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目的在合成了两亲性接枝共聚物丁酰基-羧甲基-壳聚糖(butyryl-carboxymethyl-chitosan,BR-CM-CS)的基础上,采用化学键合载药方式结合透析法制备了阿霉素pH敏感两亲性共聚物胶束并对其相关性质进行考察。方法利用芘荧光探针技术测定胶束的临界胶束浓度(CMC);通过透析法结合紫外分光光度法测定胶束的载药量及包封率;分别利用透射电镜(TEM)、扫描电镜(SEM)、动态光散射法(DLS)和zeta电位分析仪对胶束及其冷冻干燥产品的形态、粒径和表面电位进行了表征;采用透析法考察了载药聚合物胶束的体外释放行为。结果胶束的CMC值为1.0 mg.L-1,载药量可达12.5%,包封率为89.1%;胶束的粒度分布很窄,平均粒径为205.2 nm;胶束粒子为类球形且分散良好,其表面zeta电位值为25.94 mV;胶束释药行为体现pH敏感性。结论以壳聚糖为载体的化学腙键释药胶束作为抗肿瘤药物的传递系统具有可行性及良好的应用前景。 相似文献
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多柔比星壳聚糖聚合物胶束的制备及其在小鼠体内的组织分布 总被引:6,自引:0,他引:6
本文制备了多柔比星壳聚糖聚合物胶束(doxorubicin-loaded N-octyl-N′-succinyl chitosan,DOX-OSC),研究其在小鼠体内的组织分布并进行靶向性评价。采用透析法制备DOX-OSC,以多柔比星注射液(doxorubicin for injection,DOX-INJ)为对照,小鼠分别尾静脉注射5 mg·kg-1的DOX-OSC和DOX-INJ,HPLC法测定各组织中不同时间的药物量,以各组织药代动力学参数(AUC、MRT)和靶向参数(Re、Ce、Te)为靶向评价指标。DOX-OSC载药量为(35.8±0.4)%,包封产率为(75.3±1.1)%,粒径为(174±12)nm,zeta电位为(-37.1±3.0)mV,形态为球形结构。小鼠尾静脉注射DOX-OSC和DOX-INJ后,DOX-OSC表现出较好的长循环及缓释特性。与对照组比较,DOX-OSC具有肝和脾靶向特性及滞留特性,AUC分别提高20.0和47.4倍,MRT分别延长11.2和37.2倍;在心脏和肾脏中药物分布显著降低,AUC分别为对照组的17.0%和11.4%。结果表明DOX-OSC具有优良的载药性能,有利于肝和脾靶向,并能显著降低心脏和肾脏毒性,对于DOX的临床应用具有重要意义。 相似文献
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壳寡糖嫁接硬脂酸阳离子聚合物胶团的制备及其理化性质 总被引:5,自引:1,他引:5
目的考察阳离子型壳寡糖硬脂酸嫁接物胶团的理化性质及载药胶团的体外药物释放。方法以碳二亚胺为交联偶合剂制备壳寡糖硬脂酸嫁接物;芘荧光法测定该聚合物的临界聚集浓度,微粒粒度及电泳分析仪测定聚合物胶团的粒径和表面电位;以甲氨蝶呤为模型药物,考察胶团作为药物载体的可行性。结果嫁接物的临界聚集浓度为0.05 g·L-1;去离子水中的胶团粒径为26.7 nm,表面电位为(55.9±0.1) mV;三聚磷酸钠修饰可使胶团粒径增加、表面电位降低、药物包封率增加;降低胶团溶液的pH值,可使胶团的粒径和表面电位上升,药物包封率下降,体外释药速度加快。 结论壳寡糖硬脂酸嫁接物胶团是一种良好的药物载体,其体外释药具有一定的pH依赖性。 相似文献
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紫杉醇壳聚糖聚合物胶束的制备及表面电荷对其在小鼠体内组织分布的影响 总被引:2,自引:5,他引:2
目的紫杉醇壳聚糖聚合物胶束的制备及表面电荷对其在小鼠体内组织分布的影响。方法采用透析法分别制备紫杉醇阳离子(PTX-CCM)和阴离子(PTX-ACM)壳聚糖聚合物胶束;昆明种小鼠分别尾静脉注射20 mg·kg-1的PTX-CCM和PTX-ACM,HPLC法测定各组织中不同时间的药物含量,以各组织药代动力学参数(AUC,MRT,Tmax和Cmax)评价其体内分布。结果PTX-CCM和PTX-ACM粒径分别为164和180 nm,zeta电位分别为+23.7和-28.0 mV,载药量分别为26.4%和34.6%(w/w),包封率分别为76.2%和89.9%。PTX-CCM和PTX-ACM肝中最大药物分布量分别达给药量的64.72%和91.84%,MRT分别为5.50和51.39 h;PTX-CCM和PTX-ACM脾中最大药物分布量达给药量的7.08%和5.16%,MRT分别为9.04和26.82 h;PTX-CCM肺部AUC和Cmax分别为PTX-ACM的2.71和5.87倍;PTX-CCM和PTX-ACM心脏最高药物分布量仅为给药量的0.36%和0.24%,肾脏仅为给药量的0.75%和0.33%。结论PTX-CCM和PTX-ACM表面分别带正负电荷,具有优良的载药性能,两者皆显示出对肝脾的高度亲和性和滞留特性,尤以PTX-ACM更为显著;PTX-CCM较PTX-ACM具有更好的肺靶向性,但肺部滞留性相对较弱;两者在心、肾的分布均极少,可有效降低PTX对这些器官的毒副作用。 相似文献
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以壳聚糖为母体,在其侧链氨基上引入亲水基精氨酸以及疏水基辛基,合成了一种新型的具有仿穿膜肽结构的壳聚糖衍生物——N-辛基-N-精氨酸壳聚糖(OACS)。同时通过FT-IR、1H NMR、元素分析和精氨酸显色法确证了OACS的化学结构以及其辛基和精氨酸的取代度。荧光光谱法测得系列OACS的临界胶束浓度为0.12~0.27 mg.mL/1;溶解度实验表明其在pH 1~12溶液中均易溶,并可自组装形成淡蓝色略带乳光的胶束溶液;马尔文粒径测定仪显示系列OACS形成的聚合物胶束平均粒径为158.4~224.6 nm,多分散系数为0.038~0.309,ζ电位为+19.16~+30.80 mV;原子力显微镜图谱显示所得胶束粒子分散均匀、大小规则圆整;MTT实验证实所得OACS在50~1 000μmol.L?1内安全性能良好。细胞实验结果表明,随着精氨酸取代度的升高,OACS胶束进入细胞的荧光量也随之增加,与壳聚糖相比,最大增加倍数可达40倍。因此,OACS有望作为一种兼具促吸收和载药功能的新型纳米载体。 相似文献
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PCM and TAT co-modified liposome with improved myocardium delivery: in vitro and in vivo evaluations
In this study, PCM and TAT co-modified liposome was developed as a novel drug carrier for myocardium delivery with evaluation of its in vitro and in vivo properties. Liposomes containing fluorescent probe coumarin-6 were prepared by thin-film hydration. The PCM ligands specifically bind to the PCM receptors in the extracellular connective tissue of primary myocardium cells (MCs), while the TAT ligands functioned as a classical cell penetrating peptide to make liposomes internalized by MCs. The unmodified liposome (L), PCM-modified liposome (PL), TAT-modified liposome (TL) and PCM and TAT co-modified liposome (PTL) were prepared and characterized. The cellular uptake and intracellular distribution of various liposomes by MCs demonstrated that PTL had the best delivery capability. Peptide inhibition assay indicated that the uptake of PL could be inhibited by PCM. However, TAT could almost not suppress the uptake of TL. In addition, the CCK-8 experiments showed that liposomes had low cytotoxicity. In vivo fluorescent images of frozen sections and HPLC-fluorescence analysis further demonstrated that PTL had highest myocardium distribution. The results of this study demonstrated that PCM and TAT co-modifying could improve the myocardial targeting ability of liposome. 相似文献
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N-辛基-O,N-羧甲基壳聚糖聚合物胶束对紫杉醇的增溶、缓释及其安全性初步评价 总被引:2,自引:0,他引:2
本文合成了一系列两亲性壳聚糖衍生物N-辛基-O,N-羧甲基壳聚糖(OCC),以透析法制备紫杉醇(PTX)-OCC载药聚合物胶束,并考察疏水烷基取代度对包封率、载药量、粒径和zeta电位的影响,通过透射电镜(TEM)观察其形态结构,并以市售制剂为对照;通过体外溶血实验、豚鼠急性过敏实验及小鼠尾静脉注射急性毒性实验初步评价其安全性。结果表明,OCC对PTX有良好的增溶效果,在疏水基取代度为37.9%~58.6%时,载药量为24.9%~34.4%,包封率为56.3%~89.3%,且随着疏水辛基取代度的增加,载药量和包封率皆显著提高。疏水烷基链进一步提高则可能破坏胶束亲水疏水平衡而导致载药能力降低;载药胶束粒径为186.4~201.1 nm,随疏水烷基取代度的增加而减小, zeta电位为-47.5~-50.9 mV,疏水烷基取代度对其无显著影响,TEM照片显示该聚合物胶束为规则球形结构,粒径分布均匀。OCC对紫杉醇具有优良的缓释效果,未见突释,15 d累计药物释放量在60%~95%,缓释能力随疏水基取代度的增加而增强。溶血实验、 豚鼠急性过敏实验和小鼠尾静脉注射急性毒性实验结果表明,PTX-OCC溶血性和急性过敏反应低于市售制剂, PTX-OCC小鼠尾静脉注射的LD50及95%可信限为134.4(125.0~144.6) mg·kg-1,为市售制剂LD50的2.7倍。初步认为PTX-OCC是安全可靠的静脉注射用纳米制剂。 相似文献
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Fabienne Danhier Nicolas Magotteaux Bernard Ucakar Nathalie Lecouturier Marcus Brewster Vronique Prat 《European journal of pharmaceutics and biopharmaceutics》2009,73(2):230-238
Paclitaxel (PTX) is an effective anti-cancer drug currently used to treat a wide variety of cancers. Unfortunately, nonaqueous vehicle containing Cremophor® EL is associated with serious clinical side effects. This work aimed to evaluate the ability of polymeric micelles to (i) solubilize PTX without Cremophor® EL and to be used as a (ii) safe and (iii) effective delivery system for PTX. Hence, we developed novel self-assembling poly(ethyleneglycol)750-block-poly(ε-caprolactone-co-trimethylenecarbonate) (PEG-p-(CL-co-TMC)) polymeric micelles which form micelles spontaneously in aqueous solution. The solubility of PTX increased up to three orders of magnitude. The PTX-loaded micelles showed a slow release of PTX with no burst effect. The HeLa cells viability assessed by the MTT test was lower for PTX-loaded micelles than for Taxol® (IC50 10.6 vs. 17.6 μg/ml). When solubilized in micelles, PTX induced apoptosis comparable with Taxol®. The maximum tolerated doses (MTD) of PTX-loaded micelles and Taxol® in mice were 80 mg/kg and 13.5 mg/kg, respectively, after intraperitoneal administration; and 45 mg/kg and 13.5 mg/kg, respectively, after intravenous administration. Similar anti-tumor efficacy of PTX-loaded micelles and Taxol® was observed at the dose of 13.5 mg/kg on TLT-tumor-bearing mice, while the body weight loss was only observed in Taxol® group. However, as higher dose was tolerated (80 mg/kg – IP), a higher growth delay was induced with PTX-loaded micelles. These results demonstrated that PTX-loaded self-assembling micelles present a similar anti-tumor efficacy as Taxol®, but significantly reduced the toxicity allowing the increase in the dose for better therapeutic response. 相似文献
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The transmembrane transport of drug loaded micelles to intracellular compartment is quite crucial for efficient drug delivery. In the current study, we investigated the cellular internalization and anticancer activity of doxorubicin loaded micelles with folate modified stealthy PEOz corona. Folate-decorated micelles incorporating doxorubicin were characterized for particle size, degree of folate decoration, drug loading content and encapsulation efficiency, morphology, and surface charge. The targeting capability and cell viability were assessed using HeLa, KB, A549 and MCF-7/ADR cell lines. In vitro study clearly illustrated the folate receptor (FR) mediated targeting of FA modified micelles to FR-positive human HeLa, KB and MCF-7/ADR cells, while specific delivery to FR-negative A549 cells was not apparently increased at the same experimental conditions. Cytotoxicity assay showed 60% and 58% decrease in IC50 values for HeLa and KB cells, while only a slight decrease for A549 cells, following treatment with folate modified formulations. The enhanced intracellular delivery of FA modified micelles in MCF-7/ADR cells was also observed. In vivo antitumor tests revealed DOX entrapped FA-PEOz-PCL micelles effectively inhibited the tumor growth and reduced the toxicity to mice compared with free DOX. The current study showed that the targeted nano-vector improved cytotoxicity of DOX and suggested that this novel PEOz endowed stealthy micelle system held great promise in tumor targeted therapy. 相似文献
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目的:构建酸敏释药胶束并考查其酸敏释药特性。方法:用亚胺键连接PEG和苯棕榈酸脂肪链,用透析法制备载阿霉素胶束,对其粒径,载药量和包封率进行考察,用紫外分光光度法测定载药胶束在不同pH值条件下的释放。结果:载药胶束粒径为60~70 nm,PEG相对分子质量为2000 Da的胶束载药量和包封率分别为(12.7±1.1)%和(49.8±2.2)%,PEG相对分子质量为5000 Da的胶束载药量和包封率分别为(10.7±0.3)%和(39.9±2.1)%。体外释放研究表明酸敏释药胶束在pH 6.5时的累积释放率比pH 7.4时大,但在pH 5.0条件下其累积释放较pH 7.4时还要小,可能原因是胶束解聚太快致药物与材料形成复合物沉淀所致。结论:以酸敏感亚胺键连接的两亲材料载药胶束具有一定的酸敏释药特性。 相似文献
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Prashant S. Kharkar Govind Soni Vaibhavi Rathod Saritha Shetty M. K. Gupta Khushwant S. Yadav 《Drug development research》2020,81(7):823-836
Folate receptors (FRs) are expressed in vast majority of cancers. Selective targeting of the FRs is, therefore, one of the most popular and sought-after strategies for improving the efficacy of cancer therapeutics. Variety of approaches involving folate conjugation to several well-known and novel, nontoxic, biodegradable, and biocompatible (co)polymers have been attempted and successfully applied to a large number of nanoparticulate drug delivery systems (micelles, liposomes, nanoparticles, quantum dots, mesoporous silica-based materials, and others) in the last decade-and-a-half. Standard and novel synthetic approaches were utilized for the conjugation, followed by the formulation of the drug delivery modality. In most of the cases, the targeted system lived up to its reputation, validating its usefulness in targeted cancer therapeutics. The present review summarizes the progress and state-of-the-art synthetic methodologies for folate conjugation to (co)polymers, drugs, and nucleic acids. The limitations of the FR targeting are discussed in brief to give the reader the other side of the story. Finally, the information on marketed folic acid conjugates highlight their industrial applications. 相似文献
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目的:制备川芎嗪壳聚糖纳米粒,考察纳米粒在人癌细胞的靶向分布。方法:以壳聚糖为载体,用离子交联法制备川芎嗪纳米粒。用激光粒度分析仪检测粒径,用透射电镜观察纳米粒的形态。用HPLC法测定纳米粒的包封率、载药量和体外释放度。以川芎嗪溶液为对照,测定纳米粒在人乳腺癌MCF-7细胞株、人肺腺癌A549细胞株和人白血病K562细胞株中的浓度,评价其靶向性。结果:制备的川芎嗪壳聚糖纳米粒为圆球形,平均粒径为(118.6±2.2) nm,分散系数(0.117±0.016)(n=3),包封率(79.7±0.4)%,载药量(24.3±0.2)%,缓慢释药96 h累积释药率达75%。纳米粒在人乳腺癌MCF-7细胞株、人肺腺癌A549细胞株和人白血病K562细胞株中的浓度显著高于川芎嗪溶液(P<0.05)。结论:制备的川芎嗪壳聚糖纳米粒对人癌细胞有靶向浓集作用。 相似文献
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Fu-Qiang Hu Xiu-ling Wu Yong-Zhong Du Jian You Hong Yuan 《European journal of pharmaceutics and biopharmaceutics》2008,69(1):117-125
Stearic acid-grafted chitosan oligosaccharide (CSO-SA) with 3.48% amino-substituted degree (SD%) was synthesized by coupling reaction. The CSO-SA could self-aggregate to form micelle with a critical micelle concentration (CMC) at 0.035 mg/mL in the aqueous phase. The CSO-SA self-aggregate micelles indicated spatial structure with multi-hydrophobic core. One CSO-SA chain could form 2.8 hydrophobic cores. Cellular uptakes of CSO-SA micelles by using A549, LLC, and SKOV3 cells as model tumor cell lines showed the faster cellular internalization of CSO-SA micelles, and the cellular uptakes on the LLC and SKOV3 cells were higher than that on the A549 cells. Doxorubicin (DOX) was then used as a model drug to incorporate into CSO-SA micelles. To reduce the initial burst drug release from CSO-SA micelles loading DOX (CSO-SA/DOX), the shell of CSO-SA micelles was crosslinked by glutaraldehyde. The shell crosslinking of CSO-SA micelles reduced the micelle size and surface potential, but it did not significantly affect the cellular uptake and drug encapsulation efficiency of CSO-SA micelles. The cellular inhibition experiments demonstrated that the cytotoxicity of DOX was increased by the encapsulation of CSO-SA micelles. CSO-SA/DOX displayed the best antitumor efficacy in SKOV3 cell line due to the higher cellular uptake percentage of CSO-SA micelles and the lower sensitivity of free drug to the cells. The cytotoxicities of shell crosslinked CSO-SA/DOX were highly enhanced in all cell lines than those of unmodified CSO-SA/DOX. 相似文献
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Rong Zhang Yui Mano Akira Sumiyoshi Masayuki Kanamori Yukihiko Sonoda 《Drug delivery》2016,23(8):2780-2786
Convection-enhanced delivery (CED) of therapeutic agents is a promising local delivery technique that has been extensively studied as a treatment for CNS diseases over the last two decades. One continuing challenge of CED is accurate and consistent delivery of the agents to the target. The present study focused on a new type of therapeutic agent, NK012, a novel SN-38-loaded polymeric micelle. Local delivery profiles of NK012 and SN-38 were studied using rodent brain and intracranial rodent brain tumor models. First, the cytotoxicity of NK012 against glioma cell lines was determined in vitro. Proliferations of glioma cells were significantly reduced after exposure to NK012. Then, the distribution and local toxicity after CED delivery of NK012 and SN-38 were evaluated in vivo. Volume of distribution of NK012 after CED was much larger than that of SN-38. Histological examination revealed minimum brain tissue damage in rat brains after delivery of 40?µg NK012 but severe damage with SN-38 at the same dose. Subsequently, the efficacy of NK012 delivered via CED was tested in 9L and U87MG rodent orthotopic brain tumor models. CED of NK012 displayed excellent efficacy in the 9L and U87MG orthotopic brain tumor models. Furthermore, NK012 and gadolinium diamide were co-delivered via CED to monitor the NK012 distribution using MRI. Volume of NK012 distribution evaluated by histology and MRI showed excellent agreement. CED of NK012 represents an effective treatment option for malignant gliomas. MRI-guided CED of NK012 has potential for clinical application. 相似文献
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M. Abd Elgadir Md. Salim Uddin Sahena Ferdosh Aishah Adam Ahmed Jalal Khan Chowdhury Md. Zaidul Islam Sarker 《Yao wu shi pin fen xi = Journal of food and drug analysis.》2015,23(4):619
Chitosan is a promising biopolymer for drug delivery systems. Because of its beneficial properties, chitosan is widely used in biomedical and pharmaceutical fields. In this review, we summarize the physicochemical and drug delivery properties of chitosan, selected studies on utilization of chitosan and chitosan-based nanoparticle composites in various drug delivery systems, and selected studies on the application of chitosan films in both drug delivery and wound healing. Chitosan is considered the most important polysaccharide for various drug delivery purposes because of its cationic character and primary amino groups, which are responsible for its many properties such as mucoadhesion, controlled drug release, transfection, in situ gelation, and efflux pump inhibitory properties and permeation enhancement. This review can enhance our understanding of drug delivery systems particularly in cases where chitosan drug-loaded nanoparticles are applied. 相似文献
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壳聚糖是自然界中存在的唯一的带正电的碱性氨基多糖,具有来源丰富、无毒、低免疫原性、良好的生物可降解性和生物相容性等优点。壳聚糖的活性氨基和羟基,经各种化学修饰如羧基化、巯基化、季铵化、疏水修饰、长循环修饰和靶向修饰,可获得具有特殊功能特性的衍生物,广泛用作药物和基因的载体材料。是近年来药剂学领域的研究热点。本文就近年来壳聚糖及其衍生物在药物递送中的研究进展作一综述。 相似文献
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《Journal of drug targeting》2013,21(10):739-750
Polymeric micelles, based on lactobionic acid (LA)-conjugated Pluronic P105 (P105), were prepared to achieve liver-targeted delivery of silybin. In the triblock copolymer structure of PEO–PPO–PEO, LA was successfully conjugated with the terminal end of PEO to produce LA-P105. The success of synthesis was confirmed using FTIR and 1H NMR. The triblock copolymers with functional moiety were physically mixed with silybin to form micelles. Silybin-loaded LA-P105 micelles characterized by dynamic light scattering and transmission electron microscopy (TEM) were uniform spherical particles. There was a remarkable increase in the dissolubility for silybin in LA-P105 micelle solution (627?μg/mL) when compared with that for water (4.6?μg/mL). The pharmacokinetic experiments showed that the area under the curve of silybin plasma concentration–time profile in rats for LA-P105 micelles was lower than that for P105 micelles. Biodistribution studies indicated that a significantly increased amount of silybin was accumulated in liver, suggesting that LA locating on the surface of the micelles played an important role in transporting an increased amount of silybin into liver. This polymeric vehicle is, therefore, expected to be widely used as target-specific delivery vehicles for diverse water-insoluble therapeutic and diagnostic agents. 相似文献
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Sirima Soodvilai Wajee Tipparos Worranan Rangsimawong Prasopchai Patrojanasophon Sunhapas Soodvilai Warayuth Sajomsang 《Pharmaceutical development and technology》2019,24(8):927-934
This research aimed to evaluate the effects of silymarin (SM)-loaded polymeric micelles (PMs) on the renal toxicity and anticancer activity of cisplatin. Amphiphilic chitosan derivatives were employed to develop SM-loaded PMs. The permeation across an intestinal membrane, cytotoxicity, and renal toxicity of cisplatin during the treatment were evaluated. The SM-loaded PMs had small particle sizes (326–336?nm), negative surface charge, high entrapment efficiency (47–70%), and demonstrated pH-sensitive release. Rapid drug release was obtained at pH 7.4 (81–87% in 4?h). The SM-loaded PMs exhibited higher flux than free SM. Moreover, the pretreatment of SM (50–100?μg/mL)-loaded PMs increased the killing efficacy of cisplatin on the cancer cells. The renoprotective effect was witnessed (p?<?0.05) on the cells pretreated with SM-loaded benzyl-functionalized succinyl chitosan (BSC) PMs compared with those treated with only cisplatin, which the % cell viability increased from 29% to 82% and 96% for the PMs with SM concentration of 50 and 100?μg/mL, respectively. Moreover, the reduction in cell apoptosis and necrosis induced by cisplatin has been observed. In conclusion, SM-loaded BSC PMs could improve the bioavailability of SM, enhance the therapeutic effect, and protect renal damage during the treatment with cisplatin. 相似文献