Calcium‐carboxymethyl chitosan hydrogel beads for protein drug delivery system

In this study, carboxymethyl chitosan (CMC) hydrogel beads were prepared by crosslinking with Ca²⁺. The pH‐sensitive characteristics of the beads were investigated by simulating gastrointestinal pH conditions. As a potential protein drug delivery system, the beads were loaded with a model protein (bovine serum albumin, BSA). To improve the entrapment efficiency of BSA, the beads were further coated with a chitosan/CMC polyelectrolyte complex (PEC) membrane by extruding a CMC/BSA solution into a CaCl₂/chitosan gelation medium. Finally, the release studies of BSA‐loaded beads were conducted. We found that, the maximum swelling ratios of the beads at pH 7.4 (17–21) were much higher than those at pH 1.2 (2–2.5). Higher entrapment efficiency (73.2%) was achieved in the chitosan‐coated calcium‐CMC beads, compared with that (44.4%) in the bare calcium‐CMC beads. The PEC membrane limited the BSA release, while the final disintegration of beads at pH 7.4 still leaded to a full BSA release. Therefore, the chitosan‐coated calcium‐CMC hydrogel beads with higher entrapment efficiency and proper protein release properties were a promising protein drug carrier for the site‐specific release in the intestine. © 2006 Wiley Periodicals, Inc. J Appl Polym Sci 103: 3164–3168, 2007     

pH-sensitive hydrogel based on carboxymethyl chitosan/sodium alginate and its application for drug delivery

Carboxymethyl chitosan sodium salt (CMCS)/sodium alginate (SA), a pH-sensitive hydrogel composed of CMCS and SA crosslinked by 1-ethyl-3-(3-dimethyl aminopropyl) carbodiimide (EDC) and N-hydroxysuccinimide, has been evaluated in vitro as a potential carrier for protein drug delivery of bovine serum albumin (BSA). The crosslinked structures, pore morphologies, and mechanical properties of the composite CMCS/SA hydrogel at different pH have been characterized by Fourier-transform infrared (FTIR) spectroscopy, scanning electron microscopy (SEM), and dynamic mechanical analysis (DMA). The swelling behavior of the prepared hydrogel was assessed at different pH values, 1.2, 4.0, 6.86, 7.4, and 9.0. The in vitro slow release ability of the CMCS/SA hydrogel was assessed at 37°C and pH 1.2 or pH 7.4 to simulate gastrointestinal and mouth environments in vivo. The efficiency was found to be greater than 90% at pH 7.4. The composite CMCS/SA hydrogel showed no cytotoxic effect toward L-929 cells according to the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide test. These findings demonstrate that the composite hydrogel has promising potential for drug delivery. © 2018 Wiley Periodicals, Inc. J. Appl. Polym. Sci. 2019 , 136, 46911.     

Novel amphiphilic dextran copolymers nanoparticles for delivery of doxorubicin

In this work, a novel biodegradable amphiphilic copolymer based on dextran and 1,2‐dipalmitoyl‐sn‐glycero‐3‐phosphoethanolamine (DPPE) was successfully prepared. The amphiphilic copolymer may self‐assemble into polymeric micelles in an aqueous solution. Fluorescence spectroscopy, dynamic light scattering (DLS), and a transmission electron microscope (TEM) method confirmed the formation of copolymeric micelles. To estimate the feasibility as novel drug carriers, doxorubicin (DOX) was incorporated into polymeric nanoparticles. The DOX‐loaded nanoparticles exhibited greater antitumor effect than free DOX for HeLa celles, suggesting that the dextran/DPPE nanoparticles have great potential as a tumor targeting drug carrier. © 2010 Wiley Periodicals, Inc. J Appl Polym Sci, 2011     

壳聚糖烷基化改性及其纳米微球负载扑热息痛的研究

将低分子量壳聚糖经长链烷基在碱性条件下改性制得烷基化壳聚糖衍生物 ,红外光谱研究表明取代反应主要发生在壳聚糖的氨基上 ,透射电镜研究表明该衍生物在水中可自动形成粒径分布在 1 0 0nm左右的纳米微粒。以扑热息痛为模型药物 ,对烷基壳聚糖纳米微球在磷酸缓冲液 (pH =7 4)中体外释放的研究表明 ,在取代度接近的情况下 ,随着烷基链的增长 ,扑热息痛在磷酸缓冲液中的缓释作用得到改善 ,累积达到平衡时的浓度降低。     

Depolymerized chitosan nanoparticles for protein delivery: Preparation and characterization

In this article we describe our preliminary work involving the use of depolymerized, low molecular weight chitosan nanoparticles as carriers for proteins and peptides. We hypothesized that the molecular weight of chitosan could favorably modulate the particle and protein release characteristics for the delivery of certain bioactive macromolecules. Our primary objectives were to develop nanoparticle formulations that were stable and reproducible across a range of chitosan molecular weights and then characterize the physicochemical and in vitro release properties as functions of the polymer size. Using depolymerized fragments generated by NaNO₂ degradation of different chitosan salts, we prepared nanoparticle formulations based on ionotropic gelation with sodium tripolyphosphate (TPP). Regardless of the formulation, the nanoparticle size decreased with decreasing molecular weight and the ζ‐potential values remained unchanged. Similar comparisons were made with the encapsulation of insulin and tetanus toxoid as model proteins. The results indicated that the quantity of TPP in a given formulation has a greater effect on the protein encapsulation than the chitosan molecular weight. In fast release environments (i.e., buffered media), there was no significant molecular weight effect that could be discerned. These data lead to the conclusion that, under these experimental conditions, the chitosan molecular weight has a measurable effect on the particle properties, although this effect is modest relative to other formulation parameters (e.g., TPP content, type of protein loaded). Because these subtle differences could have dramatic effects physiologically, work is currently underway to elucidate the possible applications of depolymerized chitosans for peptide delivery in vivo. © 2003 Wiley Periodicals, Inc. J Appl Polym Sci 12: 2769–2776, 2003     

Design of a drug delivery system based on poly(acrylamide‐co‐acrylic acid)/chitosan nanostructured hydrogels

To obtain biodegradable materials for biomedical applications, new biopolymeric hydrogels based on blends of polyacrylamide nanoparticles and chitosan have been prepared. In this work, we have studied the behavior of the diffusion of ascorbic acid (V‐C) from poly(acrylamide‐co‐acrylic acid)/chitosan nanostructured hydrogels. The process involves the synthesis of nanoparticles of polyacrylamide by inverse microemulsion polymerization and their complexation with chitosan dissolved in an acrylic acid aqueous solution. We have studied the effect of the concentration of the polyacrylamide nanoparticles, which are crosslinked with N,N′‐methylenebisacrylamide, in the delivery of V‐C. The results indicate that the drug delivery operates by a non‐Fickian mechanism. Also, we have obtained the diffusion coefficient for V‐C in gels for different nanoparticle concentrations, using a modified form of Fick's second law that takes into account dimensional changes in the hydrogels during drug release. © 2007 Wiley Periodicals, Inc. J Appl Polym Sci 2007     

Biocompatibility and characteristics of theophylline/carboxymethyl chitosan microspheres for pulmonary drug delivery

The main aim was to evaluate the biocompatibility of theophylline/carboxymethyl chitosan/β‐cyclodextrin microspheres made by spray drying for pulmonary delivery. Haemolysis tests and cell culture experiments were used to determine blood and cell biocompatibility, and in vivo implantation experiments were used to examine tissue biocompatibility. The theophylline/carboxymethyl chitosan/β‐cyclodextrin microspheres were spherical in shape with a smooth or wrinkled surface, and showed no haemolysis activity. The cytotoxicity was dependent on concentration and showed no toxicity at low concentration. The results of implantation indicated that the inflammatory reaction gradually lessened and disappeared and had no significant difference from that of an operative suture. Therefore, theophylline/carboxymethyl chitosan/β‐cyclodextrin microspheres possess good biocompatibility and can be used as a promising carrier for pulmonary drug delivery. © 2013 Society of Chemical Industry     

Both FA- and mPEG-conjugated chitosan nanoparticles for targeted cellular uptake and enhanced tumor tissue distribution

Both folic acid (FA)- and methoxypoly(ethylene glycol) (mPEG)-conjugated chitosan nanoparticles (NPs) had been designed for targeted and prolong anticancer drug delivery system. The chitosan NPs were prepared with combination of ionic gelation and chemical cross-linking method, followed by conjugation with both FA and mPEG, respectively. FA-mPEG-NPs were compared with either NPs or mPEG-/FA-NPs in terms of their size, targeting cellular efficiency and tumor tissue distribution. The specificity of the mPEG-FA-NPs targeting cancerous cells was demonstrated by comparative intracellular uptake of NPs and mPEG-/FA-NPs by human adenocarcinoma HeLa cells. Mitomycin C (MMC), as a model drug, was loaded to the mPEG-FA-NPs. Results show that the chitosan NPs presented a narrow-size distribution with an average diameter about 200 nm regardless of the type of functional group. In addition, MMC was easily loaded to the mPEG-FA-NPs with drug-loading content of 9.1%, and the drug releases were biphasic with an initial burst release, followed by a subsequent slower release. Laser confocal scanning imaging proved that both mPEG-FA-NPs and FA-NPs could greatly enhance uptake by HeLa cells. In vivo animal experiments, using a nude mice xenograft model, demonstrated that an increased amount of mPEG-FA-NPs or FA-NPs were accumulated in the tumor tissue relative to the mPEG-NPs or NPs alone. These results suggest that both FA- and mPEG-conjugated chitosan NPs are potentially prolonged drug delivery system for tumor cell-selective targeting treatments.     

壳聚糖/羧甲基壳聚糖及其衍生物在日化方面的应用

壳聚糖及其衍生物含有大量的氨基和羟基,为壳聚糖的改性或者接枝反应提供了活性基团,壳聚糖/羧甲基壳聚糖因特殊的化学结构而使其具有优异的化学性质,如良好的生物相容性、无毒、生物可降解性以及抗微生物活性等性质,因此受到生物工程、医药、食品、化妆品以及其他一些领域的广泛关注,成为近年来研究开发的热点。对壳聚糖/羧甲基壳聚糖及其衍生物在日用化学中的应用进行了综述,并对其发展趋势进行了展望。     

水溶性壳聚糖纳米粒子的制备及其BSA载药性能

为了避免高分子量壳聚糖水溶性差以及增溶剂乙酸可能带来的负面作用,本文选择低分子量水溶性壳聚糖 (WSC)作研究对象,采用三聚磷酸(TPP)作交链剂制备不同WSC/TPP比率的WSC纳米粒子,并用于牛血清白蛋白 (BSA)的释放载体。经测得为球形形貌的纳米粒子空载和载药时粒径、Zeta电位分别在35～190 nm、35～42 mV。红外光谱及X–射线衍射证实了纳米粒子中WSC的氨基与TPP的磷酸基团发生了交联反应。纳米粒子载药性能试验表明在0.05～1 mg/mL范围内随着BSA浓度的增大,纳米粒子的载药量增加而负载率降低。体外释放实验表明水溶性壳聚糖纳米载体对蛋白质药物具有缓释特征。因此,水溶性壳聚糖有望成为新的载体应用于蛋白质药物的控制释放。     

Preparation and release kinetics of carboxymethyl chitosan/cellulose acetate microspheres as drug delivery system

Carboxymethyl chitosan, a water soluble chitosan derivative, was prepared from chitosan using monochloroacetic acid. Carboxymethyl chitosan/cellulose acetate microspheres (CCM) were prepared using the method of W/O/W and emulsification solvent evaporation as drug delivery system. The CCMs prepared were spherical, free‐flowing, and nonaggregated with the smooth appearance and many small pores on the surface. All CCMs prepared had sustained release efficiency for acetaminophen and the optimal formulation was that carboxymethyl chitosan of 2.0% and 1360 KD. In addition, the release rate of drug from CCMs in dilute hydrochloric acid was much slower than that in phosphate buffer saline (pH 6.8) during 24 h. It is illustrated that the drug loaded in CCMs released slower in simulated gastric fluid than that in simulated intestinal fluid. Furthermore, the drug release data showed better fitness with the first order model which indicated that the drug release from CCMs was depended on the drug concentration in the polymeric networks. And the release of drug from CCMs indicated diffusion‐controlled drug release based on Fickian diffusion and accompanied with anomalous transport (i.e., non‐Fickian diffusion) according to the values obtained from Higuchi model and Peppas models. So it was shown that the CCMs might be an ideal sustained release system for acid‐labile drugs both for the solubility of carboxymethyl chitosan and the release media. © 2015 Wiley Periodicals, Inc. J. Appl. Polym. Sci. 2015 , 132, 42152.     

Fabrication of polymeric nanoparticles of poly(ethylene‐co‐vinyl acetate) coated with chitosan for pulmonary delivery of carvedilol

Carvedilol is a drug with low oral bioavailability due to its high first‐pass metabolism. The purpose of the present study was to prepare a mucoadhesive dry powder inhaler of this drug loaded in poly(ethylene‐co‐vinyl acetate)(PEVA) nanoparticles for pulmonary delivery. PEVA nanoparticles were prepared by an O/W solvent evaporation method and coated with different concentrations of chitosan as a mucoadhesive polymer. Encapsulation efficiency, particle size, zeta potential, release efficiency, and mucoadhesive properties of the different formulations were evaluated on mucin substrate. The optimized formulation of nanoparticles was spray dried using lactose and mannitol as carrier powders. The flowability of the obtained powders was checked by Carr's Index and Hausner ratio and the in vitro deposition of the aerosolized drug was investigated using a Next Generation Impactor. Increasing in the particle size and zeta potential of nanoparticles confirmed the settling of the chitosan coating layer on the surface of nanoparticles. The in vitro drug release from coated nanoparticles decreased with increasing of chitosan concentration. Mucoadhesive property of chitosan‐coated PEVA nanoparticles was higher than noncoated ones. Spray‐dried powders had different aerosilization behavior. Mannitol‐based formulation was found to have low density, better flow ability, smaller aerodynamic diameter (d_aer) and higher fine powder fraction. The results of the present study allow concluding that mannitol spray dried, mucoadhesive nanoparticles of PEVA are suitable inhaler powder for pulmonary delivery of carvedilol. © 2013 Wiley Periodicals, Inc. J. Appl. Polym. Sci. 2014 , 131, 39694.     

一种新型靶向壳聚糖纳米载体的制备及性质

制备了不同乳糖取代度的乳糖化油酰壳聚糖(Lac-OCH)。通过粘度法检测了Lac-OCH的流变学特性;通过荧光法研究了Lac-OCH在溶液中的自聚集行为,随着乳糖取代度升高,临界聚集浓度(CAC)值升高;采用超声法制备Lac-OCS纳米体系;采用透射电镜观察Lac-OCH纳米球呈现椭球棒状,粒径约为200 nm;研究了Lac-OCH负载药物阿霉素后的包封率和体外释放情况。     

Preparation of nanoparticles composed of chitosan and its derivatives as delivery systems for macromolecules

Three different kinds of nanoparticles for paracellular transport were prepared using a simple and mild ionic‐gelation method. Sodium tripolyphosphate (TPP) as crosslinking agent was added into three kinds of solutions, which were chitosan solution, physical blending solution of chitosan, and glycidyl trimethylammonium chloride (GTMAC), and O‐(2‐hydroxyl) propyl‐3‐trimethyl ammonium chitosan chloride (O‐HTCC) solution respectively. O‐HTCC was synthesized by coupling of GTMAC to chitosan whose functional groups of the NH₂ groups were protected. The nanoparticles were characterized by transmission electron microscopy, atomic force microscopy, photon correlation spectroscopy, and zeta potential measurement. The results showed that increasing TPP concentration promoted the size of chitosan nanoparticles, a decrease in the size of O‐HTCC nanoparticles incurred on the contrary. The size of O‐HTCC nanoparticles is slightly bigger than that of pure chitosan nanoparticles, and smaller than that of physical blending nanoparticles (PBN). Bovine serum albumin (BSA), as a model protein drug, was incorporated into the nanoparticles. Compared with chitosan nanoparticles and PBN, high BSA loading efficiency (87.5%) and loading capacity (99.5%) are achieved by quaternized chitosan (O‐HTCC) nanoparticles, and the release profile of BSA from nanoparticles has an obvious burst effect and a slowly continuous release phase followed. © 2007 Wiley Periodicals, Inc. J Appl Polym Sci 2007     

Studies on preparations and properties of drug-eluting embolization microspheres made from oxidated alginate and carboxymethyl chitosan

Embolization microspheres were prepared through two steps. The microspheres demonstrated regular sphericity with a main size distribution in the range of 100?µm?～?270?µm. An anticancer drug doxorubicin could be loaded into the microspheres with high loading rates from 21% to 32% due to physical and ionic interaction of carboxyl groups in the microspheres and amino groups in doxorubicin. The drug could be controlled released at different pH conditions. The blank microspheres were biodegradable, non-cytotoxic, and the drug-eluting embolization microspheres could be potentially applied as embolic agents in interventional therapy.     

基于壳聚糖纳米粒子载药体系的制备与应用研究进展

壳聚糖纳米粒子载药体系因其天然无毒、生物相容性高、可生物降解等特点,在生物医学、化工和食品等领域有广阔的应用前景。本文对制备壳聚糖纳米粒子的离子交联法、聚电解质复合法、乳化交联法、喷雾干燥法和溶剂蒸发法等主要方法进行了综述,并阐述了其制备原理和优缺点。此外,本文结合国内外学者近期的研究工作,综述了壳聚糖纳米粒子载药体系在抗肿瘤药物和抑菌药物方面的应用研究进展,并对壳聚糖装载降糖药物、降脂药物、治疗骨质疏松药物和抗癫痫药物应用进行了简介。最后结合壳聚糖纳米载药体系在制备方法及应用中存在的实际问题,提出多学科研究相结合,开发壳聚糖纳米载药体系的智能控释、靶向递送功能和突破人体特殊生物屏障功能将是其近期的重点研究方向。     

Preparation and properties of crosslinked chitosan thermosensitive hydrogel for injectable drug delivery systems

The aim of this study was to prepare and investigate the physical properties of a thermosensitive crosslinked chitosan pregel solution, and evaluate the in vitro release profiles of macromolecules from this sol–gel transition system. Chitosan and poly (vinyl alcohol) were used to form an interpenetrating polymeric network with glutaraldehyde as the crosslinker, and glycerophosphate (GP) was added to transform the pH‐dependent solutions into thermosensitive pH‐dependent solutions. Rheological study showed that the gelation was dependent on the crosslink degree and GP concentration of the solution. The crosslinked gel had excellent mechanic properties and no apparent “pores” and formed an integrated hydrogel texture according to scanning electronic micrograph. Gas chromatography test guaranteed the medication safety with no detection of glutaraldehyde remnants in the hydrogels. In vitro release study showed that the gelation does not significantly affect the macromolecules diffusion but the crosslinking degree does. These results indicated that the hydrogel formed an intensified three‐dimensional hybrid network with interpenetrating molecules, which effectively buffered or delayed the macromolecules diffusion. The hydrogels sustained the drug release over 30 days and could be potentially used as in situ gelling implants. © 2006 Wiley Periodicals, Inc. J Appl Polym Sci 101: 1892–1898, 2006     

Gold/chitosan/pluronic composite nanoparticles for drug delivery

Composite nanoparticles were prepared and characterized as a sustained delivery system for paclitaxel, an anticancer drug. Gold nanoparticles were used as building blocks for constructing the composite nanoparticles. An ionic interaction between the anionic gold nanoparticles and cationic chitosan was induced to form the composite nanoparticles. Particle size analysis, field emission scanning electron microscopy, transmittance electron microscopy, and ultraviolet–visible were used to observe the formation of the composite nanoparticles. For the application of the composite nanoparticles as a drug carrier, paclitaxel was loaded into the composite nanoparticles, and the drug-release pattern was observed. © 2008 Wiley Periodicals, Inc. J Appl Polym Sci, 2008     

Novel pH,ion sensitive polyampholyte gels based on carboxymethyl chitosan and gelatin

Natural pH and ion sensitive polyampholyte gels were successfully prepared by blending carboxymethyl chitosan (CM‐chitosan) and gelatin using glutaraldehyde as crosslinking agent. Their swelling behaviour under the influence of pH and ionic strength of the solution has been studied, and molecular interaction and, morphology of the gels were investigated by infrared spectroscopy and scanning electron microscopy. At the isoelectric point (IEP) the blend gels shrunk most, and when pH deviated from the IEP they behaved as polycations or polyanions. A decrease in swelling degree (D_s) with rising NaCl concentration up to 0.15 M was observed for all gels, while addition of Ca²⁺ made them shrink due to formation of Ca²⁺ crosslinked bridges. The blended gels showed increasing sensitivity to pH and ionic strength as the weight fraction of CM‐chitosan increased. Two essential components seem to regulate the swelling behaviour of blended gel: the first is related to osmotic pressure difference caused by the redistribution of mobile ions; the second is related to the possible formation of interactions corresponding to hydrogen bonding and hydrophobic interactions. © 2003 Society of Chemical Industry     

Relationship between molecular structure and moisture‐retention ability of carboxymethyl chitin and chitosan

Carboxymethyl chitins and chitosans (CM‐chitins, CM‐chitosans) of different substitution sites were prepared under different reaction conditions, and partially depolymerized carboxymethyl chitins of various molecular weights from 24.8 × 10⁴ to 0.26 × 10⁴ were obtained by degrading with chemical reagents. Degree of substitution (DS) was estimated by potentiometric titration. Substitution site was confirmed by infrared and ¹³C‐NMR spectra. Molecular weights were determined with gel permeation chromatography and gel permeation chromatography combined with laser light scattering (GPC‐LLS). Moisture‐absorption and retention abilities of these compounds were tested in comparison with those of hyaluronic acid (HA). The results reveal that 6‐carboxymethyl group in the molecular structure of chitin and chitosan is a main active site responsible for moisture retention. Although carboxymethylation at OH‐3 and N position is not essential, they contribute to the ability. Moisture‐retention ability is also related to molecular weight; that is, higher molecular weight helps to improve moisture‐retention ability. 6‐O‐CM‐chitin (chitosan) with a DS above 0.8 and molecular weight higher than 24.8 × 10⁴ has the potential to substitute for HA for use in cosmetics and clinical medicine. © 2002 Wiley Periodicals, Inc. J Appl Polym Sci 83: 1233–1241, 2002