姜黄素PLGA-PEG-PLGA胶束的制备及理化性质研究

本文以膜透析法制备载药胶束,研究了载体材料用量、药物投入量、透析时间、溶剂等对胶束的载药量、包封率及粒径的影响。对所制得胶束的理化性质如粒径分布、微观形态及体外释放进行了研究。采用UV法研究姜黄素溶液对照和姜黄素载药胶束的体外释放,对其释放曲线进行拟合。结果显示采用膜透析法制备的PLGA PEG PLGA载药胶束,平均粒径26.29 nm,包封率(70.03±0.34)%,载药量(6.4±0.02)%。姜黄素对照溶液和姜黄素胶束体外释放分别符合双指数双相动力学模型。     

血管内皮生长因子受体靶向的紫杉醇胶束的制备及其缓释效果

利用PLGA-PEG嵌段聚合物的两亲性质制备了3种不同PEG分子量的内部包载药物的血管内皮生长因子受体靶向胶束APRPG-PEG-M。通过对制剂粒径分布、zeta电位、包封率及载药量等方面的考察,确定处方和制备工艺,并考察其制剂学性质。制备的靶向胶束呈球形或类球形,粒径109.7~119.9nm、包封率89.2%~91.5%,在体外释药试验中48h累积释放量为47.8%~60.0%,表现出明显的缓释效果。制备的紫杉醇靶向胶束在体外对药物释放具有良好的缓释效果。     

聚乳酸-聚乙二醇三嵌段共聚物包载紫杉醇纳米胶束的制备及其体外药物释放行为

以聚乙二醇和丙交酯为原料,合成了一系列分子量的聚乳酸聚乙二醇三嵌段共聚物.分别采用直接溶解法和溶剂挥发/薄膜水化法制备了包载抗癌药物紫杉醇的纳米胶束.用DLS和SEM观测纳米胶束的形态,采用HPLC研究载药胶束的载药量、包封率,在体外磷酸缓冲盐(pH 7.4),37℃模拟条件下研究载药胶束的体外释放行为,MTT法研究了空白胶束的细胞毒性以及载药胶束对C6细胞的体外抑制.结果表明使用直接溶解法得到粒径为200nm的球形胶束,使用溶剂挥发/薄膜水化法得到粒径分别为50nm和150nm的纳米胶束;溶剂挥发/薄膜水化法的载药量和包封率高于直接溶解法,缓释曲线均符合Ritger-Peppas指数模型;材料和制备方法均未引入细胞毒性,采用直接溶解法制备的载药胶束与游离紫杉醇对脑胶质瘤细胞C6的抑制效果相当.     

两亲嵌段聚合物载药胶束的绿色制备技术

为了避免制备过程中有机溶剂的使用,开发了一种两亲嵌段聚合物载药胶束的新型绿色制备法--超临界二氧化碳挥发法,在自制的实验装置中成功制备了聚(2-甲基丙烯酰氧乙基磷酰胆碱)-聚甲基丙烯酸正丁酯(PMPC-b-PBMA)载紫杉醇胶束.该胶束具有较规则的球形形貌和较小的粒径分布,平均粒径为54nm,药物的包封率和载药量分别为61.0%和12.2%,与有机溶剂挥发法制备的胶束相当.体外释药动力学研究结果表明,该胶束可在人体血液环境中平缓释药,132h内的释药量达到55%,远高于采用有机溶剂挥发法制得的胶束.超临界二氧化碳挥发法有望成为缓释药物体系的新型制备法.     

叶酸修饰pH响应壳聚糖衍生物胶束的制备及性能表征

制备了叶酸（FA）、胆固醇琥珀酸单酯（CHS）共修饰的羟丙基壳聚糖衍生物（CHS-HPCHS-FA）,该衍生物在水中能够自组装形成粒径为200~400nm的胶束。研究了疏水片段CHS的取代度对胶束的临界胶束浓度、粒径、载药及释药性能的影响,分析了胶束pH响应控释药物的机理,结果表明,疏水片段取代度高的产物,其临界胶束浓度较低,形成的胶束粒径较小,载药效率较高。体外溶出结果显示,载药胶束在pH5.5条件下释药速率明显比pH7.4条件下更快,体现了pH响应控释药物的效果。体外细胞毒性实验结果表明,胶束的生物相容性较好,且叶酸修饰的载药胶束可增强肿瘤细胞的摄取,细胞毒性明显增大。     

生物可降解哑铃状高分子共聚物替莫唑胺载药微球的制备与表征

以生物可降解的哑铃状高分子共聚物材料作为药物载体,饱和替莫唑胺水溶液为选择性溶剂,采用透析法制备了替莫唑胺载药微球。通过动态光散射仪、扫描电镜、紫外分光光度计对替莫唑胺载药微球的粒径分布、表面形貌、载药量及释放行为进行了研究。结果表明:微球载药后其平均粒径不超过800nm,载药量可以达到39.9%;体外释放时间可达900h以上,且可用n级动力学速度方程较为真实地反映其释放行为。细胞实验证明了替莫唑胺载药微球对人源性SHG-44细胞的抑制效果优于替莫唑胺纯药粉末。     

β-环糊精/聚(L-天冬氨酸)共聚物的制备及载药性能研究

通过乙二胺β-环糊精与聚丁二酰亚胺开环聚合,制备出了新型两亲性共聚物,即β-环糊精/聚(L-天冬氨酸),并用IR和1 H NMR对其结构进行了表征.利用直接水溶法制备了聚合物胶束,通过激光粒度仪对胶束粒径大小进行了测定.利用芘为荧光探针,对其临界胶束浓度进行了测定.以甲氨蝶呤为模型药物,制备了聚合物载药胶束,并且测定了载药量和在缓冲溶液中的对甲氨蝶呤的控制释放能力.结果显示,聚合物胶束的有效粒径为76nm,其临界胶束浓度为3.184×10-3 g/L.该聚合物胶束对甲氨蝶呤的载药量为18.38%,且在缓冲溶液中有良好的缓释效果.     

离子交联法制备氟尿嘧啶壳聚糖微球

以壳聚糖为药用载体,5-氟尿嘧啶为模型药物,三聚磷酸钠为离子交联剂,采用离子交联法制备壳聚糖微球制剂,考察处方和工艺因素对载药微球形态、包封率及体外释放行为的影响;采用扫描电镜、粒度分析仪和红外光谱对微球结构进行表征。结果表明:5-氟尿嘧啶壳聚糖微球的包封率可达到77.8%,平均粒径为6.4μm,30 min时体外突释为21.3%,48 h以内的累积释药率为77.0%,缓释作用明显。     

双嘧达莫嵌段共聚物胶束的制备及体外药物释放

以聚癸二酸酐-聚乙二醇-聚癸二酸酐为载体材料,采用沉淀/溶剂挥发法制备双嘧达莫载药胶束,DLS法测定胶束的粒径,紫外分光光度法测定胶束的载药量、包封率和药物的释放度.结果发现载药胶束的粒径大于空白胶束的粒径;随着共聚物中疏水链段比例的增加,胶束的载药量和包封率都上升,而且药物释放时间延长;调节嵌段共聚物的链段组成,可以调节药物的释放动力学过程.     

阿昔洛韦/赖氨酸壳聚糖纳米粒的理化性质考察

考察阿昔洛韦/赖氨酸壳聚糖纳米粒的理化性质。利用激光粒度分析仪、透射电镜、扫描电镜、高效液相色谱仪等测定载药纳米粒的形态、粒径、包封率和载药量,并考察载药纳米粒的体外释放行为。考察结果,微球呈类圆形,具有明显的核壳;载药的粒子平均粒径大小为107.96 nm;包封率为(61.24±0.68)%;载药量为(15.36±0.65)%;体外释放符合Higuchi模型。结论:阿昔洛韦/赖氨酸壳聚糖纳米粒理化性能具有良好的稳定性,符合实验设计要求。     

不同结构两亲性嵌段共聚物的合成、药物负载及释放行为研究

采用阴离子活性聚合(AROP)的方法分别合成3种不同结构的两亲性嵌段共聚物:线型共聚物聚乙氧基乙基缩水甘油醚-聚乙二醇(PEEGE-PEO-(OH))、星型聚合物PEEGE-PEO-(OH)_3以及类树枝状聚合物PEEGE-PEO-(OH)_(24).通过~1H-NMR及GPC等手段对聚合物的结构进行表征.采用透析法制备负载阿霉素的聚合物胶束,通过透射电镜(TEM)和动态光散射(DLS)对胶束的形貌及尺寸进行表征.结果表明:3种胶束均具有球形结构;与线型及星型聚合物相比,两亲性类树枝状聚合物具有最高的载药效率与载药量;体外药物释放结果显示3种聚合物均具有pH敏感释放特性,且类树枝状表面致密结构可降低药物在中性环境下的释放率.     

Novel PLGGE graft polymeric micelles for doxorubicin delivery

Novel poly{(lactic acid)-co-[(glycolic acid)-alt-(L-glutamic acid)]}-g-monomethyl poly(ethylene glycol) (PLGGE) micelles were prepared and used as carriers for anti-tumor drug delivery. Three PEGylated PLGG copolymers (PLGGE2000, PLGGE1100 and PLGGE500) were characterized by XRD, TG and DSC. The critical micelle concentrations (CMCs) of the amphiphilic copolymers were 1.04, 0.55 and 0.13 μg/mL, respectively. The TEM, AFM and DLS measurements revealed that the micelles were homogeneous spherical nanoparticles with the diameters ranged from 50 to 150 nm when THF was used as solvent in the preparation of the micelles. Interestingly, extended cylindrical micelles were obtained using CHCl 3 as solvent. The micelles could trap doxorubicin (DOX) in the core with the highest drug loading content up to 23.7%. The mean diameter of drug loaded micelles was much bigger than that of blank micelles. The in vitro drug release of the micelles was diffusion-controlled release within the first 36 h and initial burst release was not obvious. However, after 36 h, the release rate in pH 5.0 was faster than that in pH 7.4 due to the degradation. The PLGGE micelles were nontoxic to both NIH 3T3 fibroblasts and HepG2 cells. The in vitro cytotoxicity against HepG2 cells demonstrated that the drug loaded micelles exhibited high inhibition activity to cancer cells. CLSM observation of HepG2 cells showed that DOX released from the micelles could be delivered into cell cytoplasm and cell nuclei. PLGGE micelles are potential promising carriers for anti-tumor drug delivery.     

磷脂胆碱聚乳酸自组装胶束的结构与性能

用与天然磷脂结构和相对分子质量类似的磷脂月E{碱聚乳酸(Phosphorylcholine-containing poly(L-lactide),PLLA.pc)$sJ备自纽装胶束,采朋透射电镜和激光共聚焦显微镜进行观察.研究结果表明:胶束为外壳亲水内核疏水的实心球:表面张力法测得临界胶束质量浓度(Critical micelle concentration,CMC)~23 mg/L,显著低于天然磷脂胆碱质鼍浓度;当氯化钠质量分数低于0.9%时,CMC无明显变化,表明胶柬在生理盐水中较稳定:胶束被稀释时,动态光散射测得胶束粒径和粒径分布均逐渐变小,表明体系是动态体系;在37℃恒温条件下放置15 h,胶束数量、粒径和分布均变小,表明胶束可随时间降解;PLLA-PC胶束生物相容性好,可降解,可望成为新型的控释药物载体.     

Preparation and Characterization of Polymeric Micelles from Poly（D, L-lactide） and Methoxypolyethylene Glycol Block Copolymers as Potential Drug Carriers

Amphiphilic diblock copolymers composed of methoxy polyethylene glycol (MePEG) and poly(D,L- lactide) (PDLLA) were prepared for the preparation of polymeric micelles. The use of MePEG-PDLLA as drug carriers has been reported in the open literature, but there are only few data on the application of a se- ries of MePEG-PDLLA copolymers with different lengths in the medical field. The shape of the polymeric mi- celles is also important in drug delivery. Studies on in vitro drug release profiles require a good sink condi- tion. The critical micelle concentration of a series of MePEG-PDLLA has a significant role in drug release. To estimate their feasibility as a drug carrier, polymeric micelles made of MePEG-PDLLA block copolymer were prepared by the oil in water (O/W) emulsion method. From dynamic light scattering (DLS) measurements, the size of the micelle formed was less than 200 nm. The critical micelle concentration of polymeric micelles with various compositions was determined using pyrene as a fluorescence probe. The critical micelle con- centration decreased with increasing number of hydrophobic segments. MePEG-PDLLA micelles have a considerably low critical micelle concentration (0.4-0.5 μg/mL), which is apparently an advantage in utilizing these micelles as drug carriers. The morphology of the polymeric micelles was observed using scanning electron microscopy (SEM) and transmission electron microscopy (TEM). The micelles were found to be nearly spherical. The yield of the polymeric micelles obtained from the O/W method is as high as 85%.     

磁热响应复合载药胶束的热化疗协同效应

以N-异丙基丙烯酰胺(NIPAM)、N,N-二甲基丙烯酰胺(DMAM)为单体,通过可逆加成-断裂链转移聚合(RAFT),制备了一种临界相转变温度(LCST)为42.5℃的温敏性两亲性嵌段共聚物PLA29-b-P(NIPAM29-co-DMAM13)。通过高温前驱体分解法制备了单分散超顺磁性纳米粒子Mn_(0.6)Zn_(0.4)Fe_2O_4;并采用自组装得到了载有药物(喜树碱,CPT)和磁性纳米粒子的磁热温敏复合载药胶束。通过透射电子显微镜、紫外光分光光度计以及MTT等对该胶束的形态、药物控释能力和细胞毒性进行了研究。结果表明,该胶束具有良好的生物学和药物控释性能。同时,通过激光共聚焦显微镜与流式细胞仪研究了磁热温敏复合载药胶束在不同条件下对特定肿瘤细胞的生长抑制作用。结果表明,磁热疗和化疗的高效协同效应可促进肿瘤细胞对药物的吞噬,增强药物对肿瘤细胞的毒性。对该载药胶束的磁热化疗协同增效机制也进行了初步探究。     

羧甲基壳聚糖纳米胶束的制备与光响应性研究

智能响应性聚合物胶束作为药物控释传递系统的载体引起广泛关注,其中光刺激因为可控性高、清洁高效等优点被广泛研究.该文以丁二酸酐为连接臂将1-芘甲醇(PyM)接枝到羧甲基壳聚糖(CMCS)的氨基上制得两亲性大分子(PMS-g-CMCS),然后在水溶液中自组装成光响应纳米胶束.采用动态光散射(DLS)和透射电镜(TEM)表征胶束的大小和形态,并研究光刺激前后胶束的大小变化;通过核磁和荧光研究胶束的光响应机制.结果表明该胶束为类球形核-壳结构,粒径约200 nm,且具有较好储存稳定性;在紫外(UV)光照下,能发生结构改变,其光响应机制可归因于连接PyM的酯键断裂.胶束显示出可用作疏水性药物或农药光控释放载体的潜力.     

硅溶胶对硫酸庆大霉素的吸附和缓释

以单分散性好、粒径在20nm左右的二氧化硅(SiO2)溶胶为药物载体,制备了负载硫酸庆大霉素的载药纳米硅凝胶.通过红外光谱以及紫外可见吸收光谱考察了硅溶胶对硫酸庆大霉素的吸附和释放性能.结果表明,硅溶胶对硫酸庆大霉素有较大的吸附率(89.6%)和载药量(59.9%),以及较慢的缓释性能(48h内释放79.6%),作为药物载体是可行的.