pH- and sugar-sensitive layer-by-layer films and microcapsules for drug delivery

Advanced Drug Delivery Reviews 63 (2011) 809–821

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Advanced Drug Delivery Reviews j o u r n a l h o m e p a g e : w w w. e l s ev i e r. c o m / l o c a t e / a d d r

pH- and sugar-sensitive layer-by-layer films and microcapsules for drug delivery☆ Katsuhiko Sato, Kentaro Yoshida, Shigehiro Takahashi, Jun-ichi Anzai ⁎ Graduate School of Pharmaceutical Sciences, Tohoku University, Aramaki, Aoba-ku, Sendai 980-8578, Japan

a r t i c l e

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Article history: Received 1 October 2010 Accepted 30 March 2011 Available online 12 April 2011 Keywords: LbL film LbL microcapsule pH-sensitive release Sugar-sensitive release Insulin release Drug delivery

a b s t r a c t The present review provides an overview on the recent progress in the development of pH- and sugar-sensitive layer-by-layer (LbL) thin films and microcapsules in relation to their potential applications in drug delivery. pHsensitive LbL films and microcapsules have been studied for the development of peptide and protein drug delivery systems to the gastrointestinal tract, anti-cancer drugs to tumor cells, anti-inflammatory drugs to inflamed tissues, and the intracellular delivery of DNA, where pH is shifted from neutral to acidic. pH-induced decomposition or permeability changes of LbL films and microcapsules form the basis for the pH-sensitive release of drugs. Sugar-sensitive LbL films and microcapsules have been studied mainly for the development of an artificial pancreas that can release insulin in response to the presence of glucose. Therefore, glucose oxidase, lectin, and phenylboronic acid have been used for the construction of glucose-sensitive LbL films and microcapsules. LbL film-coated islet cells are also candidates for an artificial pancreas. An artificial pancreas would make a significant contribution to improving the quality of life of diabetic patients by replacing repeated subcutaneous insulin injections. © 2011 Elsevier B.V. All rights reserved.

Contents 1. 2.

Introduction . . . . . . . . . . . . . . . . . . . pH-sensitive LbL films and microcapsules . . . . . . 2.1. Electrostatic bond-based systems . . . . . . 2.1.1. Electrostatic LbL films . . . . . . . 2.1.2. Electrostatic LbL microcapsules . . . 2.2. Hydrogen bond-based systems . . . . . . . 2.2.1. Hydrogen bonded LbL films . . . . . 2.2.2. Hydrogen-bonded LbL microcapsules 2.3. Miscellaneous systems . . . . . . . . . . . 3. Sugar-sensitive LbL films and microcapsules . . . . 3.1. Phenylboronic acid-based systems . . . . . . 3.2. Protein- and cell-based systems . . . . . . . 4. Conclusion and outlook . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . .

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1. Introduction Drug delivery systems are an effective way to control the concentration of therapeutic agents in blood and to improve their bioavailability. ☆ This review is part of the Advanced Drug Delivery Reviews theme issue on “Layer-byLayer Self-Assembled Nanoshells for Drug Delivery”. ⁎ Corresponding author. Tel.: + 81 22 795 6841; fax: + 81 22 795 6840. E-mail address: [email protected] (J. Anzai). 0169-409X/$ – see front matter © 2011 Elsevier B.V. All rights reserved. doi:10.1016/j.addr.2011.03.015

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The blood level of a drug is known to rapidly increase after administration and gradually decreases below the lowest level required for therapeutic action. Consequently, repeated administration of a drug is often required for patients to maintain the blood level of the drug within the range of effective therapeutic action. However, in controlled delivery systems, drug molecules are embedded in gel matrices that can control the release rate of the drug, which results in sustained drug release. Furthermore, systems for stimuli-sensitive drug release can be constructed if the gel materials are endowed with sensitivity to specific

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stimuli. External stimuli such as temperature, light, and electric and magnetic fields, and internal stimuli including pH and biological ions and molecules are often used as the stimuli by which drug release is triggered [1–6]. In stimuli-sensitive drug delivery, required amounts of the drug can be released at the site of drug action in response to stimuli. A typical example of stimuli-sensitive drug delivery can be seen in the development of insulin formulations for the treatment of diabetic mellitus, in which much effort has been devoted to the development of glucose-sensitive microspheres or micropaticles that release insulin in response to the elevated level of blood glucose. To develop glucosetriggered insulin release, glucose-sensitive materials such as glucose oxidase, lectins, and phenylboronic acid derivatives have currently been employed [7–9]. Glucose-sensitive formulations of insulin could serve as an artificial pancreas, which would eliminate the necessity of repeated insulin injection. Another insulin formulation under extensive study is one that can be orally administrated as an alternative to subcutaneous injection [10,11]. However, the oral delivery of insulin is not presently realistic, because insulin is decomposed into peptide fragments by proteolytic enzymes in the stomach. The bioavailability of orally administrated insulin can be improved to some extent by coating the formulations with polymer films that are stable in acidic environments but are dissolved in neutral media (i.e., enteric coating). The use of enteric coatings is known to be effective for protecting insulin as well as other protein drugs from enzymatic digestion in the stomach and the drugs are then released in the small intestine at neutral pH. Synthetic polymers such as poly(acrylic acid) and cellulose derivatives with carboxyl side chains are often used for this purpose. Thus, enteric coatings open an opportunity for developing oral administrations of peptide and protein drugs including insulin, which in turn would significantly improve patient compliance. Targeted drug delivery has also been attracting much attention, due to its therapeutic advantages in improving bioavailability and minimizing systemic side effects [12]. Drug-embedded microparticles can be targeted to specific cells or tissues by modifying the particle surface with a ligand that exhibits affinity to the target cells or tissues. Recently, sugar derivatives have been explored for targeting drugs by taking advantage of the high affinity of specific sugars to lectins or sugar receptors on cell surfaces. For this goal, sugar-labeled polymers, liposomes, and microparticles have extensively been studied. For example, galactoselabeled microparticles have been developed for drugs targeting the liver (hepatocyte cells) through asialoglycoprotein receptors present on the surface of hepatocyte cells [13]. Therefore, different types of natural or synthetic materials are widely employed for the construction of devices for controlled drug delivery. Recently, layer-by-layer (LbL) deposited thin films and microcapsules have attracted much attention for the development of drug delivery systems [14–22]. This review focuses on the recent developments of LbL films and microcapsules for pH- and sugar-sensitive drug delivery. LbL-deposited thin films were first developed by Decher and co-workers [23]. They proposed a protocol for the preparation of thin films based on alternate and repeated adsorption of polycations and polyanions on the surface of a solid substrate from solution, as schematically illustrated in Fig. 1. LbL thin films with desired components can be prepared using appropriate types of cationic and anionic polyelectrolytes. The driving force of LbL deposition is not limited to attraction

by electrostatic force, but other binding interactions such as hydrogen bonding, covalent bonding, and biological affinity can also be used. A diversity of materials have been employed as building blocks for LbL films, including synthetic polymers, biopolymers (proteins, polysaccharides, DNA, etc.), inorganic nanoparticles, carbon nanotubes, and even viruses [24]. Consequently, a variety of components and functionality can be incorporated into LbL films, which forms the basis for the development of stimuli-sensitive LbL films for drug delivery. Another advantage of LbL films is that the film thickness can be regulated at the nanometer level by simply changing the number of deposited layers, which enables precise control of the drug loading in the film. Möhwald and co-workers fabricated polyelectrolyte hollow microcapsules in 1998 by LbL deposition of polyelectrolytes on the surface of colloidal particles, followed by dissolution of the core material (Fig. 2) [25]. The combination of poly(allylamine hydrochloride) (PAH) and poly (styrene sulfonate) (PSS) is a polyelectrolyte pair frequently used for microcapsule construction. Organic (polystyrene and melamine formaldehyde) and inorganic microparticles (CaCO3 and MnCO3) with diameters of a few micrometers have often been employed as core materials. With respect to drug delivery applications, the use of inorganic microparticles is plausible, because dissolution of these inorganic materials can be conducted in mild aqueous media (such as ethylenediaminetetraacetic acid (EDTA) solution) compared to the harsh conditions required for dissolution of the organic microparticles (i.e., organic solvent or strong acid). CaCO3 particles are often used recently for the preparation of polyelectrolyte microcapsules, especially for biomedical applications [26]. This is because biologically active peptides and proteins are easily incorporated in CaCO3 particles by coprecipitation upon synthesis of CaCO3 particles from a mixture of CaCl2 and (NH3)2CO3 solutions. Two distinct sites exist where drugs can be accommodated in polyelectrolyte microcapsules; the polyelectrolyte shell and the internal cavity. It is envisaged that drug molecules encapsulated in the cavity of microcapsules are released in response to chemical or physical stimuli that is detected by a receptor located on the polyelectrolyte shell. This strategy is widely adopted for the development of stimuli-sensitive drug delivery systems, as discussed in the following sections. The synthesis and properties of LbL films and microcapsules, including their applications to drug delivery, have been comprehensively reviewed by many authors [14–22,27–30]. Therefore, this review focuses on recent progress in the preparation and concepts of LbL films and microcapsules for pH- and sugar-sensitive drug delivery. 2. pH-sensitive LbL films and microcapsules The physiological pH in tissues and cells has been summarized in recent reviews in relation to drug delivery [1–5]. The pH variation along the gastrointestinal (GI) tract is well known and should be taken into consideration when developing oral administrations. The stomach has a strongly acidic pH of ca. 1.5, while the pH in the small intestine and colon is almost neutral. Therefore, acid-sensitive drugs such as peptides and proteins should not be delivered through the oral route. The extracellular pH of tumor cells slightly deviates to the acidic region from pH 7.4, by which pH-sensitive delivery of anti-cancer drugs may be developed. The pH of inflammatory tissues is also known to be acidic.

Fig. 1. Preparation of LbL thin films.

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Fig. 2. Preparation of polyelectrolyte LbL microcapsules containing drugs.

The pH variation in different cellular compartments is the basis for the pH-sensitive intracellular delivery of drugs, especially for DNA delivery. Thus, it may be possible to design pH-triggered drug delivery systems. Two different routes may be available for pH-triggered drug release from LbL films and microcapsules. Fig. 3 shows a schematic illustration of drug release from (a) LbL films and from (b) microcapsules triggered by change in pH. A drug can be embedded in LbL films and released upon change in the pH through enhanced permeability of the film or decomposition of the film entity. The enhanced permeability of the film may result in the accelerated diffusion of embedded drugs out of the film. A similar mechanism is often employed for pH-sensitive drug release from polymer gels. In this release mechanism, it is possible to construct pulsated release systems where drug release is accelerated and suppressed alternately in an on-off fashion in response to pH changes. On the other hand, decomposition of the film entity would be more straightforward to trigger a burst release of drugs. Drug release from LbL microcapsules can also be triggered through changes in permeability of capsule membrane or the decomposition of entire capsule (Fig. 3b). For LbL microcapsules, two distinct sites for drug encapsulation exist at the LbL shell and the internal cavity. It is reasonable to assume that larger amounts of drug molecules can be accommodated in the latter sites. Drug release from microcapsules is accelerated by enhanced permeability of the shell or by decomposition of the entire capsule, irrespective of the binding site of the drug. It is thus clear that one of the key issues in developing pH-sensitive LbL films and microcapsules is to design appropriate pH-sensitive polymeric materials and use suitable combinations for LbL depositions. The use of proteins as components of LbL layer may be an effective solution, because the

charge balance, conformation, and biological function of proteins are usually pH sensitive. Another strategy may also be plausible for pH-sensitive drug delivery from LbL films and microcapsules. As discussed above, pHsensitive drug delivery relies on the intrinsic pH sensitivity of the LbL layers. In contrast, pH-sensitive drug delivery could be performed on the basis of the pH response of the drug itself or drug conjugates in the films or microcapsules. Dissociable drugs embedded in LbL films should be under the influence of electrostatic forces of attraction or repulsion from the fixed charges in the film, depending on the pH of media. Consequently, dissociable drugs would be immobilized in the LbL film and released from the film upon changes in pH, even though the film is not pH-sensitive. In addition, drug release from microcapsules containing drug-polyelectrolyte conjugates may be triggered by pH changes if the binding of the drug to the conjugates is pH-dependent. The conjugates are not permeable across the capsule wall due to their large size, while dissociated drug molecules may be released out of the microcapsules, even if the microcapsule wall itself does not exhibit a pH response. In such cases, the LbL films and microcapsules serve only as a passive reservoir or porous micro-container. This chapter affords an overview on recent progress in the development of pH-sensitive drug delivery based on LbL thin films and microcapsules. 2.1. Electrostatic bond-based systems The pH-sensitive behaviors of electrostatic bonded LbL films and microcapsules have been extensively studied and it was found that weak polyelectrolyte-based LbL layers are basically pH-sensitive in

Fig. 3. Possible routes for pH-sensitive release of drugs from (a) LbL films and (b) microcapsules.

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terms of swelling, permeability, and even decomposition at extremely high or low pH. For example, the permeability of the Fe(CN)3− anion 6 through an LbL film composed of poly(ethyleneimine) (PEI) is significantly dependent on the solution pH while no pH dependent permeability is observed for LbL films composed of a strong polyelectrolyte such as poly(diallyldimethylammonium chloride) (PDDA) [31]. LbL microcapsules composed of PSS and PAH are reported to be permeable to high-molecular weight compounds such as dextran and albumin at low pH while impermeable at pH 8 or higher [32–35]. Dejugnat and coworkers observed a significant swelling and enhanced permeability of PSS-PAH microcapsules at pH 11 [36]. LbL microcapsules composed of PAH and poly(methacrylic acid) (PMA) are decomposed at pH 2.5 or lower pH and at pH 11.5 or higher [37]. The pH-sensitive properties originate from the acid–base equilibrium of the weak polyelectrolyte in the LbL layer. It should be noted that the acid–base equilibrium of weak polyelectrolytes in LbL layers is usually shifted from that in solution. In the PAH-PMA LbL film, for example, the apparent pKa values of PAH and PMA are 10.8 and 3.9 in comparison to 8.6 and 6.8 in solution, respectively [37]. 2.1.1. Electrostatic LbL films There have been several reports on the pH-sensitive release of drugs or dyes from LbL films that are prepared through electrostatic bonding. Burke and Barrett studied the pH-sensitive loading and release of dyes, indoin blue (IB) and chromotrope 2R (C-2R), in LbL films composed of PAH and hyaluronic acid (HA) [38]. The loading of IB and C-2R in the LbL film was higher in the alkaline and acidic pH regions, respectively, which suggests that these dyes are loaded through electrostatic forces of attraction in the film. The total amount of dyes released and the release rate were also pH-sensitive. Almost all IB molecules loaded were released from the (PAH/HA)10 film at pH 2.5, while only 40% and 20% were released at pH 7.0 and 9.0, respectively. The release rate of IB was higher at acidic pH than at neutral and basic pH. Akashi and co-workers studied the pH-sensitive release of a negatively-charged dye, allura red (AR), from LbL films composed of poly(vinyl amine) and poly(acrylic acid) (PAA) derivative [39]. The release of AR was accelerated in the media at pH 10 and 12, while release was very slow at neutral and slightly acidic pH. The faster release of AR in the basic solution is due to electrostatic repulsion between AR and the negatively charged PAA in the film. In addition, a significant effect of the ionic strength on the release rate was observed; the release was faster in higher ionic strength media due to shielding of the electrostatic binding between AR and the fixed positive charges in the film. The loading and release of methyl orange (MO) from PAH-PSS LbL film was also reported to be faster at neutral and basic pH due to reduced electrostatic attraction of the negatively charged MO to amino groups in the film [40]. Biocompatible LbL films prepared using poly(amino acid) have been employed for pH-sensitive drug release. Haynie and co-workers reported the release of methylene blue (MB) from LbL films composed of poly(L-glutamic acid) (PLGA) and poly(L-lysine) (PLL) [41]. The release of MB was completed within several hours in deionized water at pH 5.5, while only a few minutes was sufficient for complete release in buffered solution at the same pH. Jiang and Li also used PLGA/PLL films for tuning the release of the antibiotic drugs, cefazolin and gentamicin [42]. The amount of cefazolin released from the (PLGA/PLL)20 film was ca. 250 and 50 μg/cm2 after incubation for 1 h at pH 10 and 8.0, respectively. The released cefazolin and gentamicin retained antibiotic activity toward S. aureas. The results suggest the potential use of electrostatic bond-based LbL films for pH-sensitive drug delivery. One of the problems encountered with the pH response of LbL films is that the pH-sensitive region is determined by the polyelectrolyte materials used, so that fine tuning of the pH response is rather difficult. It is desirable that the pH-dependent release in drug delivery applications is observed within a narrow range around the physiological pH. In this context, Zhang and co-workers have succeeded in tuning the pH response for the release of porphyrin from

LbL films prepared by the alternate deposition of the PAH-porphyrin conjugate and thiol-modified PAA [43]. The pH threshold for the release of porphyrin was ca. pH 4.5 before cross-linking, while the threshold was shifted to pH 6.0 after cross-linking the thiol groups in the LbL film. Hydrolytically degradable LbL films have been constructed using degradable poly(β-amino ester) and therapeutic polysaccharides, heparin and chondroitin sulfate [44]. These LbL films were decomposed to release the polysaccharides in neutral and slightly acidic media. The decomposition of 20-bilayer films was completed within 10–15 h at pH 7.4, while the release was sustained for more than 10 days at pH 6.2. The use of poly(carboxybetaine)s may be useful for tuning the pH threshold of LbL films, because of their zwitterionic nature. Sukhishvili and co-workers reported that a poly(4-vinylpyridine) (P4VP) derivative, in which the pyridine ring was carboxyalkylated, can be built into a LbL film with PMA [45]. The LbL film exhibited pH-sensitive disintegration in neutral and acidic pH. LbL films composed of poly(sulfobetaine) and PDDA were found to be unstable at pH higher than 9.0 [46]. The use of amphoteric copolymers, whose net electric charges can be shifted from positive to negative or visa versa by changing the environmental pH, would be highly effective for tuning the pH threshold for the decomposition of LbL films. Lynn and co-workers have recently reported that LbL films containing citraconate-modified PAH degrade in weakly acidic media, while they are stable at neutral pH [47]. The results were rationalized by the conversion of the citraconate-modified PAH back to the cationic PAH in acidic media (Fig. 4). Vörös and co-workers reported that LbL films can be electrochemically removed from a surface without changing the pH of the bulk solution [48]. LbL thin films composed of PLL and heparin deposited on the surface of conducting indium tin oxide (ITO) electrode were slowly dissolved upon application of an electrode potential higher than +1.8 V, resulting in the release of heparin. The results were rationalized based on local pH changes at the electrode surface, which is in turn due to the electrochemical oxidation of water according to Eq. (1). DNA-containing LbL films were also made subject to electrolysis for controlling DNA release [49]. The release of porphyrin from PAH/PAA multilayer film was triggered by the application of electrode potential of +1.2 V or higher [50]. þ

−

H2 O→1=2 O2 þ 2H þ 2e

ð1Þ

The electrochemical manipulation of net electric charges, swelling, and permeability of LbL films and microcapsules has recently been studied for controlled drug release [51–56]. Electrochemicallycontrolled drug release has significant potential, because of the clean and controllable nature of electric signals. However, the susceptibility of drugs against applied electrode potential should be carefully addressed, especially when rather higher voltages are applied, because drug molecules are often easily oxidized or reduced on an electrode. 2.1.2. Electrostatic LbL microcapsules Biocompatible and biodegradable nano- and microparticles including LbL microcapsules have been extensively studied as drug carriers. Among these biodegradable materials, cationic polysaccharide chitosan and derivatives have attracted much attention for drug delivery applications [57–60]. Chitosan is a polysaccharide consisting of β-1,4-linked D-glucosamine residues produced by deacetylation of chitin. Peng and co-workers prepared carboxymethylcellulose (CMC)-incorporated LbL microcapsules using chitosan and alginic acid, in which anti-cancer drug daunorubicin (DNR) was successfully encapsulated through complexation with negatively charged CMC in the microcapsule [61]. The release of DNR from the microcapsule was faster in acidic medium than in neutral (pH 7.4), due to the dissociation of DNR from protonated CMC. The authors demonstrated by in vivo experiments that the released DNR is effective to suppress the growth of tumor cells. Zhang and co-workers reported the pH-sensitive release of bovine serum albumin (BSA) as a model for protein drugs from LbL microcapsules

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Fig. 4. Hydrolysis of citraconate-modified PAH (charge-shifting polymer 2) under acidic conditions (Top) and a schematic illustration of film erosion (Bottom). (Reprinted with permission from Ref. [47]. Copyright 2008, The Royal Society of Chemistry).

constructed with chitosan and dextran sulfate [62]. The encapsulated BSA was rapidly released at pH 7.4, while release was suppressed at pH 1.4. The rapid release of BSA at pH 7.4 was ascribed to the swelling of the microcapsule as a result of reduction of the positive charges of chitosan. The authors claimed the usefulness of this system for development of the oral delivery of protein drugs. The same group used thiol-modified chitosan to construct BSA-containing LbL microcapsules with crosslinked shells [63]. They observed that the microcapsules are uptaken by cells and BSA is released in the cell. Paramagnetic microcapsules were prepared with chitosan and citrate-modified metal oxide nanoparticles, from which the release of MB was pH-sensitive [64]. Zhao and Li used PLL and chondroitin sulfate as a biodegradable polyelectrolyte to construct LbL microcapsules [65]. The loading and release of BSA was controlled by changing the pH. The release of BSA from the microcapsules was slower in acidic media while the release was accelerated at pH 7.4, depending on the degree of electrostatic binding in the microcapsule. LbL microcapsules that decompose in the neutral pH region have recently been developed using P4VP. Mauser and co-workers prepared microcapsules by LbL deposition of P4VP and PMA on SiO2 particles. P4VP/PMA hollow microcapsules were stable at pH 2.0-8.0, while the capsules decomposed into a particle-like structure at pH higher than 8.1 [66]. On the other hand, microcapsules composed of P4VP and PSS were found to swell at pH higher than 6.0 and dissolve at pH 6.8 or higher [67]. Decomposition of the microcapsules was ascribed to a loss of electrostatic force of attraction and excess negative charges in the capsule wall as a result of the deprotonation of P4VP. P4VP-based microcapsules may be useful for pH-sensitive drug delivery under physiological conditions. The use of the polyphenol, tannic acid as a component for LbL films and microcapsules was proposed by Lvov and co-workers [68–70]. LbL films and microcapsules composed of tannic acid and cationic polyelectrolytes exhibited pH-dependent decomposition or permeability changes in the neutral pH region. BSA was released from LbL microcapsules consisting of tannic acid and chitosan upon change in the pH to lower than 5.0. The tannic acid-containing LbL layers in the films and microcapsules were demonstrated to be effective for the introduction of antioxidant activity [70]. LbL microcapsules with a biomimetic structure can be constructed using human serum albumin (HSA) and a lipid, L-α-dimyristoyl phosphatidic acid (DMPA), by LbL deposition [71]. HSA/DMPA microcapsules

were successfully prepared in a similar way to that for conventional polyelectrolyte microcapsules. The microcapsules are permeable to dextran (40 kDa) at pH 4.8 or lower, but impermeable at pH 7.4 or higher. An interesting microsphere was developed through LbL deposition of PAH and PAA on a mesoporous silica template followed by removal of the template [72]. Lysozyme was firmly retained in the microspheres at pH 7.4, while rapidly released at pH 2.0 due to electrostatic repulsion between lysozyme and the microspheres at acidic pH. 2.2. Hydrogen bond-based systems Since the first reports on the construction of hydrogen bond-based LbL films and their pH-sensitive disintegration [73–76], much effort has been devoted to the development of hydrogen bond-based LbL films and microcapsules as pH-sensitive materials. Polymeric materials frequently employed for the construction of hydrogen bonded LbL films and microcapsules are a combination of poly(carboxylic acid)s, such as PAA and PMA as hydrogen bonding donors, and hydrogen bonding acceptors such as poly(ethylene oxide) (PEO) and poly(4-N-vinylpyrrolidone) (PVPON). It is reasonable to assume that hydrogen bonded LbL layers are sensitive to environmental pH, because deprotonation from poly(carboxylic acid)s at higher pH results in the breaking of hydrogen bonds in the film. The low toxicity and high biocompatibility of these materials make such LbL films and microcapsules promising for biomedical applications including drug delivery. 2.2.1. Hydrogen bonded LbL films The preparation of hydrogen bonded LbL films and their pH-sensitive properties have recently been reviewed by Sukhishvili and co-workers [77–80]. Of interest with respect to drug delivery are the dye-doped LbL films composed of PMA and PEO [81]. Excess negative charges were produced in the film by slightly neutralizing solution pH and an oppositely charged dye, Rhodamin 6G, was electrostatically loaded into the film. The loaded dye was released upon acidification, due to the loss of the excess charges of PMA. The fine tuning of the pH threshold for the decomposition of hydrogen-bonded LbL films is an important task for application to drug delivery. It has been demonstrated that the pH threshold depends on the type of film components, film thickness and configuration [82–84]. For example, LbL films composed of poly(N-

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vinylcaprolactam) and oply(L-aspartic acid) decomposed at pH 3.0-4.0, while the decomposition pH were shifted to pH 5.5-7.0 by adding tannic acid as a third component in the film [83]. A variety of protocols to improve the loading and release of hydrogenbonded LbL films has been reported. Hammond and co-workers prepared LbL films composed of PAA and PEO-copolymer micelles, in which a hydrophobic uncharged drug was incorporated (Fig. 5) [85]. The antibiotic drug was released at pH 7.4 from LbL films that were prepared at pH 2.5. In an attempt to use pro-drugs, PVPON was covalently modified with the anti-inflammatory steroid prednisolone and built into the LbL film with PAA [86]. In another example, dendrimers were used to construct dye-doped LbL films through hydrogen bonding [87–89]. It was found that a carboxyl-terminated poly(amidoamine) dendrimer (PAMAM-COOH) could be assembled into LbL films by alternate deposition with PAA or PMA in acidic media through hydrogen bonding. The PAMAM-COOH/PAA or PMA films rely on hydrogen bonding between carboxylic acid residues in PAMAM-COOH and PAA or PMA, in contrast to other hydrogen bonded LbL films where the hydrogen bonding between poly(carboxylic acid) and acceptor polymers are employed. Model drugs were loaded in the PAMAM-COOH films and released in a pH-sensitive fashion. The use of dendrimers as drug containers in LbL films may be promising to enhance the loading of drugs [90,91]. 2.2.2. Hydrogen-bonded LbL microcapsules Sukhishvili and co-workers have recently produced amphoteric microcapsules by LbL deposition of PMA and PVPON followed by crosslinking with ethylenediamine [92,93]. PVPON was removed after crosslinking to afford single-component hollow microcapsules that exhibit amphoteric properties, due to amino groups in the capsule wall originating from the cross-linker. The microcapsules exhibited swelling at acidic and basic pH and were smallest at pH 5.5. The pH-sensitive loading of dextran and its release was observed in this microcapsule system. The release was also sensitive to changes in ionic strength; addition of a high concentration of NaCl accelerated the release of dextran at pH 5.5. Interestingly, adsorption of polycations on the capsule wall induced the release of dextran. It was also shown by the same group that microcapsules prepared in a similar manner using different poly (carboxylic acid)s exhibited different pH thresholds for swelling that were dependent on the acidity of the poly(carboxylic acid)s [94,95]. Recently, Tsukruk and co-workers have prepared tannic acid LbL microcapsules through hydrogen bonding with acceptor polymers such as PVPON, poly(N-vinylcaprolactam), and poly(N-isopropylacry-

lamide) [96] (Fig. 6). These microcapsules were stable over a wide pH range from 2 to 10 and exhibited pH-sensitive permeability changes to dextran. In addition, gold nano-particles (AuNP) were grown in the tannic acid-containing capsule wall under mild conditions, which suggests the possible use of AuNP as a scaffold for the introduction of proteins or DNA through electrostatic or covalent modification. 2.3. Miscellaneous systems This section focuses on pH-sensitive LbL systems containing proteins or mesoporous materials for drug delivery. Proteins are useful materials for the construction of stimuli-sensitive LbL films due to their amphoteric nature and biological affinity [97–101]. pH-sensitive LbL layers can be designed based on the amphoteric properties of proteins while the biological affinity feature enables the construction of LbL layers sensitive to specific biological stimuli. As a prototype of protein-based stimulisensitive LbL films, avidin was used for the construction of pH- and biotin-sensitive LbL films [102,103]. Avidin is a glycoprotein found in egg white and is known to contain four binding sites for biotin (binding constant, ca. 1015 M− 1). Avidin binds to 2-iminobiotin less strongly than biotin, and the affinity is pH dependent. Avidin and 2-iminobiotinbearing PEI (ib-PEI) were successively deposited to form LbL films on the surface of a quartz slide. The avidin/ib-PEI film was stable at pH 8.0 or higher, but decomposed at pH 6.0 or lower due to the reduced affinity of protonated 2-iminobiotin to avidin. The avidin/ib-PEI film was also sensitive to biotin and analogues such as desthiobiotin, lipoic acid, and 2(4′-hydroxyphenylazo)benzoic acid. The LbL film was decomposed in the presence of these compounds at concentrations of 10-7–10-3 M depending on the affinity to avidin. The avidin/ib-PEI LbL films could also be decomposed by electrical signal, or application of an electrode potential, due to local pH changes induced by the electrolysis of water or hydrogen peroxide on the electrode surface [104,105]. Therefore, these LbL films may find future applications in pH-sensitive drug delivery. pH-sensitive release of peptides and proteins is of crucial importance for the development of oral drug delivery systems. The development of oral administrations of insulin is a typical example. Insulin is a peptide drug consisting of 51 amino acid residues and is degraded by acid and enzymatic degradation in the stomach. Therefore, subcutaneous injection is currently the predominantly available route for insulin delivery in clinical practice. However, oral administration is more desirable to improve patient compliance. For this reason, a number of protocols have long been explored to develop the oral delivery of insulin [10,11].

Fig. 5. LbL deposition of PAA and drug-containing micelle through hydrogen bonding and its decomposition at pH 7.4. (Reprinted with permission from Ref. [85]. Copyright 2008, The American Chemical Society).

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prepared by the alternating deposition of insulin and polyanions such as dextran sulfate, poly(vinyl sulfate) (PVS), and PAA in acidic solutions (pH 1.0–3.0) through the electrostatic forces of attraction between positively-charged insulin and the polyanions (Fig. 7) [111,112]. The insulin-containing LbL films were decomposed when exposed to weakly acidic (pH 5.0–6.0) or neutral solutions (pH 7.4), due to a loss of electrostatic forces of attraction as a result of the charge reversal of insulin from positive to negative. The insulin-containing LbL films were found to be satisfactorily stable, even in the presence of the digestive enzyme pepsin at pH 1.4. These studies clearly demonstrate that insulin–polyanion conjugates are effective for protecting insulin from acidic and enzymatic degradation, even in a strongly acidic medium (i.e., the stomach) while insulin can be released in a neutral environment such as the small intestine. An interesting material for drug delivery has been developed by combining mesoporous silica nanoparticles and LbL films. Mesoporous materials have recently attracted much attention due to their large pore size, high surface area, and highly ordered 3D structure [113–115]. Zhu and Shi have studied the pH-controlled storage and release of gentamicin in mesoporous silica hollow capsules covered with PAHPSS LbL films [116]. Gentamicin was encapsulated in the capsules at pH 2.0, due to the high permeability of the LbL layer, although loading at pH 8.0 was severely limited. Gentamicin was not released at pH 8.0, but was rapidly released at pH 7.0 or lower, according to the pH-dependent permeability of the LbL layers. Mesoporous silica nanotubes have also been combined with PAH-PAA and alginate–chitosan LbL films for the pH-sensitive release of Doxorubicin (DOX) and fluorescein [117]. DOX was rapidly released from the LbL film-coated silica nanotubes at pH 1.2, while release was suppressed at pH 8.0. In vitro cell cytotoxicity assays revealed that the cytotoxic activity of the DOX-loaded silica nanotubes was pH-dependent. In other studies, mesoporous silica nanoparticles have been successfully used for the controlled release of insulin, BSA, and cyclic adenosine monophosphate (AMP) [118–120]. These studies clearly indicate the promising properties of LbL film-coated mesoporous silica materials for drug delivery applications. 3. Sugar-sensitive LbL films and microcapsules

Fig. 6. The confocal laser scanning microscope image of PEI(TA/PVPON)3 microcapsules in aqueous solution (a) and the scanning electron microscope image of the dried PEI (TA/PVPON)4 microcapsules collapsed on silicon wafer. (Reprinted with permission from Ref. [96]. Copyright 2010, The Royal Society of Chemistry).

Recently, LbL films and microcapsules have been studied to develop insulin drugs that can be orally administered. Insulin nanoaggregates of 100–230 nm in diameter prepared by salting out with NaCl were coated with LbL films composed of poly (α,β-L-malic acid) and chitosan [106]. Insulin was released from the LbL film-coated nano-aggregates at pH 7.4, while the release was suppressed at pH 4.0 and 5.0. The advantage of this protocol is that the insulin loading in the nanoparticles is significantly high, because the nanoaggregates consist of insulin itself. Similarly, insulin nanocrystals have been coated with LbL films to control the release rate [107,108]. LbL microcapsules containing insulin were also constructed by Tong and co-workers for pH-sensitive delivery of insulin [109]. In this protocol, electrostatic aggregates of insulin and alginic acid were encapsulated at acidic pH. Insulin was released from the microcapsules at pH 7.4 as a result of the dissociation of the insulin–alginate aggregates, which in turn was due to reversal of the net electric charges of insulin from positive to negative (isoelectric point of insulin, pH 5.4). In addition, the release rate can be tuned by changing the thickness (or the number of LbL layers) of the capsule shell. Chitosan–alginate LbL beads have proven effective for the temporary protection of protein drugs against acidic and enzymatic degradation within the GI tract [110]. We recently demonstrated that insulin-containing LbL films can be successfully

Sugar-sensitive systems would be valuable for drug delivery development, due to the key role of sugars in a broad range of biological functions. Drug delivery design analogous to pH-sensitive systems would involve different protocols for sugar-sensitive drug release from LbL films or microcapsules. The decomposition of LbL films or microcapsule shells would be induced if the linkage between polymeric materials in LbL layers could be broken in the presence of sugar, resulting in burst release of embedded drug molecules. Alternatively, sugarinduced changes in permeability or the formation of small pores in LbL layers could also result in sugar-induced drug release. Consequently, both cases have a key issue in the rational design of materials used as components of LbL layers so as to be sensitive to sugars. The glucose-triggered release of insulin is a main concern in sugarsensitive drug delivery development [121,122]. With this goal, the concept of an artificial pancreas has long been proposed and studied based on the combination of an electrochemical glucose sensor and an insulin infusion pump (i.e., closed-loop control of insulin delivery) [9,10]. Electrochemical glucose sensors that can be implanted in the body are still under extensive study [123]. In this context, LbL films have been widely used to improve the performance of electrochemical glucose sensors [124]. However, LbL film-based electrochemical glucose sensors are out of the scope of this review and are not included in this discussion. Instead, this chapter focuses on sugar-sensitive materials for the development of a molecular-based artificial pancreas, including LbL films and microcapsules. For this purpose, phenylboronic acid (PBA) derivatives, glucose oxidase (GOx), and lectin have often been used as glucose-sensitive materials. In chemical devices without electromechanical sensors and pumps, a glucose-receptor can be directly coupled

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Fig. 8. Binding equilibrium between PBA and diols.

Fig. 7. A schematic illustration for pH-triggered release of insulin from LbL film (Top) and a quartz crystal microbalance result for the preparation of LbL film composed of insulin and dextran sulfate at pH 3.0 and its decomposition at pH 7.4 (Bottom). The quartz resonator was exposed to (a) PEI, (b) buffer, (c) dextran sulfate, and (d) insulin solutions. The LbL film was exposed to medium at pH 7.4 st (e). (Reprinted with permission from Ref. [112]. Copyright 2010, The Royal Society of Chemistry).

to an insulin-releasing part without any interface. This is in clear contrast to the artificial pancreas composed of a glucose sensor and insulin pump, which relies on electrical interfaces including a computer. An additional advantage of a molecular-based artificial pancreas may be that micro- or nano-devices can be prepared. A discussion on sugarmediated targeting systems developed using LbL assemblies is also included in this chapter. 3.1. Phenylboronic acid-based systems PBA derivatives are known to bind diol or polyol compounds including sugars to form cyclic esters (Fig. 8). The binding equilibrium of PBA suggests that the PBA–sugar complex is negatively charged due to the addition of an OH− ion, while the parent PBA is in a neutral form, because the pKa values of PBA–sugar complexes are usually more acidic than those of the parent PBA. Thus, the optical and electrical properties of PBA are altered by forming the charged species. Consequently, many papers have reported on PBA-based optical and electrochemical sensors for sugar detection [125–127]. Unfortunately, PBA derivatives are not selective to glucose, but exhibit a group-selectivity to 1,2-diol and 1,3diol compounds. Nevertheless, PBA derivatives are valuable for the construction of glucose-sensitive delivery devices, because the concentration of glucose in the human blood is usually much higher than that of other sugars. Therefore, PBA derivatives have recently been used for

developing glucose-sensitive LbL films and microcapsules for future applications to insulin delivery. The first example of PBA-based glucose-sensitive microcapsules was reported by De Smedt and co-workers [128]. They used a PBA copolymer containing dimethylamino side chains (PDA) as the polycationic component to construct LbL microcapsules. Hollow microcapsules consisting of a (PDA/PSS)6 shell decomposed within 5 min upon exposure to 5 mg/mL glucose at pH 9.0, while the capsule was stable for several days without glucose. Decomposition of the microcapsule was induced at glucose concentrations higher than 2.5 mg/mL, which demonstrated that the capsules are stable at normal glucose levels (i.e., ca. 0.9 mg/mL). Unfortunately, no response to glucose was observed in a 0.1 M phosphate buffer at pH 7.0, due to the lower affinity of the PBA moiety to glucose at physiological pH. Levy and co-workers also constructed sugar-sensitive LbL films and microcapsules using a PBA-modified polymer and mannan (a polysaccharide composed of mannose residues) [129]. The LbL films and microcapsules were prepared through an ester bond formation between the PBA moieties in the PBA-modified polymer and mannan, in contrast to the (PDA/PSS)6 microcapsules developed by De Smedt and co-workers, which were constructed through electrostatic binding. Both the LbL films and microcapsules were decomposed in the presence of sugars such as fructose, mannose, galactose, and glucose depending on the concentration and pH of the medium. All data reported were collected at pH 10 or 11, because the LbL films were unstable at pH 9.0 or lower. Recently, insulin was entrapped in LbL microcapsules with a PBA-modified shell and sugar-sensitive release was reported [130]. These various results have demonstrated the possible use of PBA-bearing polymers for the construction of sugar-sensitive LbL films and microcapsules for future applications to glucose-triggered insulin delivery, although further improvement of the glucose response under physiological conditions is required. An attempt to develop LbL films sensitive to glucose at physiological pH has been reported by Zhang and co-workers [131]. They prepared LbL films using PBA-bearing PAA and poly(vinylalcohol) (PVA) and studied glucose-sensitive disassembly of the film. The decomposition of the LbL film was found to be accelerated in the presence of 5–30 mM glucose at pH 7.5 and 8.5, although the film was decomposed slowly even in the absence of glucose. An advantage of this film is that the glucose response can be observed at pH 7.4, which was rationalized by stabilization of the PBA ester by donation of nitrogen from acrylamide in the film. PBA-modified LbL films containing poly(acrylamide) and PVPON were also prepared by Zhang and co-workers. The release of a model drug from the LbL film was slightly faster in media containing 10 mM glucose at pH 8.5, while at pH 7.5 the effect of glucose was negligibly small [132]. Thus, the usefulness of PBA copolymers containing acrylamide side chains has been demonstrated for improving the response to glucose in the physiological pH region. Another possible approach to obtain glucose response under physiological conditions may be to use PBA derivatives that have pKa values

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in the physiological pH range. Therefore, electron-withdrawing groups such as nitro and halogen groups introduced to the phenyl ring of PBA may be effective [133]. However, PBA-containing LbL films and microcapsules reported so far have been constructed using polymeric PBAs without such chemical modification. The use of such substituted PBAs would improve the response in the physiological pH range. It is known that PVA forms complexes with boric acid to produce negatively charged PVA gel. Patil and co-workers recently constructed LbL films and microcapsules using a PVA–borate complex and chitosan and the glucose response was investigated [134,135]. The LbL deposition of the PVA–borate complex and chitosan successfully yielded thin films and microcapsules through electrostatic forces of attraction. The resulting LbL assemblies degraded within several hours in a solution containing 25 mM glucose, while no degradation was observed in a 5 mM glucose solution. The authors claimed a possible application of this system to the delivery of anticancer drugs based on the faster accumulation of glucose in tumor cells than in normal cells. For this reason, release of the anticancer drug DOX from the LbL film was examined and ca. 80% of encapsulated DOX was released after 10 h in 25 mM glucose solution at a physiological pH; however, in 5 mM glucose solution, only ca. 20% of DOX was released.

3.2. Protein- and cell-based systems Li and coworkers reported glucose-sensitive microcapsules composed of GOx and hemoglobin (Hb) [136]. The microcapsule wall was prepared by LbL deposition of GOx and Hb on a MnCO3 core (diameter, 6 μm) followed by a covalent cross-linking with glutaraldehyde (GA). It is also possible to construct microcapsules using only GOx or Hb by cross-linking with GA [137]. Both GOx and Hb were found to be catalytically active in the microcapsule wall; virtually no attenuated activity of GOx was observed for two weeks at 4 °C, while only 25% of the activity remained when incubated at 40 °C. The wall of the (Hb/GOx)5 microcapsule was found to be impermeable to dextran (200 kDa) in the absence of glucose. However, after incubation in 100 mM glucose solution for 3 h, dextran diffused across the wall into the microcapsule, due to enhanced permeability in the presence of glucose. The enhanced permeability was ascribed to changes in the local pH, which in turn originates from the GOx-catalyzed formation of gluconic acid according to Eq. (2). However, operational parameters of the microcapsules, such as the effects of pH, ionic strength, thickness of the capsule wall, response time, and repeatability, were not reported. If these parameters could be successfully optimized, Hb-GOx microcapsules may be useful for developing glucose-sensitive drug delivery systems. The direct coating of LbL layers on the surface of insulin crystals was also reported for the regulation of release of insulin in response to glucose [138]. Glucose þ O2 →gluconic acid þ H2 O2

ð2Þ

Drug targeting is one of the purposes of drug delivery systems for delivering drug molecules only to specific sites so as to reduce undesirable side effects of the drug to normal cells, tissues, and organs. An example is drug targeting to liver cells through strong interactions between D-galactose and asialoglycoprotein receptors, which are distributed on the surface of liver cells. Galactose coated-liposomes have been extensively studied for targeting drugs to liver cells. [139–141]. Recently, Lin and coworkers synthesized a galactose-bearing copolymer, poly(vinyl galactose ester-co-methacryloxyethyl trimethylammonium chloride) (PGEDMC), and fabricated LbL thin films and microcapsules [142–144]. The microcapsules formed aggregates in the presence of peanut agglutinin (PNA) lectin, while no aggregation was observed with concanavalin A (Con A), a lectin protein found in jack beans, which demonstrates that the galactose moieties on the surface of the microcapsules retained their binding affinity to PNA lectin [142]. Microcrystals of the antiviral drug acyclovir (ACV; 9-(2-hydroxyethoxy) methyl-guanine) were coated with PGEDMC-PSS multilayer films and

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the release of ACV and PNA recognition were examined [143]. In addition, they found that the permeability of the PGEDMC-PSS microcapsules could be tuned by heat treatment; the microcapsule exhibited thermal shrinkage (ca. 60% decrease in diameter) at 50 °C and the rate of release of encapsulated drug was significantly suppressed. The microcapsules exhibited affinity to PNA lectin even after the heat treatment [144]. In another protocol, the surface of microcapsules was coated with lipid bilayer films. Li and co-workers have recently prepared LbL microcapsules labeled with folate residues for targeting the microcapsules to cancer cells [145]. Labeled microcapsules were prepared by mixing alginate/chitosan microcapsules and a folate-bearing liposome in solution, by which the surfaces of the microcapsules were successfully coated with a folate-containing lipid bilayer film. Folate is known to exhibit high affinity to its receptor, which is over-expressed on the surface of cancer cells as a tumor marker [146]. Folate-labeled LbL microcapsules containing DOX were demonstrated to be effectively taken up by cancer cells while the uptake was suppressed by blocking the receptor with free folate. In this context, antibody-coated LbL microcapsules have also been studied for targeting drugs to colorectal cancer cells [147,148]. Con A is known to contain four identical binding sites to sugars. Therefore, Con A can be used as a material for constructing LbL films by combination with polysaccharides or sugar-bearing polymers. Lvov and co-workers first prepared LbL films using Con A and glycogen [149]. LbL films composed of Con A and dextran have also been studied for the development of fluorometric glucose sensors [150]. We have also constructed LbL films consisting of Con A and glycogen or sugar-bearing synthetic polymer and evaluated the sensitivity of the LbL films to sugars [151–153]. The Con A-containing LbL films were decomposed in the presence of sugar, because the added sugars competitively bound to Con A in the film. A 10-bilayer (Con A-glycogen)10 film was almost completely decomposed upon exposure to 10 mM solutions of mannose, methyl-α-glucose, and methyl-α-mannose at pH 7.4, while ca. 60% of the film was decomposed when the film was exposed to 10 mM glucose, and no decomposition was observed in the presence of galactose. The sensitivity of the (Con A-glycogen)10 film corresponds with the sequence of the binding affinity of Con A to the sugars, which confirms the preferential binding of the added sugar to the binding sites of Con A in the film, followed by the expulsion of glycogen from the binding sites. The LbL assembly of Con A and glycogen was further employed to develop insulin-containing microcapsules for glucose-induced insulin release [154]. Microcapsules were prepared by coating Con A-glycogen LbL films on the surface of CaCO3 cores containing insulin, followed by core dissolution. The Con A-glycogen LbL films were supported by inner and outer LbL layers of PEI and PVS, because the microcapsules could not be formed without supports. Insulin was released slowly from the microcapsules, even in the absence of sugar, which suggests the microcapsule wall has a rather porous structure, probably due to the lower density of cross-linking sites between Con A and glycogen compared with microcapsules prepared through electrostatic binding of linear polyelectrolytes. In contrast, the release of insulin was accelerated in the presence of 100 mM glucose, while the effect was rather small when 10 mM glucose was added. It is desirable for insulin microcapsules to release insulin in the presence of 10 mM glucose, because a normal blood level of glucose is around 5 mM. Further improvements are required for such microcapsules with Con A–glycogen LbL layers prior to in vivo study. We now consider the LbL encapsulation of pancreatic islets for the development of a bio-artificial pancreas. The transplantation of pancreatic islets of Langerhans cells embedded in polymer microgels has been studied for the treatment of diabetes mellitus. Polymeric materials including agarose, alginate, chitosan, and PLL have often been employed for gel components, by which the islets can be isolated from the host immune system. In the islet-embedded microgels, islets are usually

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dispersed as clusters in the gels, which often induces problems such as insufficient supply of oxygen and nutrients to the islet cells. In addition, the ratio of encapsulated cell volume to overall gel volume is rather low, which limits the use of islet-encapsulated gels. Therefore, islet encapsulation has not yet reached clinical practice, despite the long-term studies of these systems. To overcome these problems, encapsulation of islet cells has recently been examined using LbL deposition of thin films on the surface of islet cells. Krol and co-workers have successfully coated the surface of islet cells with LbL films and found that the LbL film-coated islet cells exhibit glucose-dependent release of insulin and the LbL film provided protection against islet-specific antibody recognition [155]. Iwata and co-workers have also developed LbL film-coated islet cells to improve the properties of islet-containing microcapsules [156–158]. Poly(ethylene glycol)-modified phospholipids (PFG-lipid) with a terminal functional group have been anchored to the membrane of islet cells as a scaffold on which LbL films were deposited. For example, an amino group-functionalized PEG-lipid was anchored to make the surface charge of islet cells positive and then a first alginate layer was electrostatically deposited followed by deposition of a PLL layer (Fig. 9) [156]. PEG-lipid containing terminal maleimide groups was also employed as a scaffold material [157]. Islet cells with surface maleimide groups were first covered with a monolayer of thiol-modified PVA (PVA-SH) through the formation of covalent bonds between thiol and maleimide groups. The PVA-SH covered islet cells were further covered with a PVA monolayer by depositing PVA bearing dithiopyridine side chains (PVA-PD), which formed a dithio linkage with the PVA-SH layer on the surface through a thiol/disulfide exchange reaction. Repeated deposition of PVA-SH and PVA-PD thus afforded LbL multilayers on the surfaces of the islet cells. The encapsulated islets released insulin at

70–120 ng/h (per 50 islet cells) in the presence of 1 g/L glucose, while the encapsulated cells secreted 270 ng insulin when exposed to higher glucose levels (3 g/L). A further improvement of the function of encapsulated islets has been reported by Iwata and Teramura on the basis of surface modification with the fibrinolytic enzyme urokinase and anticoagulant heparin [158]. In this case, PEG-lipid with a biotin terminal group was anchored on islet cells and LbL films composed of streptavidin and biotin-labeled albumin were coated on the cell surface through avidin–biotin affinity. The surface was modified with heparin or urokinase through electrostatic or covalent bonding, respectively. Surface modification did not impair insulin release in the presence of glucose. The authors claimed that the present protocol could help to improve the durability of islet microcapsules by preventing thrombosis on the surface due to the high fibrinolytic activity of urokinase. 4. Conclusion and outlook LbL films and microcapsules have been successfully employed for the development of pH- and sugar-sensitive drug delivery systems. LbL films and microcapsules constructed with weak polyelectrolytes through electrostatic forces of attraction are basically pH sensitive and their permeability is dependent on the environmental pH, by which a variety of drugs have been made subject to pH-triggered release. One of the challenges in pH-sensitive drug release is fine tuning of the pH threshold at which drug release is triggered. Other useful materials for developing pH-sensitive LbL layers are hydrogen bonding polymers, including poly (carboxylic acid)s, and hydrogen bonding acceptor polymers such as PEO and PVPON. The pH threshold for decomposition of hydrogen-bonded LbL films and microcapsules is dependent on the type of polymers used.

Fig. 9. Preparation of NH2-terminated lipid (a) and its use as a scaffold for LbL coating of the surface of islet cells (b). (Reprinted with permission from Ref. [156]. Copyright 2006, Elsevier).

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High biocompatibility is another advantage of these materials. Sugarsensitive LbL films and microcapsules have been studied mainly for the development of glucose-sensitive insulin delivery systems. GOx, lectin, and PBA derivatives are typically employed as glucose-sensitive materials. Such glucose-sensitive systems would be valuable as an artificial pancreas if the glucose sensitivity under physiological conditions could be improved. References [1] P. Gupta, K. Vermani, S. Garg, Hydrogels: from controlled release to pH-responsive drug delivery, Drug Discov. Today 7 (2002) 569–579. [2] D. Schmaljohann, Thermo- and pH-responsive polymers in drug delivery, Adv. Drug Deliv. Rev. 58 (2006) 1655–1670. [3] K. Glinel, C. Déjugnat, M. Prevot, B. Dchöler, M. Schönhoff, R.V. Klitzing, Responsive polyelectrolyte multilayers, Colloid Surface A 303 (2007) 3–13. [4] S. Kim, J. Kim, O. Jeon, I.C. Kwon, K. Park, Engineered polymers for advanced drug delivery, Eur. J. Pharm. 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