聚合物胶束递药系统逆转肿瘤多药耐药性的研究进展

聚合物胶束是近年来抗肿瘤药物递药系统研究中发展较快的一种新型递药载体,可显著提高药物抗肿瘤效果,尤其在逆转肿瘤多药耐药现象方面表现出极大的潜在价值。本文主要综述了聚合物胶束递药系统抑制肿瘤多药耐药现象的过程和机制,总结了该领域研究的最新进展,以期为聚合物胶束递药系统今后在该领域的研究提供参考。     

多西他赛Pluronic F127聚合物胶束的制备与表征

目的制备多西他赛(DTX)的F127聚合物胶束,对其药剂学特征进行评价。方法薄膜分散法制备胶束,并在单因素考察的基础上,以正交试验优化处方;透射电镜观察胶束形态;粒度分布测定仪测定其粒径、粒度分布;离心过滤法测定胶束的包封率和载药量;以DTX注射液作对照,采用动态膜透析法考察载药胶束的体外释药情况。结果薄膜分散法制备的胶束呈球形或类球形,平均粒径为(30.2±2.56)nm,平均包封率为(86.66±2.46)%,平均载药量为(0.42±0.01)%;体外释放实验结果表明该胶束具有一定的缓释能力。结论该胶束制备工艺简单,成型好,包封率高,具有一定的缓释能力。     

多柔比星聚合物胶束制备、表征及其体外释药研究

目的 制各多柔比星的soluplus聚合物胶束,并对其进行体外评价.方法 采用薄膜分散法-pH诱导法相结合制备多柔比星聚合物胶束;采用粒径测定仪、透射电镜、X-射线衍射(XRD)、差示扫描量热法(DSC)及红外光谱(FTIR)对其进行表征;采用HPLC法测定胶束的包封率和载药量;采用动态膜透析法考察载药胶束的体外释药特性.结果 本研究制备的胶束呈球形或类球形,平均粒径为(67.57±2.9)nm,平均包封率为(77.81±4.03)％,平均载药量(10.15±1.56)％;XRD和DSC结果表明多柔比星以无定型状态或分子状态包载在聚合物胶束中;FTIR结果表明多柔比星分子中羟基和聚合物的羰基之间形成了氢键;体外释放结果表明多柔比星的soluplus聚合物胶束具有缓释作用.结论 该胶束制备工艺简单,其粒径、包封率、载药量可控,具有缓释作用.     

载多烯紫杉醇Solutol HS15/Pluronic F127混合胶束及叶酸接枝的Solutol HS15/Pluronic F127载药混合胶束的制备、优化及对比表征(英文)

采用薄膜水化法制备了载多烯紫杉醇Solutol HS15/Pluronic F127混合胶束(SF-DTX)及叶酸接枝的Solutol HS15/Pluronic F127载药混合胶束(FSF-DTX)。体外表征实验表明,两种载药混合胶束体系均呈球型,粒径分别为(22.2±0.43)nm,(24.3±0.26)nm;均具备较高包封率,SF-DTX为99.05%,FSF-DTX为90.28%,且均有缓释特性。同时,细胞摄取及细胞毒性实验结果表明两种混合胶束体系均在一定程度上可以逆转肿瘤多药耐药性(MDR),且FSF较之于SF胶束体系能更明显增强耐药人口腔上皮细胞癌细胞(KBv)对DTX的摄取,是一种潜在的肿瘤靶向性载药体系。     

叶酸介导肿瘤细胞靶向紫杉醇聚合物胶束的制备与表征

以叶酸-聚乙二醇-二硬脂酰磷脂酰乙醇胺(FA-PEG 3350-DSPE)和甲氧基聚乙二醇-二硬脂酰磷脂酰乙醇胺(mPEG 2000-DSPE)(摩尔比1:100)作为混合载体材料,采用固体分散-水化法,制备包载紫杉醇(1)的聚合物胶束,以星点设计-效应面法进行处方优化,并考察了聚合物胶束的理化性质、体外抑制肿瘤细胞生长效果及对巨噬细胞摄取的影响.结果表明,优化所得胶束的包封率为81%、载药量为2.7%、平均粒径为12～16 nm,可持续释放24 h;制品可有效提高1体外抑制肿瘤细胞生长的效果,加入1%的FA-PEG 3350-DSPE可略减弱mPEG 2000-DSPE规避巨噬细胞吞噬的效果.     

紫杉醇聚合物胶束纳米粒(NK105)的研究进展

紫杉醇( paclitaxel,PTX)是从红豆杉属植物紫杉的树干和树皮中提取的一种天然抗癌活性成分,临床研究表明紫杉醇在治疗多种实体瘤方面有显著的作用,包括乳腺癌、晚期卵巢癌、肺癌、脑部和颈部肿瘤以及急性白血病等[1-2].1971年Wani等[3]获得了紫杉醇纯品,同时确证其结构为二萜类化合物.紫杉醇通过微管蛋白稳定化作用抑制微管分解,使细胞分裂阻断在G2期和M期,促进肿瘤细胞死亡,从而抑制肿瘤的生长[4-5].目前临床上使用较多的是紫杉醇注射液,但由于紫杉醇在水中的溶解度很低,因此常需在注射液中加入聚氧乙烯蓖麻油(CrEL)和乙醇(1∶1),以达到增加紫杉醇的溶解度和提高其稳定性的目的[6].     

聚合物胶束作为肿瘤靶向给药载体的研究

聚合物胶束是近年来出现的一种新型胶态药物载体,具有很多优良的性能,如体内外稳定性高、良好的生物相容性、难溶性药物的增溶作用等.它可以作为靶向肿瘤的给药载体,通过多种机制,如环境响应的聚合物胶束、特异性配基耦合的聚合物胶束、免疫聚合物胶束、通透性增强与滞留(EPR)效应、肿瘤的血管系统等途径来实现药物靶向给药.现主要讨论肿瘤给药的靶向策略和聚合物胶束作为靶向肿瘤给药载体的研究进展.     

膀胱肿瘤多药耐药性的逆转

膀胱肿瘤的治疗基本上是以手术结合腔内灌注化疗为主。然而化疗后的复发率很高,其中一个重要的原因是由于化疗过程中肿瘤细胞多药耐药(MDR)的产生。MDR是指肿瘤细胞接触一种化疗药物后,不仅对该药产生耐受性,而且对其他结构及作用机制不同的药物也产生交叉耐受。交叉耐药的产生     

肿瘤多药耐药性逆转剂研究进展

1．肿瘤多药耐药性多药耐药性是指肿瘤细胞因暴露于一种细胞毒药物而致对广泛结构和功能无关化合物发展交叉耐药性这一现象．而其产生原由则多与此类细胞特定蛋白如胞膜转运蛋白表达提高有关。后者由于能够降低药物胞内浓度，故成为影响许多类型肿瘤化疗治疗成功的主要障碍之一。从临床实践经验看，和肿瘤多药耐药性关联最为密切的细胞毒药物多是疏水性的两性天然产品。     

Self-assembly and characterization of Pluronic P105 micelles for liver-targeted delivery of silybin

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.     

Pharmacokinetics and biodistribution of paclitaxel-loaded pluronic P105 polymeric micelles

A novel polymeric micelle formulation of paclitaxel (PTX) has been prepared with the purpose of improving in vitro release as well as prolonging the blood circulation time of PTX in comparison to a current PTX formulation, Taxol injection. This work was designed to investigate the preparation, in vitro release, in vivo pharmacokinetics and tissue distribution of PTX-loaded Pluronic P105 micellar system. The micelles were prepared by thin-film method using a nonionic surfactant Pluronic P105 and a hydrophobic anticancer drug, PTX. With a dynamic light scattering sizer and a transmission electron microscopy, it was shown that the PTX-loaded micelles had a mean size of approximately 24 nm with narrow size distribution and a spherical shape. The in vitro release profiles indicated that the release of PTX from the micelles exhibited a sustained release behavior. A similar phenomenon was also observed in a pharmacokinetic study in rats, in which t _1/2β and AUC of the micelle formulation were 4.9 and 5.3-fold higher than that of Taxol injection. The biodistribution study in mice showed that the PTX-loaded micelles not only decreased drug uptake by liver, but also prolonged drug retention in blood and increased distribution of drug in lung, spleen and kidney. These results suggested that the P105 polymeric micelles may efficiently load, protect and retain PTX in both in vitro and in vivo environments, and could be a useful drug carrier for i.v. administration of PTX.     

Glucose transporter and folic acid receptor-mediated Pluronic P105 polymeric micelles loaded with doxorubicin for brain tumor treating

Abstract

In this study, glucose transporter and folic acid (FA) receptor-mediated Pluronic P105 polymeric micelles loaded with DOX (GF-DOX) were prepared for enhancing the blood–brain barrier (BBB) transportation and improving the drug accumulation in the glioma cells. The pH-triggered DOX release of GF-DOX indicating a comparatively fast drug release at weak acidic condition and stable state of the carrier at physiological environment. The transport of GF-DOX across the in vitro BBB model showed that GF-DOX exhibited higher BBB transportation ability with the transporting ratio of 21.47% in 4?h. The carrier was internalized into C6 glioma cells upon crossing the BBB model for the combined effect of the brain targeting by transportation of glucose transporter and active tumor cell targeting by FA receptor-mediated endocytosis. Moreover, minimized weight changes and high suppression ratio of tumor growth were observed after intravenous injection of GF-DOX. In conclusion, the glucose transporter and FA dual-targeting micelles would provide a safe and effective strategy for new modalities to treat brain tumor.     

Pluronic F127 polymeric micelles for co-delivery of paclitaxel and lapatinib against metastatic breast cancer: preparation,optimization and in vitro evaluation

Abstract

The aim of this study was to develop and characterize the paclitaxel (PTX)-lapatinib (LPT) loaded micelles for simultaneous delivery against metastatic breast cancer. Efflux pump-mediated drug resistance influences the efficacy of chemotherapeutic regimens. However, in the newly developed delivery system, LPT was selected to act as chemosensetizer. LPT increases the intracellular level of PTX by inhibition of efflux pumps. Pluronic F127 was selected for the preparation of the micelles, and its critical micelle concentration was determined to be 0.012?mg/ml. D-optimal design was used to analyze the impact of different experimental parameters on PTX and LPT encapsulation ratio. PTX encapsulation ratio was optimized at 68.3%, while LPT encapsulation ratio found to be 70.1%. Transmission electron microscope analyses demonstrate that micelles possess a good core–shell structure without any sharp edge. Laser scattering method results indicated that size of the optimized micelles is 64.81?nm with acceptable polydispersity index (0.309). In vitro release studies showed a sustain release pattern. PTX–LPT-loaded micelles suppressed the proliferation of resistant T-47D cell line (IC₅₀?=?0.6?±?0.1?µg/ml) compared to binary mixture of PTX and LPT (IC₅₀?=?6.7?±?1.2?µg/ml). Therefore, it is concluded that the developed formulation might increase the therapeutic efficacy in drug resistant metastatic breast cancer.     

Cytotoxicity of Triptolide and Triptolide loaded polymeric micelles in vitro

Triptolide (TP), a diterpenoid triepoxide purified from the Chinese herb Tripterygium wilfordii Hook F is characterized by strong anti-tumor effects on various cancer cells. Except its anti-tumor effects, TP also shows multiple pharmacological side activities, such as anti-inflammatory, immune-suppressive and male anti-fertility. In order to reduce these side effects, especially the immuno-suppressive activity when used to cure cancer, a novel polymeric micelle system containing TP (TP-PM) was constructed. The immune-modulation effects of TP-PM have been evaluated by previous studies. In this study, we compared the cytotoxicity of TP and TP-PM on Jurkat and HT29 cells. Therefore, we determined the cell viability, membrane integrity, cell proliferation, apoptosis, and caspase 3/7 activity after exposure to TP and TP-PM. The results demonstrated that actually low concentrated TP and TP-PM could induce an inhibition of cell growth and proliferation as well as membrane damage in both tumor cell lines. TP and TP-PM induced apoptosis and caused activation of caspase 3/7 even at low concentrations. Both formulations destroyed the membrane of Jurkat cells, nevertheless, TP-PM showed stronger pernicious effects. In general, TP-PM induced in both tested cell lines stronger effects than TP. Therefore, polymeric micelles can be considered as promising carriers for TP in cancer therapy.     

紫杉醇/低分子肝素-胱胺-维生素E琥珀酸酯胶束的制备及其体外细胞毒性

目的 优化紫杉醇/低分子肝素–胱胺–维生素E琥珀酸酯（PTX/LMWH-cys-TOS）胶束的处方,评价其制剂学特性和体外细胞活性。方法 以载药率和包封率为指标,考察有机溶剂、药物载体比例对胶束载药能力的影响,优化最佳处方。利用冷冻干燥法制备了胶束冻干粉针并考察复溶稳定性,采用透析法研究了胶束在不同浓度的二硫素糖醇溶液中的释放动力学,采用CCK8法研究了胶束在紫杉醇敏感和耐药细胞上的抗肿瘤活性,利用HPLC法测定了紫杉醇在肿瘤细胞内的质量浓度。结果 紫杉醇和LMWH-cys-TOS的最佳比例是1∶3.6,使用乙醇作为有机溶剂。加入冻干保护剂的胶束产品外观良好,复溶后的胶束应该在4 ℃保存,而且要尽快使用;在二硫苏糖醇存在的释放介质中,紫杉醇释放速度随着二硫苏糖醇浓度的增加而增加,二硫苏糖醇的浓度是20 mmol/L时,紫杉醇的36 h的累积释放量高达93%。胶束能提高紫杉醇在耐药细胞HCT-15/Taxol上的毒性和药物在肿瘤细胞内的质量浓度。结论 PTX/LMWH-cys-TOS胶束改善了紫杉醇的溶解度,实现了靶向给药。     

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

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。     

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

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，T_max和C_max)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C_max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。     

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

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。     

Sequestration and ultrasound-induced release of doxorubicin from stabilized Pluronic P105 micelles

Controlled drug delivery from micelles requires that the micelles remain stable when diluted below their critical micelle concentration, such as upon injection into blood. A cross-linked, interpenetrating network of N,N-diethylacrylamide (NNDEA) was polymerized in the core of Pluronic P105 micelles to stabilize temporarily the micelles at concentrations below the critical micellar concentration of free P105. The stabilized Pluronic micelles (called Plurogels) were able to sequester the drug doxorubicin (Dox) and protect HL-60 cells from the drug at concentrations where non-stabilized Pluronic provided no protection. The protection lasted ~ 12 hr, which is similar to the half-life of the particles. Application of low-frequency ultrasound resulted in a synergistic killing effect with Dox and low concentrations of either Pluronic P105 or stabilized Plurogels, most probably due to release of Dox and permeabilization of the cell membrane.