52] prepared DOX-conjugated Au nanoparticles that exhibited a pH-responsive drug release profile. Au nanoparticles were stabilized by thiolated methoxy poly(ethylene glycol) and methyl thioglycolate in equal molar ratio, and the anticancer drug DOX was conjugated to the methyl thioglycolate segments of the thiol-stabilized Au nanoparticles by using hydrazine as the linker. The resulting hydrazone bonds formed between the DOX molecules and the methyl thioglycolate segments of thiol-stabilized Au nanoparticles were acid cleavable, which provided a strong pH-responsive drug release profile. The DOX release rate from the DOX-conjugated Au nanoparticles in an acidic medium (i.e., pH 5.3) was dramatically higher than in physiological conditions (pH 7.4). Figure 4 shows the DOX release profiles from the DOX-conjugated Au nanoparticles in a releasing medium with a pH value of 5.3 or 7.4. After 5 h, 80 % of the loaded DOX was released in the pH 5.3 medium, whereas only 10 % of the DOX was released in the pH 7.4 medium. This result shows that the release of DOX from the DOX-conjugated Au nanoparticles in an acidic environment was governed by the acid-cleavable characteristic of the hydrazone linkage between the DOX molecules and Au nanoparticles. In recent years, nanostructured drug-delivery systems with multiple functions have aroused much interest and have been demonstrated to show promising applications in a variety of biomedical fields. Garcia-Gradilla et al.[53] reported acoustically driven Au/Ni/Au nanowire motors with multiple functions, such as magnetic guidance, coordinated motion, cargo towing, sorting of biological targets, pH-responsive drug delivery, operation in diverse media, and improved speed through the dualtemplating fabrication technique. The functionalization with various bioreceptors allowed the use of acoustically driven

2.2. Inorganic-Nanostructured-Materials-Based pH-Responsive Drug-Delivery Systems There are an increasing number of papers published regarding inorganic pH-responsive drug-delivery systems in recent years owing to their advantages in terms of thermal stability, biocompatibility, rich variety, and easy control of morphology, size, and structure. The most reported inorganic materials as pH-responsive drug carriers include Au nanostructures, carbonbased nanostructures, mesoporous silica, and calcium phosphate-based nanostructured materials. Of these inorganic materials, calcium phosphate-based nanostructured materials are very promising as excellent pH-responsive drug carriers owing to their high biocompatibility and pH sensitivity; calcium phosphates can dissolve to form Ca2 + and PO43 ions in acidic environments, which are fundamental constituents in vivo. In addition, calcium silicate-based materials are also promising pH-responsive drug carriers owing to their high biocompatibility and biodegradability. However, they have been less investigated and reported in the literature. We propose that more re&

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Figure 4. The drug release profiles of DOX-conjugated Au nanoparticles at pH 5.3 and 7.4. Reprinted from reference [52]. Copyright 2009 The Royal Society of Chemistry.

nanomotors for capturing and isolating biological targets, and pH-induced drug release from the polymeric segment was also realized. An electropolymerized polypyrrole-polystyrene sulfonate segment served as a carrier for the brilliant green drug. This positively charged drug was retained by electrostatic force on the surface of the negatively charged polypyrrole-polystyrene sulfonate polymeric backbone. A pH-sensitive triggered release of brilliant green was achieved in acidic medium (pH 4) and thus the polypyrrole-polystyrene sulfonate carrier was protonated. 78 % of the loaded brilliant green drug was released within 30 min at pH 4, and up to 95 % was released within 120 min. A control experiment at physiological pH 7.4 over the same 30 min period displayed a much lower drug release (25 %), and a nearly similar limited drug release over the entire 120 min period. Kang et al.[54] investigated the nanoparticle plasmon effect and drug-delivery dynamics in single cells by using Raman/ fluorescence imaging spectroscopy; a pH-responsive drug-release profile was obtained through the conjugation of DOX to Au nanoparticles by a pH-sensitive hydrazone linkage. When DOX was bound to the surface of the Au nanoparticle, its surface-enhanced Raman (SERS) spectrum could be observed, but its fluorescence was quenched. When DOX was released, its Raman enhancement was greatly reduced due to the acidic pH in the lysosomes, which changed the acquired Raman spectrum and in turn allowed for the visualization of its fluorescence signal. The plasmonic-tunable Raman/fluorescence properties enabled the tracking of the DOX release and delivery process from the Au nanoparticle surface to the lysosomes of single living cells under the acidic pH change of the microenvironments. Figure 5 shows a schematic diagram of the nanoparticle design for pH-responsive drug release and the tracking principle behind the DOX release in single living cells. DOX was adopted as the model drug because DOX has a red fluorescence emission and a strong Raman scattering signal. DOX was conjugated to the Au nanoparticles through a pH-sensitive hydrazone linkage by using methyl thioglycolate and hydraChem. Asian J. 2014, 9, 1 – 23

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Figure 5. a) Illustration of an Au nanoparticle functionalized with DOX by using a pH-sensitive hydrazone linkage. b) Schematic diagram of pH-triggered drug release tracking in acidic lysosomes by monitoring the surfaceenhanced Raman spectra (SERS) and fluorescence signal from the DOX molecules. Reprinted from reference [54]. Copyright 2013 American Chemical Society.

zine (Figure 5a). When DOX molecules were conjugated to the Au nanoparticle surface, the Raman signal of DOX was significantly enhanced by the near-field plasmon of the Au nanoparticles, whereas the fluorescence signal was quenched. This condition is referred to as the “drug-loaded” state, in which the SERS signal was strong and the fluorescence signal was quenched (Figure 5b). When the DOX-loaded Au nanoparticles were internalized by cells and transported into the acidic environment of the lysosomes, the hydrazone bond broke and DOX molecules were released. When DOX molecules were detached from the Au nanoparticles and diffused into the cellular environment, the Raman signal of the DOX molecules was significantly decreased; however, the fluorescence signal was recovered. This work provides potential for tracking the drug release process from Au nanoparticles to living cells in real time.[54] Mesoporous silica has also been investigated as a pH-responsive drug carrier. Jiao et al.[55] used poly(tert-butylacrylate) nanospheres as soluble core templates for the preparation of mesoporous silica hollow nanospheres. Both the poly(tert-butylacrylate) core and the structure-directing surfactant, cetyltrimethylammonium bromide, could be removed through solvent extraction in ethanol, and the hollow core diameter and shell thickness of mesoporous silica hollow nanospheres could be tuned; the in vitro tests indicated that the release rate of DOX-loaded mesoporous silica hollow nanospheres was dependent on the shell thickness and pH-responsive drug release behaviors. Li et al.[56] prepared mesoporous silica hollow microspheres with diameters in the range of 100 to 500 nm and wall thicknesses of approximately 50 nm by using cetyltrimethylam9


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Focus Review monium bromide by the microfluidization technique, and the as-prepared mesoporous silica hollow microspheres were effective for drug loading and pH-responsive drug release. Ma et al.[57] used mesoporous silica hollow spheres with perpendicular nanochannels that connected to internal hollow cores as the carrier for DOX/siRNA co-delivery; and folic acid-conjugated polyethyleneimine was coated on mesoporous silica hollow spheres under neutral conditions to block the mesopores and prevent the loaded drugs from leaking. Folic acid acted as the targeting ligand and enabled the co-delivery system to selectively bind with and enter into the target cancer cells. In vitro pH-responsive drug/siRNA co-delivery experiments were conducted on HeLa cell lines with high folic acid receptor expression and MCF-7 cell lines with low folic acid receptor expression for comparison, and showed effective targeted delivery to the HeLa cells through folic acid receptor meditated cellular endocytosis. The mesoporous silica hollow sphere co-delivery system had pH-dependent drug-delivery behavior; the DOX release under neutral conditions (pH 7.4) was less than 10 % and no further release was observed after more than 30 h. Under acidic conditions, folic acid-conjugated polyethyleneimine was positively charged due to the protonation of amine groups and thus generated strong Columbic repulsion toward each other, which led to swelling and the dissociation of the folic acid-conjugated polyethyleneimine layer from the mesoporous silica hollow sphere surface. In addition, the dissociation of the folic acid-conjugated polyethyleneimine layer in an acidic intracellular environment also led to the delivery of siRNA.[57] Nanostructured materials of iron oxides, such as Fe3O4 and g-Fe2O3, have also been used as pH-responsive drug carriers with a magnetic function for targeted drug delivery. Zhu et al.[58] reported superparamagnetic hollow iron oxide nanoshells (diameter (139.8 2.7) nm and shell thickness (39.4 1.5) nm) as the drug carrier for curcumin and DOX, and they investigated the intracellular delivery of hydrophobic anticancer drugs in glioblastoma U-87 MG cells. After internalization by U87 MG cells, the hollow iron oxide nanoshells localized at the acidic compartments of endosomes and lysosomes. In endosome/lysosome-mimicking buffers with pH values of 4.5–5.5, the drug release was pH-dependent for curcumin- or DOXloaded hollow iron oxide nanoshells. The intracellular curcumin content delivered by using curcumin-loaded hollow iron oxide nanoshells was 30-fold higher than the free drug. The intracellular DOX content delivered by using DOX-loaded hollow iron oxide nanoshells was also increased, and fast intracellular DOX release was also observed due to its protonation in the acidic environment. Nanostructured calcium phosphates are promising pH-responsive drug carriers with high biocompatibility. Calcium phosphates are stable in physiological pH, but dissolve to form nontoxic ions of Ca2 + and PO43 in acidic environments, such as in endosomes and lysosomes of cells. Of the calcium phosphates, amorphous calcium phosphate (ACP) is the initial solid phase formed in an aqueous solution that contains Ca2 + ions and phosphate ions. The ACP phase is an intermediate phase in the preparation of other crystalline calcium phosphate materials. ACP generally forms as an unstable precursor that &

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easily transforms into a stable crystalline phase of calcium phosphates, such as hydroxyapatite and octacalcium phosphate, in the absence of any stabilizer in aqueous solution. ACP has a relatively high solubility and excellent bioactivity and biocompatibility. Recently, this research group reported the microwave-assisted hydrothermal rapid synthesis of highly stable ACP porous microspheres with a relatively uniform size and an average pore diameter of about 11 nm by using adenosine 5’-triphosphate (ATP) disodium salt as a biocompatible organic phosphorous source and stabilizer; the as-prepared ACP porous microspheres had a high stability in phosphate-buffered saline (PBS) for more than 150 h without phase transformation to hydroxyapatite. The as-prepared ACP porous microspheres were efficient for anticancer drug loading and sustained drug release and they are also promising pH-responsive drug carriers.[59] In a further work, we prepared amorphous calcium phosphate (Zn/ACP) mesoporous microspheres doped with zinc ions by using CaCl2, ZnCl2, and ATP as a biocompatible organic phosphorus source by using a microwave-assisted hydrothermal method, and found that ATP was the main factor for stabilizing ACP in aqueous solution and Zn2 + ions were doped in ACP to give an antibacterial benefit. The as-prepared Zn/ACP mesoporous microspheres exhibited pH-sensitive Zn2 + ion release behavior and good antibacterial activity against Staphylococcus aureus and Escherichia coli.[60] Qi et al.[61] reported a DNA-templated hydrothermal strategy for the synthesis of hydroxyapatite nanosheet-assembled hollow microspheres with a nanoporous structure (average pore size 21.8 nm). The as-prepared hydroxyapatite porous hollow microspheres exhibited a relatively high drug loading capacity, high protein adsorption ability, and sustained drug and protein release, by using ibuprofen as a model drug and hemoglobin as a model protein. The hemoglobin release behavior of the hydroxyapatite porous hollow microsphere protein adsorption system in PBS were dependent on the pH value, and the amount of hemoglobin released from hydroxyapatite porous hollow microspheres in PBS at pH 7.4 was much larger than that at pH 4.0, and the cumulative amount of released hemoglobin reached a plateau of 1200 mg at pH 7.4 and 750 mg at pH 4.0 after 50 h. This may be explained by the fact that when the pH value of the PBS solution was below the isoelectric point of hemoglobin, the hemoglobin molecules became positively charged at pH 4.0.[61] Zhao et al.[62] reported a simple and environmentally friendly hydrothermal synthesis of hydroxyapatite nanorods and nanowires by using the biocompatible biomolecule riboflavin-5’phosphate monosodium salt (RP) as a new phosphorus source. In this method, the RP molecules hydrolyze to form inorganic phosphate ions under hydrothermal conditions, and these phosphate ions react with calcium ions to form hydroxyapatite nanorods or nanowires after nucleation and crystal growth. They found that the hemoglobin loading capacity of hydroxyapatite nanowires and nanorods increased with an increasing initial hemoglobin concentration, and the hemoglobin release of hemoglobin-loaded hydroxyapatite nanowires and hydroxyapatite nanorods was pH-dependent in PBS with different pH values, as shown in Figure 6. The hemoglobin release rates of 10



Focus Review profile, the released amount of hemoglobin from hydroxyapatite hollow microspheres in PBS at pH 7.4 was much higher than that at pH 6.0 and pH 4.5, and the release rate decreased in the following order: pH 7.4 > pH 6.0 > pH 4.5. Carbonate materials can also be used as pH-responsive drug carriers because of their solubility in acidic environments. For example, Qian et al.[65] prepared SrCO3 structures with a dumbbell-shaped morphology as the pH-sensitive drug carrier for etoposide by using SrCl2·6 H2O, Na2CO3, and citric acid in a mixture of ethanol and deionized water. They found that the cumulative release of etoposide from the SrCO3 drug-delivery system was pH-dependent and exhibited a low leakage at pH 7.4 with only 23 % of the drug released after 72 h, whereas the release rate was significantly enhanced to 66 % at a pH of 5.8 and 83 % at a pH of 3.0. Silicates also show promise for application in pH-responsive drug delivery. Liu et al.[66] reported a drug-delivery system based on hollow iron silicate nanospheres. Fe3 + ions on the surface of the nanospheres could effectively bind with DOX drug molecules through coordination bonds, which were stable in a neutral environment but could easily break up in an acidic environment. The release of DOX from hollow iron silicate nanospheres into cancer cells could be triggered by a pH decrease caused by endocytosis. DOX-loaded hollow iron silicate nanospheres released only 5 % of the loaded drug in PBS (pH 7.4) in 2 d, whereas in an acidic environment (PBS, pH 5.0) the continuous release of DOX reached up to 78.7 % in the first 10 h. DOX-loaded hollow iron silicate nanospheres exhibited a higher efficiency in killing cancer cells than free DOX. In addition to various pH-responsive drug-delivery systems discussed above, many other inorganic materials may also be potential pH-responsive drug carriers. For example, a drug-delivery system with pH-triggered DOX release behavior was also reported based on DOX-conjugated NaYF4 :Yb3 + /Tm3 + nanoparticles with the ability to release DOX by cleavage of the hydrazone bond in mildly acidic environments.[67] Due to their unique properties of high thermal/chemical/ biological stability, inorganic-nanostructured-materials-based pH-responsive drug-delivery systems have shown many advantages in drug delivery applications, such as multifunctional properties and resistance to corrosion under physiological conditions. Compared with polymeric materials, control over the structure, size, morphology, and functionalization of inorganic nanostructured materials is more facile and successful. Therefore, with considerable freedom of choices of the structure, size, morphology, and functions, various inorganic materials, such as rare earth oxides/fluorides, noble metals, iron oxides, silica, calcium phosphates, calcium carbonate, and calcium silicates, have been investigated for applications in pH-responsive drug delivery. These nanostructured inorganic pH-responsive drug carriers with additional functions, such as magnetism, photothermic therapy, and bioimaging, have great potential for application in clinical diagnosis and simultaneously drug delivery for the treatment of various human diseases. Although achievements have been made in previous studies, the investigation of novel nanostructured-inorganic-materialsbased pH-responsive drug-delivery systems are still a long-

Figure 6. Cumulative hemoglobin (Hb) release from Hb-loaded hydroxyapatite nanowires and hydroxyapatite nanorods at different pH values of 4.5 and 7.4 in PBS at 37 8C. Reprinted from reference [62]. Copyright 2013 The Royal Society of Chemistry.

both hemoglobin-loaded hydroxyapatite nanowires and Hbloaded hydroxyapatite nanorods were relatively rapid in the first 10 h in PBS at pH 7.4. Then the hemoglobin release of the two samples underwent a slow and sustained process within 142 h. The cumulative hemoglobin release percentages of Hbloaded hydroxyapatite nanowires and Hb-loaded hydroxyapatite nanorods in PBS at pH 7.4 reached 37 and 45 %, respectively, after a release time of 171 h. The cumulative amounts of hemoglobin released in PBS at pH 4.5 were obviously lower than those at pH 7.4. The isoelectric point of hemoglobin is about 7.0, thus, the hemoglobin molecules are uncharged in neutral aqueous solution but will become positively charged in solutions with a pH value below 7.0. The zeta potentials of hydroxyapatite nanowires and nanorods in PBS at pH 7.4 were 18.9 and 21.2 mV, respectively; however, the zeta potential values in PBS at pH 4.5 were 12.9 and 13.3 mV, respectively. Thus, there were strong electrostatic interactions between the positively charged hemoglobin molecules and the negatively charged hydroxyapatite nanowires and nanorods in PBS with a pH value of 4.5, and the strong electrostatic interactions effectively inhibited hemoglobin release from hemoglobinloaded hydroxyapatite nanowires and nanorods in PBS at pH 4.5.[62] Zhao et al. also reported a surfactant-free rapid microwave-assisted hydrothermal synthesis of hydroxyapatite nanosheet-assembled flower-like hierarchical nanostructures, and the morphology of the product could be adjusted from flower-like to polyhedra by adjusting the microwave heating temperature; the loading capacities of the as-prepared hydroxyapatite nanosheet-assembled flower-like hierarchical nanostructures for bovine serum albumin, hemoglobin, and fish sperm DNA were 165, 164, and 112 mg g 1, respectively; the protein release process was conducted at different pH values (pH 7.2, 5.5, and 4.8) in PBS, and the pH-controlled protein release behavior was found.[63] Qi et al.[64] reported a new strategy for the rapid synthesis of hydroxyapatite hierarchically nanostructured porous hollow microspheres by using creatine phosphate disodium salt as an organic phosphorus source in aqueous solution by using a microwave-assisted hydrothermal method; the hemoglobin release behavior of the hydroxyapatite porous hollow microsphere protein adsorption system in PBS at different pH values exhibited a pH-responsive release Chem. Asian J. 2014, 9, 1 – 23

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Focus Review term research direction. The design and preparation of nanostructured inorganic pH-responsive drug-delivery systems with excellent multifunctional properties, high biocompatibility, high drug loading capacities, and controlled drug release profiles are the main aim of future studies. The biocompatibility of inorganic drug carriers is crucial for their applications. To date, a large number of bioinert inorganic materials have been investigated, such as rare earth oxides/fluorides, noble metals, carbon-based materials, such as carbon nanotubes and graphene, and silica. However, positive results for the in vivo distribution and degradation process of these bioinert inorganic drug-delivery systems are not abundant. Therefore, more studies should be conducted to develop novel inorganic pH-responsive drug carriers with high biocompatibility and biodegradability in vivo. However, more evaluation studies on the in vivo distribution pathways, biodegradability, and biotoxicity in the body are necessary for their further applications. In this respect, inorganic materials that are made from nontoxic elements, such as calcium phosphates, calcium carbonate, and calcium silicates, show great promise in future applications in the field of pH-responsive drug delivery.

Figure 7. Schematic illustration of the synthesis of ZnO quantum dots@mesoporous silica nanoparticles/DOX and the working protocol for pH-triggered release of DOX to the cytosol by the selective dissolution of ZnO quantum dots in the acidic intracellular compartments of cancer cells. Reprinted from reference [68]. Copyright 2011 American Chemical Society.

2.3. Inorganic/Inorganic-Nanocomposites-Based pH-Responsive Drug-Delivery Systems

Fe3O4 is usually used as an excellent magnetic material for biomedical applications, and nanostructured Fe3O4 materials are promising pH-responsive drug carriers. Chen et al.[69] prepared a magnetic nanocomposite that consisted of ultrathin hydroxyapatite nanosheets and magnetic Fe3O4 nanoparticles (HAPUN/MNs) by using a rapid microwave-assisted route. The as-prepared magnetic HAPUN/MNs nanocomposite was investigated as a drug nanocarrier for hemoglobin and docetaxel (Dtxl). They found that the adsorption amount of hemoglobin on the magnetic nanocomposite increased with increasing initial hemoglobin concentration and the release of hemoglobin from the magnetic nanocomposite was essentially governed by a diffusion process. The magnetic nanocomposite had a good sustained release profile for Dtxl and exhibited a good pH-responsive drug release profile (Figure 8), which can be explained by the gradual dissolution of the drug nanocarrier in a low-pH environment. Dtxl was gradually released from the magnetic nanocomposite drug-delivery system at pH 7.4 and 4.5 over a time period of 24 h, and then the Dtxl-loaded magnetic nanocomposite exhibited a stable cumulative drug release level (about 30 %) at a high pH value (pH 7.4) after the initial drug release stage. In contrast, the cumulative Dtxl release percentages in PBS with a pH value of 4.5 reached a higher level of about 80 and 98 % at a release time of 24 h and 108 h, respectively. The higher cumulative drug release percentage at a lower pH value may be attributed to the increased dissolution of the nanocarrier in an acidic environment. They also investigated the cytotoxicity of the HAPUN/MNs nanocomposite without and with Dtxl drug loading by using SGC-7901 cells, and the results of the MTT assays showed little toxicity when the cells were co-cultured with the HAPUN/MNs nanocomposite at concentrations in the range of 1 to 100 mg mL 1 (Figure 8b); the high biocompatibility may be explained by the

A nanocomposite is a multiphase solid material in which at least one constituent has at least one dimension of less than 100 nm. It is usually a solid combination of a bulk matrix and nanostructures, and the constituents have different properties, structure, and chemistry. The properties of the nanocomposite are different from those of the component materials. Inorganic/inorganic-nanocomposites-based pH-responsive drug-delivery systems have been less reported in the literature. Muhammad et al.[68] adopted ZnO quantum dots to seal the nanopores of mesoporous silica nanoparticles to inhibit premature DOX drug release (Figure 7). The advantages of adopting ZnO quantum dots as nanolids are based on the fact that they are easy to fabricate, inexpensive, and exhibit an adequate response to acid (they are stable at pH 7.4 but rapidly dissolve at pH < 5.5). In addition, ZnO quantum dots can not only protect the drug from premature release but also exhibit cytotoxic effects at their destination. After internalization into HeLa cells, the ZnO quantum dots lids were rapidly dissolved in the acidic intracellular compartments and the loaded drug was released into the cytosol from the mesoporous silica nanoparticle drugdelivery system. ZnO quantum dots not only acted as lids but also exhibited a synergistic antitumor effect. It was found that negligible DOX was released from this DOX-loaded mesoporous silica nanoparticle drug-delivery system at physiological pH 7.4, which implies efficient inhibition of DOX release by capping with ZnO quantum dots. In contrast, fast release of DOX was observed at pH 5.0, which is consistent with the dissolution of ZnO nanolids in the acidic environment. A control experiment without ZnO caps was also carried out and revealed that approximately 5 % of the loaded DOX was released at pH 7.4. &

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Focus Review rate increased with decreasing pH value due to the dissolution of hydroxyapatite at low pH values. Li et al.[72] prepared silica nanotubes functionalized with magnetic and up-conversion luminescent NaYF4 :Yb/Er/Gd nanocrystals by using single-nozzle electrospinning based on a phase-separation effect without any template. In their preparation, hydrophilic cubic NaYF4 :Yb/ Er/Gd nanocrystals decorated with polyethyleneimine were prepared by using a hydrothermal method. Then, NaYF4 :Yb/Er/ Gd nanocrystals were dispersed into the electrospinning precursor solution, which contained polyvinylpyrrolidone and tetraethylorthosilicate, followed by the preparation of precursor nanotubes by using an electrospinning process. Finally, after annealing at 600 8C, the nanocomposite was obtained. DOX·HCl was loaded into the nanocomposite and the as-prepared drug-delivery system exhibited pH-dependent drug release behavior. Huang et al.[73] synthesized luminescent GdVO4 :Eu3 + /mesoporous silica nanoparticles and found that these nanoparticles had a pH-dependent drug release behavior for DOX, and the DOX release rate was higher at acidic pH values than at pH 7.4; the cumulative DOX release was 61 % after 60 h at pH 2.0, much higher than at pH values of 4.0 and 7.4 (39 and 11 %, respectively). Cheng et al.[74] reported YVO4 :Eu3 + functionalized porous silica microspheres as a drug carrier. The porous microspheres exhibited a relatively high loading capacity and encapsulation efficiency (87.6 %) for the anticancer drug DOX·HCl. They found that the YVO4 :Eu3 + /SiO2 microspheres exhibited a highly pH-dependent drug release behavior and the DOX-loaded YVO4 :Eu3 + /SiO2 microspheres had a similar or even greater anticancer activity against HeLa cells compared with free DOX. Inorganic nanocomposites with double or multiple components provide promising applications in pH-responsive drug delivery with various functions, such as magnetic targeting and bioimaging. By combining different inorganic materials in one drug-delivery system, there will be multiple ways of consolidation, such as structure–structure, structure–function, and function–function. For example, mesoporous structural materials can be used to encapsulate functional inorganic nanoparticles to prepare pH-sensitive drug-delivery systems with different additional properties, such as magnetism and fluorescence, and the properties of the inorganic/inorganic-nanocomposite drug carriers will be different from those of the individual components. In addition, we propose that inorganic nanostructured materials with excellent biocompatibility and biodegradation, such as calcium phosphates, calcium silicates, and calcium carbonate, should be preferentially considered as the inorganic components for the construction of pH-sensitive drugdelivery systems. More research is needed to design, prepare, characterize, and analyze these novel inorganic/inorganicnanocomposite pH-responsive drug-delivery systems and explore their applications in this exciting research field.

Figure 8. a) The cumulative drug release percentages of docetaxel (Dtxl) from the HAPUN/MNs nanocomposite drug-delivery system in PBS with pH values of 7.4 and 4.5. b) Cell viability tests for the HAPUN/MNs nanocomposite without and with Dtxl drug loading. Reprinted from reference [69]. Copyright 2013 The Royal Society of Chemistry.

chemical nature of the as-prepared HAPUN/MNs nanocomposite. In addition, in the presence of the Dtxl-loaded HAPUN/ MNs nanocomposite, the cell viability decreased with increasing concentration of the Dtxl-loaded HAPUN/MNs drug-delivery system; the cell viabilities were only 43 and 17 % when the concentrations of the sample were 1 and 100 mg mL 1, respectively.[69] Qi et al.[70] synthesized amorphous calcium carbonate (ACC) by using adenosine 5’-triphosphate (ATP) disodium salt as the stabilizer and investigated the transformation of the ACC under microwave hydrothermal conditions; ACC/ACP composite nanospheres and carbonated hydroxyapatite nanospheres were successfully prepared. The as-prepared ACC/ACP composite nanospheres had excellent biocompatibility and high protein adsorption capacity. They found that the released amount of hemoglobin from the ACC/ACP composite nanosphere protein-adsorption system in PBS was pH-dependent, and the cumulative amount of released hemoglobin decreased with decreasing pH value. This result may be explained by the electrostatic interaction between the hemoglobin molecules and the ACC/ACP composite nanospheres. Some examples of other inorganic/inorganic-composite pHresponsive drug-delivery systems are described below. Lin et al.[71] prepared hollow magnetic hydroxyapatite microspheres with a hierarchically mesoporous structure by using hollow CaCO3/Fe3O4 microspheres as the sacrificial hard template in aqueous Na3PO4 by using a hydrothermal method at 180 8C for 3 d. The magnetization of the as-prepared products could be adjusted by changing the amount of Fe3O4. The drug release rate of vancomycin from the hollow magnetic hydroxyapatite microspheres was pH responsive, and the drug release Chem. Asian J. 2014, 9, 1 – 23

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2.4. Inorganic/Organic-Composite pH-Responsive Drug-Delivery Systems In recent years, inorganic/organic nanocomposites have received much attention due to their interesting properties and 13


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Focus Review potential applications. In inorganic/organic nanocomposites, inorganic nanoparticles with high specific surface areas and unsaturated atoms may interact with an organic polymer, which leads to enhanced properties of the nanocomposite. Zheng et al.[75] reviewed coordination complexes with the ability to store and release drugs through the formation and cleavage of coordination bonds, respectively, in response to a pH change. They discussed recent advances in coordination-bonding-based pH-responsive systems; various strategies have been developed for drug molecules with and without coordination binding sites. They also discussed the construction of various pH-responsive systems by using different categories of carriers, including mesoporous silica nanoparticles, mesoporous hybrid monoliths, mesoporous metal oxides, and coordination polymer nanoparticles. The strength of coordination bonding architectures can be adjusted by tailoring the type and number of functional groups of ligands, which leads to different structures of the coordination complexes. Various strategies, such as the directing method, vector method, and coating method were used to build pH-responsive systems for drugs with different coordinative binding sites. The pH-responsive releasing properties can be significantly altered by changing the metal source, including both the metal ion and the counterion. A multifunctional gold-nanorod-based nanocarrier capable of co-delivering small interfering RNA (siRNA) and the anticancer drug DOX was developed for combined chemotherapy and siRNA-mediated gene silencing.[76] The Au nanorod was conjugated with 1) DOX through a pH-labile hydrazone linkage to enable pH-controlled drug release; 2) polyarginine, a cationic polymer that complexes siRNA; and 3) octreotide, a tumor-targeting ligand, to specifically target cancer cells with overexpressed somatostatin receptors. The Au-nanorod-based nanocarriers exhibited a uniform size distribution and pH-sensitive drug release. The octreotide-conjugated Au-nanorod-based nanocarriers (Au–DOX–octreotide, targeted) exhibited a much higher cellular uptake by a human carcinoid cell line than nontargeted Au-nanorod-based nanocarriers (Au–DOX).[76] Zheng et al.[77] reported the preparation of a “host-metaldrug” coordination-bonding system in a mesostructured surfactant/silica hybrid for pH-responsive drug delivery. The mesostructures were synthesized by self-assembly of F127 Pluronic nonionic surfactant and silica source; metal ions, such as Zn, Cu, and Fe, and drugs were introduced simultaneously into the reaction system to form an F127-metal-drug coordinationbonding architecture. The cleavage of the coordination bonds that are sensitive to variations in the pH value led to the release of the drug under weakly acidic conditions. The drug-delivery system was stable under physiological conditions, but released the encapsulated drug under low pH conditions in a sustained manner. A further work was done by the same research group;[78] they prepared a mesoporous chitosan–silica composite by self-assembly of nonionic surfactant F127 Pluronic, chitosan and silica source. They developed a pH-responsive drugdelivery system based on the coordinate bonding of a “hostmetal-guest” architecture, in which host, metal, and guest represent the amino groups of chitosan units, metal ions, and drug molecules, respectively. Daunorubicin was chosen as &

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a typical anticancer drug. A NH2-Zn-daunorubicin coordination bonding architecture was constructed, accompanied by the formation of a chitosan–silica mesostructured hybrid. This NH2Zn-daunorubicin coordination bonding system was stable under physiological pH conditions and released the encapsulated drug in response to a decrease in the pH value due to breakdown of both or either the NH2-Zn and Zn-daunorubicin coordination bonds. The release of daunorubicin could be achieved through cleavage of coordination bonds that are sensitive to variations in the pH value. The release of daunorubicin was observed at pH 5 to 6, whereas negligible release was observed under physiological conditions. The existence of chitosan in the mesoporous silica enhanced both the biodegradability and the strength of the host-metal-guest coordination bond.[78] He et al.[79] reported a pH-responsive multi-drug-delivery system with particle sizes of (100 13) nm and good monodispersity prepared by in situ co-self-assembly between water-insoluble DOX, surfactant micelles (cetyltrimethylammonium bromide, CTAB), and silicon species, which formed drugs/surfactant micelles-co-loaded mesoporous silica nanoparticles. The multi-drug-delivery system based on mesoporous silica nanoparticles had pH-responsive drug release behavior both in vitro and in vivo, and exhibited high drug efficiencies against drugresistant MCF-7/ADR cells and drug-sensitive MCF-7 cells. Figure 9 shows the in vitro pH-responsive drug release behavior of the mesoporous silica nanoparticles-based multi-drugdelivery system in release media at different pH values. A small amount of DOX was released from the mesoporous silica nanoparticles-based multi-drug-delivery system in a very slow fashion in PBS at pH 7.4, which simulates normal physiological conditions, and less than 2 % of DOX was released after immersion for as long as 14 d. When the pH value of the release media was decreased from 6.5 to 4 to simulate cancer conditions, both the DOX release rate and the released-DOX concentration

Figure 9. In vitro pH-responsive drug release behavior of the mesoporous silica nanoparticles-based multi-drug-delivery system in release media at different pH values, which were used to simulate the alkalescent conditions in normal tissues and blood (pH 7.4) and acidic conditions in tumor (pH 4– 6.8). The mesoporous silica nanoparticles-based multi-drug-delivery system barely released DOX in the pH 7.4 release medium, but responsively released DOX in pH 4–6.8 acidic media. Reprinted from reference [79]. Copyright 2011 Elsevier Ltd.

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Focus Review observed. The cumulative ibuprofen release from the drug-delivery system was 15.2 % after 2 h, 80.2 % after 4 h, 87.2 % after 6 h, and 93.2 % after 24 h, which indicated that the ibuprofen release was substantially slowed in simulated gastric fluid, whereas the release was increased in simulated intestinal fluid. In contrast, the drug-release profile of the drug-delivery system of the solvent-extraction sample could be controlled by using poly(allylamine hydrochloride) as a pH-responsive gate. Under acidic conditions the ibuprofen release was 25.7 % after 2 h, but as the pH value was changed from 1.2 to 6.8 a jump in the ibuprofen release of up to 40.7 % was observed, after which the release was almost stopped, and even after 48 h only 43 % of ibuprofen was released in the medium. In contrast, about 93 % of the drug was released from the calcined sample within 24 h.[84] Yang et al.[2] reported a pH-responsive drug (vancomycin) delivery system constructed by using the oppositely charged ionic interaction between carboxylic acid-modified SBA-15 silica rods and poly-(dimethyldiallylammonium chloride); this system could function as a drug-delivery device that contains drug reservoirs and environment-sensitive orifices, and the state of the orifices (closed or opened) could be controlled by the pH value. As shown in Figure 10, polycations poly-(dime-

increased; the released-DOX percentage reached approximately 26.6 % in pH 4 release medium after immersion for 14 d. The released amounts of intracellular drug from the mesoporous silica nanoparticles-based multi-drug-delivery system were high enough to kill MCF-7 and MCF-7/ADR cells efficiently through the specific synergistic effect between CTAB and DOX.[79] Hu et al.[80] reported the synthesis of pH-responsive chitosan-capped mesoporous silica nanoparticles as nanocapsules to load drug molecules. Subsequently, (3-glycidyloxypropyl)trimethoxysilane was grafted onto the surface of mesoporous silica nanoparticles, which served as a bridge to link mesoporous silica nanoparticles and chitosan. The loading and release of DOX·HCl were carried out in vitro, and the drug-delivery system showed excellent environmental response; as the pH value of the media decreased, the degree of drug release correspondingly increased. Chen et al.[81] fabricated a novel chitosan-enclosed mesoporous silica nanoparticles as drug nanocarriers with a pH-response ability over a narrow pH range (pH 6.8–7.4). Xing et al.[82] reported coordination-polymercoated mesoporous silica nanoparticles for pH-responsive drug release; drug release was triggered by H + cleavage of the coordination bond of the coordination polymer nanolayer. Yang et al.[83] prepared two pH-controlled drug-delivery systems that consisted of mesoporous silica nanotubes and pH-responsive polyelectrolytes by using a layer-by-layer self-assembly: one system was based on alternatively loading poly(allylamine hydrochloride) and sodium poly(styrene sulfonate) onto as-prepared mesoporous silica nanotubes with the positively charged drug DOX; the other system was synthesized by alternately coating sodium alginate and chitosan onto amine-functionalized mesoporous silica nanotubes to load the negatively charged drug sodium fluorescein. Controlled drug release from these drug-delivery systems was achieved by adjusting the pH value of the release medium, and the in vitro cell cytotoxicity assays indicated that the cell-killing efficacy of the loaded DOX against human fibrosarcoma (HT-1080) and human breast adenocarcinoma (MCF-7) cells was pH-dependent. Begum et al.[84] reported a pH-controlled drug-delivery system based on suitably functionalized monodisperse mesoporous silica spheres. The release of ibuprofen from the mesoporous silica samples was investigated in simulated gastric fluid (pH 1.2) followed by simulated intestinal fluid (pH 6.8) to simulate the behavior of the drug-delivery system after oral administration because ibuprofen is mainly adsorbed in the stomach and proximal intestine. The surfactant was removed from the as-synthesized mesoporous silica spheres by two different methods, that is, calcination and solvent extraction. It was found that the removal of surfactant by calcination and solvent extraction to create porosity in mesoporous silica spheres could result in materials with different surface properties and thus different drug release profiles. The drug-delivery system of the calcined sample could release ibuprofen preferentially in the intestine rather than in the stomach in a pH-dependent manner, and the ibuprofen release was found to proceed slowly under acidic conditions. As the pH was changed from 1.2 to 6.8, a jump of 64 % in the ibuprofen release was Chem. Asian J. 2014, 9, 1 – 23

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Figure 10. Schematic representation of a pH-responsive storage–release drug-delivery system. This pH-controlled system is based on the interaction between negative carboxylic acid-modified SBA-15 silica rods with polycations poly-(dimethyldiallylammonium chloride). Reprinted from reference [2]. Copyright 2005 American Chemical Society.

thyldiallylammonium chloride), adsorbed to anionic SBA-15 through an oppositely charged ionic interaction, acted as closed gates for the storage of drugs in the mesopores. When ionized carboxylic acid species (COO ) were transformed into protonated groups (COOH) by adjusting the pH value, polycations could be separated from the surface of modified SBA-15, which led to the opening of the gates for the drug release from the mesopores. When the pH was mildly acidic, vancomycin could be steadily released from the pores of SBA-15. 15


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Focus Review There have been significant efforts devoted to investigations of inorganic/organic-nanocomposites-based pH-responsive drug-delivery systems that contain nanostructured magnetic iron oxide. Xing et al.[85] used the dopamine plus human serum albumin method to modify hollow iron oxide nanoparticles and load DOX within them, and this system could load more drug than solid iron oxide nanoparticles of the same core size by using the same coating strategy. The hollow Figure 11. a) Particle sizes of N-naphthyl-O-dimethymaleoyl chitosan-based drug-loaded magnetic nanoparticles at iron oxide nanoparticle drug-de- different pH values. b) pH-sensitive drug release profiles of N-naphthyl-O-dimethymaleoyl chitosan-based druglivery system had a pH-depen- loaded magnetic nanoparticles. Reprinted from reference [88]. dent drug release behavior with faster release kinetics at lower pH values. Compared with free DOX, the hollow iron oxide in an acidic environment; N-naphthyl-O-dimethymaleoyl chitonanoparticle drug-delivery system could be more effectively san-based drug-loaded magnetic nanoparticles in a solution at taken up by multidrug-resistant OVCAR8-ADR cells and were pH 9.8 showed particle sizes of approximately (100.3 4.9) nm, consequently more potent in killing drug resistant cancer cells. but their sizes increased slightly with increased buffer solution The hollow iron oxide nanoparticle drug-delivery system could acidity ((185.3 13.5) nm at pH 5.5 and (158.8 10.6) nm at also be used as a contrast agent for magnetic resonance imagpH 7.4; see Figure 11a). DOX was abruptly released from Ning while also acting as a drug-delivery vehicle. Zhao et al.[86] naphthyl-O-dimethymaleoyl chitosan-based drug-loaded magprepared Fe3O4 nanoparticles ( 14 nm) as the nanocarrier for netic nanoparticles under acidic conditions (pH 5.5) with aploading DOX by using the acid-labile imine bond, and the reproximately 90 % of drug released within 24 h (Figure 11b), sulting drug-delivery system exhibited higher cytotoxicity whereas only 20 % of DOX was released under higher pH contoward cancer cells than free DOX; the arginine-glycine-aspartditions (pH 7.4 and 9.8) during the same time period, and both ic acid-modified magnetic nanocarrier could recognize specific release profiles showed sustained drug release patterns for 8 d. cells effectively and exhibit increased cytotoxicity towards After internalization of N-naphthyl-O-dimethymaleoyl chitosancancer cells under external magnetic fields. Das et al.[87] reportbased drug-loaded magnetic nanoparticles by endocytosis, drug release could be further accelerated inside the acidic ened a multifunctional nanostructured system that combined dosomes of tumor cells.[88] The pH-responsive drug-delivery cancer-targeted magnetic resonance, optical imaging, and pHsystem consisting of Fe3O4 nanoparticles, CdTe quantum dots, sensitive drug release into one system. The multifunctional and the drug cefradine incorporated into chitosan nanopartisystem was composed of a superparamagnetic iron oxide as cles that were cross-linked with glutaraldehyde was also rethe core modified with a hydrophilic coating of N-phosphonoported.[89] methyl iminodiacetic acid; functional molecules such as rhodaLi et al.[90] reported mesoporous magnetic Fe3O4 colloidal mine B isothiocyanate, folic acid, and methotrexate were counanocrystal clusters that were stabilized by agarose; the hypled to the amine-derivatized iron oxide support by using apdroxyl groups of agarose were modified with vinyl groups, folpropriate spacers to enable simultaneous targeting, imaging, lowed by a click reaction with mercaptoacetyl hydrazine to and intracellular drug-delivery capability. Phosphonic acid form the terminal hydrazide ( CONHNH2). DOX was then conchemistry was exploited to develop a stealth multifunctional jugated to the Fe3O4 colloidal nanocrystal clusters through a hynanoprobe that could selectively target, detect, and kill cancer cells that overexpressed the folate receptor while allowing drazone bond to provide a pH-sensitive drug release capability, real-time monitoring of the tumor response to drug treatment and the release rate of DOX was dramatically improved in low through dual-modal fluorescence and magnetic resonance pH environments, whereas almost no DOX was released at imaging. The overall drug release rate was much higher at neutral pH values. Zou et al.[91] prepared superparamagnetic a lower pH range (pH 2–5) and negligible drug release was obiron oxide nanoparticles (SPIO, 10 nm) coated with amphiphilic served at physiological pH.[87] polymers and PEGylated. The antibody HuCC49DCH2 and fluorescent dye 5-FAM were conjugated to the PEG on iron oxide Lim et al.[88] reported chitosan-based intelligent theragnosis nanoparticles, and the anticancer drugs DOX, azido-doxorubinanocomposites, N-naphthyl-O-dimethymaleoyl chitosan-based cin (Adox), MI-219, and 17-DMAG, which contain primary drug-loaded magnetic nanoparticles, which were capable of amine, azide, secondary amine, and tertiary amine, respectively, pH-sensitive drug release with magnetic resonance-guided were encapsulated into the iron oxide nanoparticles. imaging. This drug-delivery system exhibited rapid DOX release &

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Focus Review Zhao et al.[98] synthesized calcium phosphate hybrid nanoparticles in aqueous solution through self-assembly by using two oppositely charged polyelectrolytes (poly-(diallyldimethylammonium chloride) (PDADMAC) and poly(acrylate sodium) (PAS) as dual templates. Figure 12 shows the main idea and

HuCC49DCH2-SPIO increased cancer-cell targeting, and DOX, MI-219, and 17-DMAG showed pH-dependent release whereas Adox did not. Fluorescent imaging demonstrated the accumulation of HuCC49DCH2-SPIO nanotheranostics in endosomes/lysosomes. The encapsulated DOX was released in the acidic lysosomes and diffused into cytosol and nuclei; in contrast, the encapsulated Adox only showed limited release in endosomes/ lysosomes. Chang et al.[92] prepared a pH-responsive drug-delivery system based on conjugates of dendrimer-DOX and Fe3O4 nanoparticles, and the anticancer drug DOX was conjugated to the dendrimer segments of amino-stabilized Fe3O4 nanoparticles by using hydrazine as the linker through a hydrazone bond. He et al.[93] reported water-dispersible dendritic-linearbrush-like triblock copolymer polyamidoamine-b-poly(2-(dimethylamino)-ethyl methacrylate)-b-poly(poly(ethylene glycol) methyl ether methacrylate)-grafted superparamagnetic iron oxide nanoparticles by a two-step copper-mediated atom transfer radical polymerization method. The as-prepared dendritic-linear-brush-like triblock copolymer-grafted iron oxide nanoparticles had a uniform hydrodynamic particle size with an average diameter of less than 30 nm. DOX was used as a model drug and loaded into the dendritic-linear-brush-like triblock copolymer-grafted iron oxide nanoparticles, and the drug-delivery system showed pH-responsive drug release behavior in phosphoric acid buffer solution at pH 4.7, 7.4, or 11.0 at 37 8C. Lee et al.[94] prepared multifunctional composite nanoparticles for fluorescence, magnetic resonance imaging, and pH-sensitive drug release by immobilizing pH-responsive hydrazone bonds, Fe3O4 nanoparticles, and fluorescent dyes in mesoporous silica nanoparticles; the hydrazine functional group was introduced on the surface of the pores for pH-responsive linkages and DOX was conjugated through pH-sensitive hydrazone bonding, which resulted in pH-dependent DOX release. Chen et al.[95] fabricated multifunctional Fe3O4@poly(acrylic acid)/SiO2 core/shell nanostructures that consisted of a single Fe3O4 nanoparticle, poly(acrylic acid), and SiO2, and the as-prepared core-shell nanostructures had multiple functions of fluorescence imaging, high drug loading capacity, and pH-responsive drug release. Li et al.[96] reported a multifunctional fluorescent-magnetic (concentricFe3O4@SiO2)@polyacrylic acid core-double shell nanocomposite with ultrahigh drug storage capacity for cell imaging and pHresponsive drug delivery. This synthetic strategy was also extended to fabricate monodisperse (concentric-NaYF4 :Yb/Er/ Gd@SiO2)@polyacrylic acid core-double shell nanocomposite. Mu et al.[97] reported a magnetically targeted pH-responsive drug-delivery system prepared by layer-by-layer self-assembly of the polyelectrolytes (oligochitosan as the polycation and sodium alginate as the polyanion) through an electrostatic interaction with oil-in-water-type hybrid emulsion droplets that contained Fe3O4 nanoparticles and dipyridamole drug as the cores, and the cumulative release of dipyridamole from the drug-delivery system was nearly 100 % after 31 h at pH 1.8; in contrast, the cumulative drug release was only 3.3 % at pH 7.4 even after 48 h.

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Figure 12. Illustration of the preparation of calcium phosphate hybrid nanoparticles (CaP-HNP) through self-assembly of two oppositely charged polyelectrolytes, poly(diallyldimethylammonium chloride) (PDADMAC) and poly(acrylate sodium) (PAS), as dual templates for drug loading and release. Reprinted from reference [98]. Copyright 2013 Wiley-VCH.

working principle of as-prepared calcium phosphate hybrid nanoparticles (CaP-HNPs) as a drug nanocarrier. First, the poly(acrylate sodium)/Ca2 + and poly-(diallyldimethylammonium chloride)/PO43 complexes are formed through electrostatic interactions and then the two complexes self-assembled into calcium phosphate hybrid nanoparticles after mixing. The as-prepared calcium phosphate hybrid nanoparticles exhibited a spherical morphology with a narrow size distribution, good dispersibility, and high colloidal stability in water; They showed excellent biocompatibility, high drug loading capacity for the anticancer drug docetaxel, pH-sensitive drug-release behavior, and high anticancer effect after being loaded with docetaxel.[98] Victor et al.[99] prepared a pH-sensitive poly(methacrylic acid)calcium-deficient hydroxyapatite nanocomposite that consisted of nanoneedles as the drug carrier. The in vitro loading and release studies with albumin as a model drug indicated that the nanocomposite had a high drug-loading ability and exhibited a good uptake in C6 glioma cells. Li et al.[100] prepared amphiphilic gelatin/iron oxide core/calcium phosphate shell nanoparticles and loaded them with DOX by using electrolytic co-deposition during calcium phosphate shell formation. The shell of calcium phosphate played an important role by not only acting as a drug depot but also by rendering the drug release rate in a highly pH-dependent controlled manner. Bastakoti et al.[101] prepared core-shell-corona-type polymeric micelles of asymmetric triblock copolymer (poly(styrene-acrylic acid-ethylene glycol) (PS-PAA-PEG) with multiple functions, which included the ability to accommodate hydrophobic dyes into the core and hydrophilic drug into the shell in addition to pH-triggered drug release. The neutral and hydrophilic corona sterically stabilized the multifunctional polymeric micelles in 17


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Focus Review aqueous solution, and the mineralization of calcium phosphate on the poly(acrylic acid) domain not only enhanced the diagnostic efficacy of organic dyes, but also acted as a diffusion barrier for the controlled release. Cisplatin, an anticancer drug, was incorporated into the poly(acrylic acid) shell and the pHsensitive poly(acrylic acid) shell enabled faster drug release at mildly acidic pH (5.0) compared with physiological pH (7.4). The neutral and hydrophilic PEG corona could prevent the aggregation of micelles and, more importantly, provided steric protection against the intermicellar crosslinking. Min et al.[102] reported the preparation of mineral (calcium phosphate, CaP)-reinforced core-shell-corona micelles and investigated their application as a DOX nanocarrier. The polymer micelles of poly(ethylene glycol)-b-poly(l-aspartic acid)-bpoly(l-phenylalanine) (PEG-PAsp-PPhe) in aqueous solution have three functional domains: the hydrated PEG outer corona for prolonged circulation, an anionic PAsp middle shell for CaP mineralization, and a hydrophobic PPhe inner core for DOX loading. CaP mineralization occurred through an electrostatic interaction between Ca2 + ions and anionic PAsp shells, and CaP formed upon addition of phosphate anions. The CaP-mineralized micelles exhibited enhanced serum stability. DOX release from the DOX-loaded mineralized micelles (DOX-CaP-PM) at physiological pH was efficiently inhibited; however, at an endosomal pH (pH 4.5), DOX release was accelerated due to rapid dissolution of the CaP mineral layer. The in vivo tissue distribution and tumor accumulation of DOX-CaP-PM labeled with a near-infrared fluorescent dye (Cy5.5) indicated that the DOX-CaP-PM exhibited enhanced tumor specificity due to the prolonged stable circulation in the blood and an enhanced permeation and retention (EPR) effect compared with DOXloaded nonmineralized polymer micelles (DOX-NPM). The DOXCaP-PM exhibited enhanced therapeutic efficacy in tumorbearing mice compared with free DOX and DOX-NPM. Figure 13 shows the changes in tumor volume in C3H/HeN male mice after intravenous administration of saline, NPM, CaP-PM, free DOX, DOX-NPM (7.8 wt % DOX), and DOX-CaP-PM (7.8 wt % DOX). To evaluate the in vivo antitumor efficacy, DOX-CaP-PM and DOX-free or DOX-containing control groups were injected every 3 d into MDA-MB231 human breast tumor-

bearing mice via the lateral tail vein. DOX-free groups (saline and DOX-free micelles (NPM and CaP-PM)) did not show any noticeable inhibition of tumor growth. Administration of free DOX was effective in tumor regression to some extent, but the free DOX had low efficacy compared with the DOX-NPM or the DOX-CaP-PM. DOX-CaP-PM had higher efficacy for tumor reduction compared with non-mineralized DOX-NPM. After administration, the tumor volume was remarkably decreased in the DOX-CaP-PM-treated group. They explained the enhanced in vivo efficacy of DOX-CaP-PM by the enhanced accumulation of the DOX-CaP-PM at the tumor site due to enhanced nanocarrier stability and by the effective preservation of DOX within the core domains against leakage in the bloodstream and the facilitated intracellular release of DOX.[102] Xu et al.[103] prepared hydroxyapatite-coated liposomes (HACL) loaded with the hydrophobic drug indomethacin (IMC). The liposomes were formed from 1,2-dimyristoyl-sn-glycero-3phosphate (DMPA) and 1,2-dimyristoyl-sn-glycero-3-phosphocholine (DMPC). They found that adjusting their relative ratios could affect the drug-loading efficiency. The hydroxyapatite coating of the liposome decreased the release rate of IMC compared with uncoated liposomes; 70 % of the drug was released after approximately 5 h from the liposome, but coating with hydroxyapatite increased the release time to over 20 h. For uncoated liposomes, IMC was released at a greater rate at pH 7.4 than at pH 4. However, the hydroxyapatite coating reversed this trend and the release rate was greater at pH 4 than at pH 7.4. This result can be explained by the fact that IMC is more soluble under basic conditions, but hydroxyapatite is more soluble under acidic conditions. Luo et al.[104] prepared supramolecular microcapsules with drug-loaded wall layers for pH-controlled drug delivery by using a layer-by-layer technique based on the self-assembly between polyaldenhyde dextran-graft-adamantane and carboxymethyl dextran-graft-b-cyclodextrin on CaCO3 particles. Simultaneously, adamantine-modified doxorubicin was also loaded on the layer-by-layer wall through host–guest interaction. Because the adamantine groups were linked with polyaldenhyde dextran or DOX by pH-cleavable hydrazone bonds, adamantine moieties could be removed under the weak acidic conditions, which led to destruction of the supramolecular microcapsules and release of DOX. In vitro studies showed that the cytotoxicity of these drug-loaded supramolecular microcapsules under physiological conditions was much lower than that in acidic conditions, and the loaded drug could be rapidly released to induce tumor cell apoptosis due to the trigger of the acidic environment. Wu et al.[105] prepared amorphous calcium silicate hydrate/ block copolymer monomethoxy(polyethyleneglycol)-blockpoly(lactide-co-glycolide) hybrid nanoparticles in aqueous solution by using a facile coprecipitation route at room temperature. The ibuprofen loading capacity of the hybrid nanoparticles was ultrahigh ( 1.9 g of drug per gram of carrier), and the ibuprofen loading efficiency reached as high as about 100 %. The loaded ibuprofen could be released from the hybrid nanoparticles in simulated body fluid (SBF) for a long period of time ( 300 h) and the nanocarrier completely trans-

Figure 13. Changes in tumor volumes after injection of saline, NPM, CaP-PM, free DOX, DOX-NPM (7.8 wt % DOX), and DOX-CaP-PM (7.8 wt % DOX). Reprinted from reference [102]. Copyright 2012 Elsevier Ltd.

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Focus Review formed to hydroxyapatite, which exhibited good bioactivity. The release of the loaded docetaxel in PBS at pH 5.5 was obviously faster than that at pH 7.4, which is promising for applications in cancer therapy. In addition, the hemoglobin loading capacity of the as-prepared hybrid nanoparticles was high (995 mg g 1). Wu et al.[106] reported multifunctional nanocomposites that integrated a mesoporous structure and luminescent properties into a single system. Oleic acid-capped bNaYF4 :Ce3 + /Tb3 + nanoparticles were encapsulated with a uniform mesoporous silica shell followed by surface modification with poly(ethylene glycol), which led to the formation of water-dispersible core-shell structured b-NaYF4 :Ce3 + /Tb3 + @mSiO2-PEG nanospheres that exhibited a pH-sensitive drug release pattern for DOX·HCl, and the drug release was faster at lower pH values. Jing et al.[107] reported the covalent attachment of Mn-porphyrin onto DOX-loaded poly(lactic acid) nanoparticles for potential magnetic resonance imaging and pHsensitive drug delivery. Chen et al.[108] reported smart radioluminescent Gd2O2S:Eu nanocapsules with an X-ray-excited optical luminescence spectrum that varied during the release of the optically absorbing chemotherapy drug DOX. X-ray-luminescent nanocapsules were coated with eight layers of negatively charged poly(styrenesulfonate sodium) and seven layers of positively charged poly(allylaminehydrochloride) to encapsulate DOX with a layerby-layer assembly. They investigated in vitro pH-triggered DOX release rates from nanocapsules coated with a pH-responsive polyelectrolyte multilayer; the drug loading amount was over 5 % by weight and was released from the nanocapsules with a time constant in vitro of around 36 d at pH 7.4 and 21 h at pH 5.0. The nanocapsules were paramagnetic at room temperature, but the sulfur increased the radioluminescence intensity and shifted the spectrum. The empty nanocapsules accumulated in the liver and spleen of mice following tail vein injection and could be observed in vivo by using X-ray-excited optical luminescence. The bright radioluminescence of the nanocapsules could be used to track the delivered drug and monitor the drug release process. Other inorganic/organic-nanocomposite pH-responsive drug-delivery systems have also been reported. Some examples include graphene/poly(acrylic acid) hydrogel loaded with DOX[109] hollow nanospheres of chitosan/silica loaded with DOX,[110] poly(l-glutamic acid) grafted mesoporous silica nanoparticles/DOX·HCl,[111] poly(methacrylic acid-co-vinyl triethoxylsilane)/mesoporous silica microspheres/ibuprofen,[112] R (R = folate (FA) or methoxy)-poly(ethylene glycol)-poly(glutamate hydrozone doxorubicin)-poly(ethylene glycol)-acrylate/Fe3O4 loaded with DOX,[113] folic acid-conjugated poly(ethylene glycol)-modified dendrimer/iron oxide nanoparticles with DOX,[114] folate-conjugated porous ZnO nanorods loaded with DOX,[115] CaF2 :Ce3 + /Tb3 + -poly(acrylic acid)/DOX·HCl composite microspheres,[116] poly(acrylic acid)-modified lanthanide Ln3 + (Ln = Yb/Er, Yb/Ho, Yb/Tm)-doped GdVO4 nanocomposites loaded with DOX·HCl,[117] polyacrylic acid/zeolitic imidazolate framework-8 with DOX.[118] and vitamin B12-loaded microcapsules composed of crosslinked chitosan that acts as a pH-responsive capsule membrane, embedded magnetic nanopartiChem. Asian J. 2014, 9, 1 – 23

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cles to realize site-specific targeting, and embedded temperature-responsive submicrospheres that serve as micro-valves.[119] From the above-discussed examples, one can see that inorganic/organic-nanocomposites-based pH-responsive drug-delivery systems have displayed interesting properties and promising applications. The nanostructured inorganic components of these pH-responsive drug-delivery systems can provide various novel structures with well-defined size, morphology, and multifunctionality. Usually, the porous structure and high specific surface area of inorganic components in the nanocomposite can enhance the drug loading capacity and have an effect on the drug release profile. In addition, the high thermal, chemical, and biological stabilities of the inorganic components in the inorganic/organic nanocomposite can inhibit the fast corrosion and decomposition of the drug carriers in the physiological environment. Additional multifunctionality, such as magnetism, fluorescence, and pH-responsive drug delivery, will benefit the applications of the inorganic/organic-nanocomposite pH-responsive drug-delivery systems. Also, the presence of polymers offers advantages to the inorganic/organic-nanocomposite-based drug-delivery systems; inorganic nanoparticles with high specific surface areas and unsaturated atoms may interact with the organic polymer to lead to enhanced properties in the nanocomposite. For example, pH-labile linkages, degradation, and structural transformation of the pH-sensitive polymers can help to realize the pH-responsive drug release of some bio-inert inorganic materials. Hydrophilic polymers can be used to modify the inorganic drug carriers to achieve high dispersibility in aqueous solution, and smart polymeric materials can be adopted to modify the inorganic materials to realize targeted drug delivery through specific biological identification and binding. Currently, research on inorganic/organic-nanocompositesbased pH-responsive drug-delivery systems has become a hot topic and will attract more and more interest in the future. We would like to emphasize that the studies on the interactions between the drug molecules and inorganic/organic carriers will be very important for the design of novel drug-delivery systems, which would enhance drug loading capacity and control over drug delivery, and for further understanding of the related mechanisms. The construction of various pH-responsive inorganic/organic-nanocomposite drug carriers can be designed by intelligent choices of different inorganic components and polymers with different functional groups. In this way, desirable multiple functions, including pH-responsive drug delivery, can be achieved for the applications in various biomedical fields.

3. Conclusions and Perspectives There are various stimuli-responsive drug-delivery systems, including pH-responsive drug-delivery systems, enzyme-sensitive drug-delivery systems, DNA/RNA-sensitive drug-delivery systems, thermosensitive drug-delivery systems, magnetically responsive drug-delivery systems, ultrasound-responsive drugdelivery systems, and light-sensitive drug-delivery systems. Of these stimuli-responsive drug-delivery systems, the differences 19


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Focus Review synthetic calcium phosphate-based nanostructured materials and their nanocomposites for future applications. Further research is needed to deeply understand how these pH-responsive drug-delivery systems, composed of different materials, function both in vitro and in vivo, and how they work and are cleaned up in the physiological environment in vivo. More investigations should be conducted with pH-responsive drug-delivery systems in vivo to further advance to their clinical applications. We propose that the studies on the interactions between the drug molecules and inorganic/organic carriers will be very important for the design of novel drugdelivery systems, to enhance drug loading capacity and control over drug delivery, and for further understanding of the related mechanisms. However, the rapid development of nanotechnology will contribute to the design and synthesis of novel nanostructured materials for applications in multifunctional pH-responsive drug-delivery systems that can enable multimodal therapy and simultaneous bioimaging. As more and more experimental data on pH-responsive drug-delivery systems both in vitro and in vivo are available, it is expected that these pHresponsive drug-delivery systems will play a key role in applications in clinical and other biomedical fields, such as bioimaging, sensing, surface modification, and tissue engineering.

in the pH value of various tissues and cellular compartments have been used as a popular stimulus in the design of pH-sensitive drug-delivery systems, and pH-responsive drug-delivery systems can dramatically release drugs when they are transported to tumor tissues and internalized by cells through endocytosis. Diverse forms of mechanisms can be adopted for pH-responsive drug-delivery systems, which include chemical bond breaking, phase transformation, structural change, assembly/disassembly, molecular release, and materials dissolution. Therefore, pH-responsive drug-delivery systems offer great advantages in controlled drug delivery, thus they are very promising for the applications in various biomedical fields. Currently, pH-responsive drug-delivery systems have become a hot research topic, and significant progress in pH-responsive drug-delivery systems has been made over the past several decades. As a result, a large volume of experimental data has been documented in the literature and there have been many reports on organic polymer based pH-responsive drug-delivery systems in the literature. However, increasing number of papers have been published regarding inorganic and, in particular, inorganic/organic composite pH-responsive drug-delivery systems in recent years owing to their advantages in terms of thermal/chemical stability, biocompatibility, rich variety, and feasible control over morphology, size, and structure. Although significant advances have been made, however, there are still some issues which need to be resolved. For example, despite the design and preparation of many drug carriers for pH-responsive drug-delivery systems, these materials have not yet reached the stage of practical use; the ideal drug-delivery systems should have desirable multifunctionality and need to be engineered with more functional components to improve their performance in terms of specific-site targeting ability, intelligent pH-responsive drug release, and diagnostic capabilities. Furthermore, the facile, low-cost, and controlled synthesis of pH-responsive drug-delivery systems with well-defined structure, size, morphology, and chemical properties remains a big challenge; the controlled synthesis of novel pH-responsive drug-delivery systems by using biocompatible/biodegradable inorganic or inorganic/organic-composite nanostructured materials is crucial for practical use but has been less reported. In addition to organic materials, inorganic nanostructured materials, in particular inorganic/organic nanocomposites, hold great potential for applications in pH-responsive drug-delivery systems. Inorganic materials, such as noble metals, metal oxides, silica, and carbon (e.g., carbon nanotubes, carbon dots, graphene), have shown unique properties, such as high thermal/chemical stability, and they have been investigated for applications in various biomedical fields. However, because of their poor biodegradation behavior, the in vivo applications of these materials will be limited. We expect that the biodegradable nanostructured inorganic materials with high biocompatibility, such as calcium phosphate-based nanostructured materials and their nanocomposites, will provide promising applications for the pH-responsive drug-delivery systems; however, efforts should be made to improve the structure/size/morphology control, surface modification, and functionalization of &

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Acknowledgements Financial support from the National Basic Research Program of China (973 Program, no. 2012CB933600), and the National Natural Science Foundation of China (51172260) is gratefully acknowledged. Keywords: biomaterials · drug carriers · drug delivery · nanostructures · pH-responsive [1] V. Balamuralidhara, T. M. Pramodkumar, N. Srujana, M. P. Venkatesh, N. Vishal Gupta, K. L. Krishna, H. V. Gangadharappa, Am. J. Drug Discovery Dev. 2011, 1, 24 – 48. [2] Q. Yang, S. C. Wang, P. W. Fan, L. F. Wang, Y. Di, K. F. Lin, F. S. Xiao, Chem. Mater. 2005, 17, 5999 – 6003. [3] D. Schmaljohann, Adv. Drug Delivery Rev. 2006, 58, 1655 – 1670. [4] P. Gupta, K. Vermani, S. Garg, Drug Discovery Today 2002, 7, 569 – 579. [5] J. Berger, M. Reist, J. M. Mayer, O. Felt, N. A. Peppas, R. Gurny, Eur. J. Pharm. Biopharm. 2004, 57, 19 – 34. [6] A. Vashist, A. Vashist, Y. K. Gupta, S. Ahmad, J. Mater. Chem. B 2014, 2, 147 – 166. [7] P. Basak, B. Adhikari, J. Mater. Sci. Mater. Med. 2009, 20, S137 – S146. [8] M. M. C. Bastings, S. Koudstaal, R. E. Kieltyka, Y. Nakano, A. C. H. Pape, D. A. M. Feyen, F. J. van Slochteren, P. A. Doevendans, J. P. G. Sluijter, E. W. Meijer, S. A. J. Chamuleau, P. Y. W. Dankers, Adv. Healthcare Mater. 2014, 3, 70 – 78. [9] J. C. Garbern, E. Minami, P. S. Stayton, C. E. Murry, Biomaterials 2011, 32, 2407 – 2416. [10] Y. J. Pan, Y. Y. Chen, D. R. Wang, C. Wei, J. Guo, D. R. Lu, C. C. Chu, C. C. Wang, Biomaterials 2012, 33, 6570 – 6579. [11] V. Kozlovskaya, J. Chen, C. Tedjo, X. Liang, J. Campos-Gomez, J. Oh, M. Saeed, C. T. Lungu, E. Kharlampieva, J. Mater. Chem. B 2014, 2, 2494 – 2507. [12] T. S. Anirudhan, A. M. Mohan, RSC Adv. 2014, 4, 12109 – 12118. [13] X. Y. Gao, Y. Gao, X. F. Song, Z. Zhang, X. L. Zhuang, C. L. He, X. S. Chen, Macromol. Biosci. 2014, 14, 565 – 575.

20



Focus Review [14] J. Chen, M. Chu, K. Koulajian, X. Y. Wu, A. Giacca, Y. Sun, Biomed. Microdevices 2009, 11, 1251 – 1257. [15] Y. Bae, K. Kataoka, Adv. Drug Delivery Rev. 2009, 61, 768 – 784. [16] Y. Bae, N. Nishiyama, S. Fukushima, H. Koyama, M. Yasuhiro, K. Kataoka, Bioconjugate Chem. 2005, 16, 122 – 130. [17] X. J. Wang, G. L. Wu, C. C. Lu, W. P. Zhao, Y. N. Wang, Y. G. Fan, H. Gao, J. B. Ma, Eur. J. Pharm. Sci. 2012, 47, 256 – 264. [18] G. Y. Liu, L. P. Lv, C. J. Chen, X. S. Liu, X. F. Hu, J. Ji, Soft Matter 2011, 7, 6629 – 6636. [19] K. T. Oh, Y. T. Oh, N. M. Oh, K. Kim, D. H. Lee, E. S. Lee, Int. J. Pharm. 2009, 375, 163 – 169. [20] K. T. Oh, D. Kim, H. H. You, Y. S. Ahn, E. S. Lee, Int. J. Pharm. 2009, 376, 134 – 140. [21] R. Vivek, V. N. Babu, R. Thangam, K. S. Subramanian, S. Kannan, Colloids Surf. B 2013, 111, 117 – 123. [22] L. Fan, F. Li, H. T. Zhang, Y. K. Wang, C. Cheng, X. Y. Li, C. H. Gu, Q. Yang, H. Wu, S. Y. Zhang, Biomaterials 2010, 31, 5634 – 5642. [23] J. W. Cui, Y. Yan, G. K. Such, K. Liang, C. J. Ochs, A. Postma, F. Caruso, Biomacromolecules 2012, 13, 2225 – 2228. [24] M. S. Yang, F. D. Cui, B. G. You, L. Wang, P. Yue, Y. Kawashima, Int. J. Pharm. 2004, 286, 99 – 109. [25] C. L. Du, D. W. Deng, L. L. Shan, S. N. Wan, J. Cao, J. M. Tian, S. Achilefu, Y. Q. Gu, Biomaterials 2013, 34, 3087 – 3097. [26] D. Y. Chen, Z. T. Luo, N. J. Li, J. Y. Lee, J. P. Xie, J. M. Lu, Adv. Funct. Mater. 2013, 23, 4324 – 4331. [27] D. W. Dong, B. Xiang, W. Gao, Z. Z. Yang, J. Q. Li, X. R. Qi, Biomaterials 2013, 34, 4849 – 4859. [28] H. Ding, S. Inoue, A. V. Ljubimov, R. Patil, J. Portilla-Arias, J. W. Hu, B. Konda, K. A. Wawrowsky, M. Fujita, N. Karabalin, T. Sasaki, K. L. Black, E. Holler, J. Y. Ljubimova, Proc. Natl. Acad. Sci. USA 2010, 107, 18143 – 18148. [29] C. X. Liu, F. X. Liu, L. X. Feng, M. Li, J. Zhang, N. Zhang, Biomaterials 2013, 34, 2547 – 2564. [30] H. B. Wang, F. M. Xu, D. D. Li, X. S. Liu, Q. Jin, J. Ji, Polym. Chem. 2013, 4, 2004 – 2010. [31] J. Huang, F. Gao, X. X. Tang, J. H. Yu, D. X. Wang, S. Y. Liu, Y. P. Li, Polym. Int. 2010, 59, 1390 – 1396. [32] R. P. Tang, W. H. Ji, D. Panus, R. N. Palumbo, C. Wang, J. Controlled Release 2011, 151, 18 – 27. [33] M. Kamimura, J. O. Kim, A. V. Kabanov, T. K. Bronich, Y. Nagasaki, J. Controlled Release 2012, 160, 486 – 494. [34] K. T. Oh, E. S. Lee, Polym. Adv. Technol. 2008, 19, 1907 – 1913. [35] S. H. Ning, Q. Y. Huang, X. Y. Sun, C. L. Li, Y. Zhang, J. Li, Y. N. Liu, Soft Matter 2011, 7, 9394 – 9401. [36] U. Termsarasab, H. J. Cho, D. H. Kim, S. Chong, S. J. Chung, C. K. Shim, H. T. Moon, D. D. Kim, Int. J. Pharm. 2013, 441, 373 – 380. [37] F. Bigucci, B. Luppi, A. Musenga, V. Zecchi, T. Cerchiara, Drug Delivery 2008, 15, 289 – 293. [38] M. H. Hsiao, K. H. Lin, D. M. Liu, Soft Matter 2013, 9, 2458 – 2466. [39] J. Q. Zhao, H. Y. Wang, J. J. Liu, L. D. Deng, J. F. Liu, A. J. Dong, J. H. Zhang, Biomacromolecules 2013, 14, 3973 – 3984. [40] C. L. Tu, L. J. Zhu, F. Qiu, D. L. Wang, Y. Su, X. Y. Zhu, D. Y. Yan, Polymer 2013, 54, 2020 – 2027. [41] H. Z. Zhao, H. H. P. Duong, L. Y. L. Yung, Macromol. Rapid Commun. 2010, 31, 1163 – 1169. [42] J. T. Guo, H. Hong, G. J. Chen, S. X. Shi, Q. F. Zheng, Y. Zhang, C. P. Theuer, T. E. Barnhart, W. B. Cai, S. Q. Gong, Biomaterials 2013, 34, 8323 – 8332. [43] C. Y. Yu, B. C. Yin, W. Zhang, S. X. Cheng, X. Z. Zhang, R. X. Zhuo, Colloids Surf. B 2009, 68, 245 – 249. [44] W. C. She, N. Li, K. Luo, C. H. Guo, G. Wang, Y. Y. Geng, Z. W. Gu, Biomaterials 2013, 34, 2252 – 2264. [45] M. Q. Li, W. T. Song, Z. H. Tang, S. X. Lv, L. Lin, H. Sun, Q. S. Li, Y. Yang, H. Hong, X. S. Chen, ACS Appl. Mater. Interfaces 2013, 5, 1781 – 1792. [46] C. Zheng, X. P. Yao, L. Y. Qiu, Macromol. Biosci. 2011, 11, 338 – 343. [47] H. Wu, L. Zhu, V. P. Torchilin, Biomaterials 2013, 34, 1213 – 1222. [48] X. Guo, C. L. Shi, J. Wang, S. B. Di, S. B. Zhou, Biomaterials 2013, 34, 4544 – 4554. [49] D. Sutton, R. Durand, X. T. Shuai, J. M. Gao, J. Appl. Polym. Sci. 2006, 100, 89 – 96. Chem. Asian J. 2014, 9, 1 – 23

www.chemasianj.org


[50] Y. J. Gu, J. P. Cheng, J. F. Jin, S. H. Cheng, W. T. Wong, Int. J. Nanomed. 2011, 6, 2889 – 2898. [51] J. Zhu, L. Liao, X. J. Bian, J. L. Kong, P. Y. Yang, B. H. Liu, Small 2012, 8, 2715 – 2720. [52] S. Aryal, J. J. Grailer, S. Pilla, D. A. Steeber, S. Q. Gong, J. Mater. Chem. 2009, 19, 7879 – 7884. [53] V. Garcia-Gradilla, J. Orozco, S. Sattayasamitsathit, F. Soto, F. Kuralay, A. Pourazary, A. Katzenberg, W. Gao, Y. F. Shen, J. Wang, ACS Nano 2013, 7, 9232 – 9240. [54] B. Kang, M. M. Afifi, L. A. Austin, M. A. El-Sayed, ACS Nano 2013, 7, 7420 – 7427. [55] Y. F. Jiao, J. Guo, S. Shen, B. S. Chang, Y. H. Zhang, X. G. Jiang, W. L. Yang, J. Mater. Chem. 2012, 22, 17636 – 17643. [56] M. Li, C. Zhang, X.-L. Yang, H.-B. Xu, J. Sol-Gel Sci. Technol. 2013, 67, 501 – 506. [57] X. Ma, Y. Zhao, K. W. Ng, Y. L. Zhao, Chem. Eur. J. 2013, 19, 15593 – 15603. [58] X. M. Zhu, J. Yuan, K. C. F. Leung, S. F. Lee, K. W. Y. Sham, C. H. K. Cheng, D. W. T. Au, G. J. Teng, A. T. Ahuja, Y. X. J. Wang, Nanoscale 2012, 4, 5744 – 5754. [59] C. Qi, Y. J. Zhu, X. Y. Zhao, B. Q. Lu, Q. L. Tang, J. Zhao, F. Chen, Chem. Eur. J. 2013, 19, 981 – 987. [60] J. Zhao, Y. J. Zhu, J. Q. Zheng, F. Chen, J. Wu, Microporous Mesoporous Mater. 2013, 180, 79 – 85. [61] C. Qi, Y. J. Zhu, B. Q. Lu, X. Y. Zhao, J. Zhao, F. Chen, J. Mater. Chem. 2012, 22, 22642 – 22650. [62] X. Y. Zhao, Y. J. Zhu, F. Chen, B. Q. Lu, C. Qi, J. Zhao, J. Wu, CrystEngComm 2013, 15, 7926 – 7935. [63] X. Y. Zhao, Y. J. Zhu, F. Chen, B. Q. Lu, J. Wu, CrystEngComm 2013, 15, 206 – 212. [64] C. Qi, Y. J. Zhu, B. Q. Lu, X. Y. Zhao, J. Zhao, F. Chen, J. Wu, Chem. Eur. J. 2013, 19, 5332 – 5341. [65] W. Y. Qian, D. M. Sun, R. R. Zhu, X. L. Du, H. Liu, S. L. Wang, Int. J. Nanomed. 2012, 7, 5781 – 5792. [66] P. X. Liu, M. Chen, C. Chen, X. L. Fang, X. L. Chen, N. F. Zheng, J. Mater. Chem. B 2013, 1, 2837 – 2842. [67] Y. L. Dai, D. M. Yang, P. A. Ma, X. J. Kang, X. Zhang, C. X. Li, Z. Y. Hou, Z. Y. Cheng, J. Lin, Biomaterials 2012, 33, 8704 – 8713. [68] F. Muhammad, M. Y. Guo, W. X. Qi, F. X. Sun, A. F. Wang, Y. J. Guo, G. S. Zhu, J. Am. Chem. Soc. 2011, 133, 8778 – 8781. [69] F. Chen, C. Li, Y. J. Zhu, X. Y. Zhao, B. Q. Lu, J. Wu, Biomater. Sci. 2013, 1, 1074 – 1081. [70] C. Qi, Y. J. Zhu, F. Chen, ACS Appl. Mater. Interfaces 2014, 6, 4310 – 4320. [71] K. L. Lin, L. Chen, P. Y. Liu, Z. Y. Zou, M. L. Zhang, Y. H. Shen, Y. Q. Qiao, X. Y. Liu, J. Chang, CrystEngComm 2013, 15, 2999 – 3008. [72] X. J. Li, Z. Y. Hou, P. A. Ma, X. Zhang, C. X. Li, Z. Y. Cheng, Y. L. Dai, J. S. Lian, J. Lin, RSC Adv. 2013, 3, 8517 – 8526. [73] S. S. Huang, Z. Y. Cheng, P. A. Ma, X. J. Kang, Y. L. Dai, J. Lin, Dalton Trans. 2013, 42, 6523 – 6530. [74] Z. Y. Cheng, P. A. Ma, Z. Y. Hou, W. X. Wang, Y. L. Dai, X. F. Zhai, J. Lin, Dalton Trans. 2012, 41, 1481 – 1489. [75] H. Q. Zheng, L. Xing, Y. Y. Cao, S. A. Che, Coord. Chem. Rev. 2013, 257, 1933 – 1944. [76] Y. L. Xiao, R. Jaskula-Sztul, A. Javadi, W. J. Xu, J. Eide, A. Dammalapati, M. Kunnimalaiyaan, H. Chen, S. Q. Gong, Nanoscale 2012, 4, 7185 – 7193. [77] H. Q. Zheng, C. B. Gao, B. W. Peng, M. H. Shu, S. A. Che, J. Phys. Chem. C 2011, 115, 7230 – 7237. [78] H. Q. Zheng, Z. H. Huang, S. A. Che, Dalton Trans. 2012, 41, 5038 – 5044. [79] Q. J. He, Y. Gao, L. X. Zhang, Z. W. Zhang, F. Gao, X. F. Ji, Y. P. Li, J. L. Shi, Biomaterials 2011, 32, 7711 – 7720. [80] X. X. Hu, Y. Wang, B. Peng, Chem. Asian J. 2014, 9, 319 – 327. [81] F. Chen, Y. C. Zhu, Microporous Mesoporous Mater. 2012, 150, 83 – 89. [82] L. Xing, H. Q. Zheng, Y. Y. Cao, S. A. Che, Adv. Mater. 2012, 24, 6433 – 6437. [83] Y. J. Yang, X. Tao, Q. Hou, Y. Ma, X. L. Chen, J. F. Chen, Acta Biomater. 2010, 6, 3092 – 3100. [84] G. Begum, M. V. Laxmi, R. K. Rana, J. Mater. Chem. 2012, 22, 22174 – 22180.

21


&

&

Focus Review [85] R. J. Xing, A. A. Bhirde, S. J. Wang, X. L. Sun, G. Liu, Y. L. Hou, X. Y. Chen, Nano Res. 2013, 6, 1 – 9. [86] Z. H. Zhao, D. T. Huang, Z. Y. Yin, X. Q. Chi, X. M. Wang, J. H. Gao, J. Mater. Chem. 2012, 22, 15717 – 15725. [87] M. Das, D. Mishra, P. Dhak, S. Gupta, T. K. Maiti, A. Basak, P. Pramanik, Small 2009, 5, 2883 – 2893. [88] E.-K. Lim, W. Sajomsang, Y. Choi, E. Jang, H. Lee, B. Kang, E. Kim, S. Haam, J.-S. Suh, S. J. Chung, Y.-M. Huh, Nanoscale Res. Lett. 2013, 8, 467. [89] L. L. Li, D. Chen, Y. Q. Zhang, Z. T. Deng, X. L. Ren, X. W. Meng, F. Q. Tang, J. Ren, L. Zhang, Nanotechnology 2007, 18, 405102. [90] D. Li, J. Tang, C. Wei, J. Guo, S. L. Wang, D. Chaudhary, C. C. Wang, Small 2012, 8, 2690 – 2697. [91] P. Zou, Y. K. Yu, Y. A. Wang, Y. Q. Zhong, A. Welton, C. Galbn, S. M. Wang, D. X. Sun, Mol. Pharm. 2010, 7, 1974 – 1984. [92] Y. L. Chang, X. L. Meng, Y. L. Zhao, K. Li, B. Zhao, M. Zhu, Y. P. Li, X. S. Chen, J. Y. Wang, J. Colloid Interface Sci. 2011, 363, 403 – 409. [93] X. H. He, X. M. Wu, X. Cai, S. L. Lin, M. R. Xie, X. Y. Zhu, D. Y. Yan, Langmuir 2012, 28, 11929 – 11938. [94] J. E. Lee, D. J. Lee, N. Lee, B. H. Kim, S. H. Choi, T. Hyeon, J. Mater. Chem. 2011, 21, 16869 – 16872. [95] L. L. Chen, L. Li, L. Y. Zhang, S. X. Xing, T. T. Wang, Y. A. Wang, C. G. Wang, Z. M. Su, ACS Appl. Mater. Interfaces 2013, 5, 7282 – 7290. [96] L. Li, C. Liu, L. Y. Zhang, T. T. Wang, H. Yu, C. G. Wang, Z. M. Su, Nanoscale 2013, 5, 2249 – 2253. [97] B. Mu, P. Liu, P. C. Du, Y. Dong, C. Y. Lu, J. Polym. Sci. Part A 2011, 49, 1969 – 1976. [98] X. Y. Zhao, Y. J. Zhu, F. Chen, B. Q. Lu, C. Qi, J. Zhao, J. Wu, Chem. Asian J. 2013, 8, 1306 – 1312. [99] S. P. Victor, C. P. Sharma, Colloids Surf. B 2013, 108, 219 – 228. [100] W. M. Li, S. Y. Chen, D. M. Liu, Acta Biomater. 2013, 9, 5360 – 5368. [101] B. P. Bastakoti, K. C. W. Wu, M. Inoue, S. Yusa, K. Nakashima, Y. Yamauchi, Chem. Eur. J. 2013, 19, 4812 – 4817. [102] K. H. Min, H. J. Lee, K. Kim, I. C. Kwon, S. Y. Jeong, S. C. Lee, Biomaterials 2012, 33, 5788 – 5797. [103] Q. G. Xu, Y. Tanaka, J. T. Czernuszka, Biomaterials 2007, 28, 2687 – 2694. [104] G. F. Luo, X. D. Xu, J. Zhang, J. Yang, Y. H. Gong, Q. Lei, H. Z. Jia, C. Li, R. X. Zhuo, X. Z. Zhang, ACS Appl. Mater. Interfaces 2012, 4, 5317 – 5324.

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[105] J. Wu, Y. J. Zhu, F. Chen, X. Y. Zhao, J. Zhao, C. Qi, Dalton Trans. 2013, 42, 7032 – 7040. [106] Y. Wu, D. M. Yang, X. J. Kang, P. A. Ma, S. S. Huang, Y. Zhang, C. X. Li, J. Lin, Dalton Trans. 2013, 42, 9852 – 9861. [107] L. J. Jing, X. L. Liang, X. D. Li, Y. B. Yang, Z. F. Dai, Acta Biomater. 2013, 9, 9434 – 9441. [108] H. Y. Chen, T. Moore, B. Qi, D. C. Colvin, E. K. Jelen, D. A. Hitchcock, J. He, O. T. Mefford, J. C. Gore, F. Alexis, J. N. Anker, ACS Nano 2013, 7, 1178 – 1187. [109] J. Q. Liu, L. Cui, N. Kong, C. J. Barrow, W. R. Yang, Eur. Polym. J. 2014, 50, 9 – 17. [110] E. Y. Yan, Y. Ding, C. J. Chen, R. T. Li, Y. Hu, X. Q. Jiang, Chem. Commun. 2009, 2718 – 2720. [111] J. Zheng, X. J. Tian, Y. F. Sun, D. R. Lu, W. L. Yang, Int. J. Pharm. 2013, 450, 296 – 303. [112] Q. Gao, Y. Xu, D. Wu, Y. H. Sun, X. A. Li, J. Phys. Chem. C 2009, 113, 12753 – 12758. [113] X. Q. Yang, J. J. Grailer, I. J. Rowland, A. Javadi, S. A. Hurley, V. Z. Matson, D. A. Steeber, S. Q. Gong, ACS Nano 2010, 4, 6805 – 6817. [114] Y. L. Chang, N. A. Liu, L. Chen, X. L. Meng, Y. J. Liu, Y. P. Li, J. Y. Wang, J. Mater. Chem. 2012, 22, 9594 – 9601. [115] S. Mitra, B. Subia, P. Patra, S. Chandra, N. Debnath, S. Das, R. Banerjee, S. C. Kundu, P. Pramanik, A. Goswami, J. Mater. Chem. 2012, 22, 24145 – 24154. [116] Y. L. Dai, C. M. Zhang, Z. Y. Cheng, P. A. Ma, C. X. Li, X. J. Kang, D. M. Yang, J. Lin, Biomaterials 2012, 33, 2583 – 2592. [117] X. J. Kang, D. M. Yang, Y. L. Dai, M. M. Shang, Z. Y. Cheng, X. Zhang, H. Z. Lian, P. A. Ma, J. Lin, Nanoscale 2013, 5, 253 – 261. [118] H. Ren, L. Y. Zhang, J. P. An, T. T. Wang, L. Li, X. Y. Si, L. He, X. T. Wu, C. G. Wang, Z. M. Su, Chem. Commun. 2014, 50, 1000 – 1002. [119] J. Wei, X. J. Ju, X. Y. Zou, R. Xie, W. Wang, Y. M. Liu, L. Y. Chu, Adv. Funct. Mater. 2014, 24, 3312 – 3323.

Received: June 27, 2014 Revised: July 21, 2014 Published online on && &&, 0000

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Focus Review

REVIEW & Drug Delivery

Get a response! pH-Responsive drugdelivery systems have promising applications because they are “smart” or “intelligent” in overcoming the shortcomings of conventional drug formulations and are able to deliver drugs in a controlled manner at specific sites and times, which results in high therapeutic efficacy. Recent progress obtained for pH-responsive drug-delivery systems and future perspectives is presented.

Chem. Asian J. 2014, 9, 1 – 23

www.chemasianj.org


Y.-J. Zhu,* F. Chen && – && pH-Responsive Drug-Delivery Systems

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Systems biology approach to developing "systems therapeutics".

Toxin-antitoxin systems as multilevel interaction systems.

Medical systems as changing social systems.

Systems biology as an integrated platform for bioinformatics, systems synthetic biology, and systems metabolic engineering.

FM systems.

Expression systems.

Systems Toxicology.

Expression systems.

Systems medicine: evolution of systems biology from bench to bedside.

Systems vaccinology: Enabling rational vaccine design with systems biological approaches.

Systems oncology: toward the clinical application of cancer systems biology.

The Systems SOAP Note: A Systems Learning Tool.

Seizures and brain regulatory systems: consciousness, sleep, and autonomic systems.

Multiple memory systems as substrates for multiple decision systems.

Systems vaccinology: probing humanity's diverse immune systems with vaccines.

[IT systems in radiology and IT systems for radiologists].

Electronic nicotine delivery systems.

Supramolecular systems chemistry.

Integrative radiation systems biology.

Toward standardardized VCG systems.

Implantable drug-delivery systems.

Mobile sensing systems.

Systems biology and reproduction.

Nursing personnel systems.