丙泊酚mPEG-PLA/普朗尼克混合胶束的制备和性质(英文)

采用生物相容性聚合物胶束材料聚乙二醇-聚乳酸(mPEG-PLA)和普朗尼克P105(P105),构建了全新的混合胶束体系,用于提高难溶性麻醉药—丙泊酚的溶解度。相对于单纯由mPEG-PLA构建的载药胶束,该载药混合胶束能有效提高药物溶解度。最优化处方为mPEG-PLA:P105:丙泊酚=10:4:5(w/w/w),粒径约为90nm,多分散指数为0.2左右。载药混合胶束中游离药物浓度显著低于市售品脂肪乳(P<0.05)。此混合胶束于4oC条件下放置6个月,其粒径、多分散指数、游离药物浓度和载药量均无明显变化,说明4oC条件下该体系在6个月内是稳定的。混合胶束在各时间点的体外释放百分率显著高于市售品脂肪乳,这可能有利于更快发挥药效。睡眠/苏醒试验结果表明,混合胶束、单一胶束以及市售品脂肪乳的翻正反射消失时间和恢复时间没有显著性差异(P>0.05)。上述结果表明该混合胶束有望成为静脉给药系统应用于临床。     

半胱氨酸修饰的荷载紫杉醇聚离子复合物胶束口服给药的体内体外研究

本文合成了普朗尼克F127-壳聚糖(F127-CS)和普朗尼克F127-半胱氨酸(F127-CT)共聚物,采用薄膜分散法以F127-CS、F127-CT和胆酸钠(Na C)为材料构建了聚离子复合物胶束,并以该复合物胶束作为药物载体运载紫杉醇进行口服给药。通过物理化学性质研究,包括粒径分布、Zeta电位、外观形态和临界胶束浓度,进一步证实形成了纳米级球形结构的胶束,并对胶束的体外释放及体内药动力学进行考察。与普朗尼克胶束的载药量(3.35%)相比,F127-CS/F127-CT/Na C胶束载药量提高到12.77%。通过临界胶束浓度的测定证实:在水溶液中F127-CS/F127-CT/Na C胶束比Na C胶束更稳定。药物动力学实验结果显示F127-CS/F127-CT/Na C紫杉醇载药胶束的药-时曲线下的面积是紫杉醇溶液的4倍。因此,F127-CS/F127-CT/Na C胶束是一种理想的紫杉醇口服给药系统。     

两亲性嵌段共聚物普朗尼克的细胞毒性及细胞摄取

目的：考察不同型号、混合普朗尼克对MCF-7及耐药MCF-7的细胞毒性和细胞摄取,筛选出可供后续胶束研究的混合普朗尼克最优配比。方法：选取Pluronic F68、F127、P85、P105、P123,按HLB值分为2组,以一定比例交叉混合,采用CCK-8法和高效液相色谱法,测定普朗尼克、混合普朗尼克对MCF-7及耐药MCF-7的细胞毒性和细胞摄取量。结果：试验结果表明,F68、F127对细胞的毒性较小,而P85、P105、P123对细胞的毒性相对较大;当2种普朗尼克配比使用的质量浓度小于100 μg·mL^-1时,MCF-7及耐药MCF-7 2种细胞的存活率均大于70%。随着混合普朗尼克的浓度增加,细胞毒性均逐渐增强;F68与P85配比使用时,细胞毒性最大,且配比浓度为1：4时的细胞毒性大于1：2。Pluronic P85、P105、P123均可促进肿瘤细胞的药物摄取,Pluronic F68、F127基本不促进药物的摄取。F127-P123较其他混合普朗尼克表现出更强的摄取能力。结论：随着HLB值的降低及浓度的增大,普朗尼克对MCF-7及耐药MCF-7细胞的毒性增加。混合普朗尼克可以促进肿瘤细胞对于化疗药物的摄取。     

紫杉醇聚氰基丙烯酸正丁酯纳米粒对人卵巢癌细胞的毒性

目的:评价制备紫杉醇聚氰基丙烯酸正丁酯纳米粒(PTX-PBCA-NPs)的原料的生物安全性以及PTX-PBCA-NPs的细胞毒性。方法:采用四噻唑蓝法(MTT法)和检测乳酸脱氢酶(LDH)活性的方法考察空白PBCA-NPs及其聚合的原料、PTX-PBCA-NPs对L-02人正常肝细胞、卵巢癌敏感株(A2780)和卵巢癌耐紫杉醇肿瘤细胞株(A2780/T)的细胞毒性。结果:制备的空白PBCA-NPs只有在大于608 ng·mL-1时,对于L-02细胞具有明显的毒性(P<0.05);在质量浓度304～608 ng·mL-1,空白PBCA-NPs对A2780和A2780/T细胞有明显毒性(P<0.05)。与同一浓度PTX溶液比较,PTX-PBCA-NPs对A2780和A2780/T细胞的毒性作用明显(P<0.05)。结论:空白PBCA-NPs有一定的生物安全性,PTX-PBCA-NPs在对卵巢癌肿瘤细胞有一定的杀伤能力。     

氰基丙烯酸正丁酯纳米载体促进紫杉醇粒抗脑胶质瘤作用的实验研究

目的:动物实验水平研究聚氰基丙烯酸正丁酯纳米载体促进紫杉醇粒抗脑胶质瘤的作用。方法:1紫杉醇-聚氰基丙烯酸正丁酯纳米粒悬液的制备。2制备胶质瘤模型,制备的胶质瘤模型随机分成四组,每组20只,Ⅰ组注射生理盐水、Ⅱ组注射紫杉醇、Ⅲ组注射PBCA+NP、Ⅳ组注射紫杉醇+PBCA+NP,15d后观察Wistar大鼠的变化,观察肿瘤病理切片,检测肿瘤细胞的凋亡率。结果:1Wistar大鼠的生存状态,Ⅳ组好于其它三组。2Ⅱ组和Ⅲ组Wistar大鼠脑胶质瘤血管的减少和坏死肿瘤组织比Ⅳ组少。3Wistar大鼠脑胶质瘤调亡率Ⅳ组高于Ⅱ组、Ⅲ组,具有统计学显著差异(P<0.05)。结论:聚氰基丙烯酸正丁酯纳米载体明显提高紫杉醇抗Wistar大鼠脑胶质瘤的作用。     

氧化苦参碱聚氰基丙烯酸正丁酯毫微粒制备工艺研究

目的 优化氧化苦参碱聚氰基丙烯酸正丁酯毫微粒（OM-PBCA-NP）的处方和制备工艺。方法 以粒径、包封率和载药量为综合评价指标，通过单因素试验初选、均匀设计法精选，优化处方和制备工艺；以高效液相色谱法测定毫微粒中氧化苦参碱的含量。结果 确定了最佳制备工艺为三步法，最佳处方为：氧化苦参碱50mg，聚氰基丙烯酸正丁酯0．1ml，普流罗尼克F68200mg，右旋糖苷．70100mg，焦亚硫酸钠40mg；制得的氧化苦参碱毫微粒平均粒径为144．2nm，粒子圆整，载药量为17．8％，包封率为82．6％。结论 优化筛选后的处方工艺，为氧化苦参碱聚氰基丙烯酸正丁酯毫微粒的最佳制备工艺。     

大蒜素聚氰基丙烯酸正丁酯纳米粒的制备工艺研究

目的：研制大蒜素聚氰基丙烯酸正丁酯纳米粒并对处方与制备工艺进行优化筛选。方法：以生物降解型聚氰基丙烯酸正丁酯为载体材料，采用乳化聚合法制备大蒜素聚氰基丙烯酸正丁酯纳米粒；以载药量、包封率、形态和粒径分布为评价指标，通过单因素试验考查、均匀设计法优化制备工艺。结果：按优化处方与制各工艺条件，制得纳米粒球形圆整、分散良好，算术平均粒径为113．4nm，粒径分布范围为11．7—146．8nm，载药量为18．57％，包封率为92．87％。结论：经优化筛选出的工艺是大蒜素聚氰基丙烯酸正丁酯纳米粒的最佳制备工艺。     

米托蒽醌聚氰基丙烯酸正丁酯毫微粒的研究

用乳化聚合法制备了米托蒽醌聚氰基丙烯酸正丁酯毫微粒,并对其表面荷电特性、形态、大小及其分布、体外释药性质、载药量、初步稳定性和在动物体内的分布进行了研究。结果表明,粒径d_av=55.23nm,载药量为46.77%,包封率为84.89%,表面带负电荷。体外释药符合双相动力学规律。其胶体溶液能经受煮沸30min灭菌。经氚标记液闪计数技术测定证实其iv后主要集中于肝脏,并有一定的肝肿瘤和肝细胞的靶向性。提示其对于提高米托蒽醌抗肝癌的效果和降低其全身毒副作用有重要意义。     

吡罗昔康普朗尼克磷脂有机凝胶的体外评价和局部组织分布

目的制备普朗尼克磷脂有机凝胶,以吡罗昔康为模型药物,评价其体外性能并考察其局部组织分布特征。方法应用椎-板模型流变仪测定普朗尼克磷脂有机凝胶的流变学参数,Franz扩散池法测试其体外释放和经皮通透性,考察大鼠局部给药的局部组织分布。结果普朗尼克磷脂有机凝胶具有典型的凝胶的流变学特征;48 h体外累积释放率和经皮通透率分别为(81.56±3.09)%和(3.80±1.59)%;皮肤和肌肉的药时曲线具有双峰特征,给药侧的组织药物浓度高于血药浓度和对侧相同组织的浓度,原因在于药物的直接通透和系统再分布。结论普朗尼克磷脂有机凝胶适用于皮肤局部给药的载体。     

紫杉醇嵌段共聚物纳米粒的制备及体外实验研究

目的：制备紫杉醇嵌段共聚物纳米制剂，研究其理化性质和体外抗癌活性。方法：采用界面沉积法制备了负载紫杉醇的聚乙二醇单甲醚-乳酸羟基醋酸共聚物（mPEG-PLGA）嵌段共聚物纳米粒，运用粒径分析仪测其粒径及Zeta电位，透射电镜表征纳米粒的形态，研究了投药量及mPEG在共聚物中的不同含量对纳米粒的影响，考察所制纳米粒对癌细胞的作用。结果：所制纳米粒为球形．粒径为纳米级，与临床用的紫杉醇注射液相比，癌细胞的存活率明显降低，且对癌细胞作用时间越长，细胞毒性作用越明显。结论：该试验可为开发紫杉醇新型静脉注射制剂提供了实验依据。     

星点设计-效应面法优化紫杉醇-PluronicP123共聚物胶束处方工艺

目的以星点设计-效应面法优化紫杉醇-Pluronic P123共聚物胶束处方工艺,以期提高难溶性药物紫杉醇在Pluronic P123载体中的包封率和载药量,并对其理化性质进行表征。方法采用薄膜分散法制备紫杉醇-Pluronic P123胶束,以包封率、载药量和胶束溶液药物浓度为考察指标,紫杉醇投药量和水相用量为自变量,采用星点设计-效应面法优化处方,并对模型进行验证,对粒径、体外释放等理化性质进行表征。结果二次多项式非线性回归模型是描述因素与指标关系的最佳模型,根据所优化处方,制得共聚物胶束的包封率约为85.64%,载药量约为1.68%,平均粒径约为(25.2±2.9)nm,zeta电位为(-11.23±2.64)m V。胶束制剂与普通制剂(Taxol注射液)在4 h内的累积释放分别为50.1%和90.5%,前者具有较强的缓释作用。结论通过采用星点设计-效应面优化法确定的处方工艺,可制备具有较高包封率的紫杉醇-Pluronic P123共聚物胶束,所建模型有较好的实用性和预测性。Pluronic P123可有效增溶难溶性药物紫杉醇,并形成具有较强缓释作用的纳米级共聚物胶束制剂,具有应用于肿瘤治疗的潜力。     

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.     

Influence of drug-carrier compatibility and preparation method on the properties of paclitaxel-loaded lipid liquid crystalline nanoparticles

The main objective of this paper is to elucidate the influence of drug-carrier compatibility and preparation method on the properties of Paclitaxel (PTX)-loaded lipid liquid crystalline nanoparticles (LLCNs). Here, glyceryl monooleate (GMO), glycerol monolinoleate (GML), glyceryl monolinolenate (GMLO) were selected as the lipids, and Soluplus, Poloxamer 407 (P407), Tween 80 were selected as the stabilizer to prepare LLCNs. First of all, PTX-carrier compatibility was screened by molecular dynamic simulation using Flory?Huggins interaction parameter as the criteria. Thereafter, PTX-loaded LLCNs were prepared under different energy input conditions and were characterized. Influence of lipid type, stabilizer type, drug-lipid ratio and preparation method on properties of the LLCNs was explored. It was found that both lipid and stabilizer type had significant influence on drug encapsulation efficiency. Compared to the LLCNs prepared under high energy condition, PTX-loaded LLCN prepared under low energy input had higher drug encapsulation efficiency, smaller particle size (211.6 nm versus 346.8 nm) and a sustained release behavior. In conclusion, molecular dynamic simulation is an effective tool to select the most appropriate composition of LLCNs for a specific drug substance, and LLCNs prepared using low energy input methods was particularly applicable for industrial manufacture.     

紫杉醇Pluronic P105聚合物胶束的制备、表征与逆转肿瘤多药耐药性的体外研究

药物递送系统是克服肿瘤多药耐药性(MDR)的一种新策略。本文以聚合物胶束系统和难溶性药物紫杉醇(PTX)为研究对象，旨在制备一种新型的PTX给药系统，既能增溶难溶性药物，又具有克服肿瘤MDR的能力。以Pluronic P105为载体，采用固体分散-水化法制备PTX聚合物胶束，并以星点设计-效应面优化法进行处方优化。对其粒径、体外释放等性质进行表征后，以人耐药卵巢癌细胞SKOV-3/PTX为细胞模型，体外评价PTX聚合物胶束的细胞摄取及其逆转肿瘤细胞耐药性的作用。结果显示，聚合物胶束制剂的载药量约为1.1%、药物浓度约为700 μg·mL^-1、平均粒径约为24 nm。胶束制剂与普通制剂(Taxol)在6 h内的累积释放分别为45.4%和95.2%，前者具有较强的缓释作用；胶束制剂与Taxol对SKOV-3/PTX的IC₅₀值分别为1.14和5.11 μg·mL^-1，二者的耐药逆转指数(RRI)分别为9.65和2.15。胶束制剂可促进耐药细胞对P-糖蛋白(P-gp)底物(PTX或Rhodamine-123)的摄取。结果表明，Pluronic P105可有效增溶难溶性药物PTX，并形成具有较强缓释作用的纳米级聚合物胶束制剂，该制剂可显著提高PTX对人卵巢癌耐药细胞的细胞毒性，能逆转其耐药性。     

Effect of process and formulation variables on the preparation of parenteral paclitaxel-loaded biodegradable polymeric nanoparticles: A co-surfactant study

The purpose of this study was to evaluate the effect of process (homogenization speed and evaporation time) and formulation (aqueous/organic phase ratio, surfactant concentration, polymer type and concentration, and drug amount) variables on the preparation of paclitaxel-loaded biodegradable polymeric nanoparticles using modified solvent evaporation technique. Thereafter, a formulation was selected and subjected to evaluation of inclusion of a co-surfactant for further reduction of particle size. Particle size, encapsulation efficiency and in-vitro drug release kinetics were evaluated. It was observed that the inclusion of vitamin E TPGS (0.01%), Poloxamer 188 (0.5%) or Tween 80 (0.25%) reduced the particle size of nanoparticles to 230, 244 or 301 nm from 438 nm, respectively. Encapsulation efficiency increased for both vitamin E TPGS and Poloxamer 188 up to concentration at 0.010% and 0.25%, respectively, while this was not the case for Tween 80. Comparison of drug release kinetics demonstrated that drug release accelerated from paclitaxel-loaded biodegradable nanoparticles prepared with the inclusion of Tween 80 but was delayed for Poloxamer 188 and vitamin E TPGS. Thus, it was concluded that the particle size of the nanoparticles could be reduced further and the paclitaxel release kinetics could easily be adjusted by taking advantage by the inclusion of a co-surfactant.     

Studies on paclitaxel-loaded glyceryl monostearate nanoparticles

Solid lipid nanoparticles (SLNs) of Paclitaxel were prepared by modified Hot homogenization method using Glyceryl monostearate (GMS). The SLNs were characterized for its physicochemical characteristics such as mean particle size, percentage entrapment efficiency and zeta potential, which were found to be 226 nm, 92.43% and ?29.4 mV, respectively. The Transmission Electron Microscopy (TEM) studies showed that prepared SLNs were of spherical shape. The drug retarding efficiency of the lipid (GMS) was better in pH 7.4 compared to pH 3.5. The release profile showed a tendency to follow Higuchi diffusion pattern at pH 7.4 and Peppas-Korsenmeyer model at pH 3.5. Chemosensitivity assay carried out using B16F10 cell lines showed that anti-proliferative activity of Paclitaxel was not hindered due to encapsulation.     

普鲁兰多糖接枝聚乳酸紫杉醇大分子胶束的制备及体内初步毒性评价

目的以一种新型两亲性大分子材料普鲁兰多糖接枝聚乳酸(pullulan-grafted-poly(D,L-lactide),PPLA)为载体材料,制备普鲁兰多糖接枝聚乳酸紫杉醇(paclitaxel,PTX)大分子胶束(PPLAPTX),以期降低紫杉醇的不良反应。方法采用薄膜水化法制备PPLA-PTX,以粒径、粒径分布(particle distribute index,PDI)、载药量(drug loading,DL)、包封产率(encapsulation efficiency,I.E)为指标,应用单因素联合星点设计效应面法,对胶束的处方及工艺进行优化,采用多元线性回归及二项式拟合,预测较优参数。对按照最优处方所制备的PPLA-PTX的结构特性和制剂学性质进行表征,并以紫杉醇注射液(PTX-solution,PTX-S)为对照,考察PPLA-PTX的体内毒性。结果二次多项式非线性回归模型是描述因素与指标关系的最佳模型,紫杉醇在PPLA-PTX中以分子或无定型形式存在,根据所得优化处方制得共聚物胶束的包封产率约为86.39%,载药量质量分数约为7.58%,透射电镜下粒子呈圆形均匀分布,采用马尔文激光粒度仪测定胶束粒径约为117.7 nm,PDI值0.158,Zeta电位为-3.43 mV,PPLA-PTX体外释放分为两阶段,第一阶段(0~4 h)符合Higuchi释放动力学,第二阶段(4~12 h)符合一级释放动力学。小鼠体内毒性实验表明,PPLAPTX的给药剂量为PTX-S的1.8倍时,前者的小鼠存活率为70%,后者全部死亡,连续给药7 d,前者的白细胞数约为后者的1.6倍,给药结束后7 d,PPLA-PTX组白细胞数回升至生理盐水组的83%。结论通过单因素与星点设计效应面法对处方和工艺优化,成功制备了普鲁兰多糖接枝聚乳酸紫杉醇大分子胶束,其粒径小而均匀,且具有较高的载药量和包封产率,与PTX-S相比,其具有更高的耐受剂量,更低的骨髓毒性,具有潜在的研究价值。     

紫杉醇两亲嵌段共聚物纳米囊的研究

目的探讨负载紫杉醇的聚乙二醇-b-聚(D,L-乳酸)两亲性嵌段共聚物核-壳型纳米囊(PMT)。方法采用固相分散法制备PMT,动态光散射(DLS)测定PMT的粒径,透射电子显微镜(TEM)和¹HNMR表征PMT的形态,研究共聚物相对分子质量和紫杉醇投药量对PMT的影响,考察PMT对昆明鼠肝癌H22的疗效。结果PMT呈核-壳结构球形,粒径为纳米级,随着PEDLLA中疏水嵌段相对分子质量或载药量的增大而增大,PMT具有与Taxol类似的抑制肿瘤作用。结论本研究为开发紫杉醇新型静脉注射制剂提供了实验依据。