温度/pH双敏感嵌段共聚物胶束的体外性质研究

本文采用透析法制备了新型温度/pH双敏感聚组氨酸-聚乳酸羟基乙酸-聚乙二醇-聚乳酸羟基乙酸-聚组氨酸(PHis-b-PLGA-b-PEG-b-PLGA-b-PHis)嵌段共聚物的空白胶束与阿霉素(DOX)载药胶束。采用荧光探针技术测定其临界胶束浓度(CMC);应用光透射法研究了聚合物胶束的温度和pH敏感性质;测定了阿霉素载药胶束的粒径、形态、包封率和载药量;并对阿霉素载药胶束的温度和pH响应释药行为进行了研究。结果表明,制备的嵌段共聚物的临界胶束浓度为7.5×10-3 g.L-1;随胶束溶液温度升高或pH降低,其透光率升高;载药胶束的包封率为(85.2±3.1)%,载药量为(10.4±4.5)%;载药胶束粒径为(91.1±15.8)nm,为类球形结构;与模拟生理条件下(37℃,pH 7.4)释药行为相比,升高温度(41℃)、降低pH(pH 7.0、pH 6.5、pH 5.0)和同时升温并降低pH(41℃,pH 5.0)后胶束释药行为明显加快,表明该胶束的释药行为具有温度和pH敏感性。研究结果可见,PHis-b-PLGA-b-PEG-b-PLGA-b-PHis共聚物胶束具有pH/温度双重响应性质,有望成为抗肿瘤...     

阿霉素共聚物胶束的制备及体外性质研究

目的制备阿霉素共聚物胶束并研究其体外性质。方法采用开环聚合法合成聚乙二醇单甲醚-聚乳酸羟基乙酸（mPEG—PLGA）嵌段共聚物;用透析法、溶剂蒸发法制备空白及载阿霉素胶束;动态光散射仪（DLS）测定其粒径分布;采用紫外分光光度法测定胶束的包封率和载药量。通过体外释药实验研究了载阿霉素胶束的释药特性。结果采用透析法制备载阿霉素胶束大小均匀,平均粒径为（91．1±15．8）nm;药物胶束的包封率为85．2％,载药量为10．4％;与市售阿霉素注射剂相比,载阿霉素胶束具有良好的缓释性能。结论共聚物胶束可作为疏水性药物阿霉素的载体。     

紫杉醇pH敏感嵌段共聚物胶束的制备与体外评价

目的应用pH敏感聚组氨酸-聚乳酸-聚乙二醇(poly(L-histidine)-poly(D,L-lactide)-poly(ethylene glycol),PHis-PLA-mPEG)聚合物为载体材料,采用溶剂挥发法制备紫杉醇pH敏感嵌段共聚物胶束,并对其体外性质进行评价。方法采用芘荧光探针法测定PHis-PLA-mPEG聚合物的临界胶束浓度(critical micelle concentration,CMC);超速离心法测定紫杉醇共聚物胶束的包封率和载药量;分别利用动态光散射法和Zeta电位分析仪对胶束的粒径分布和表面电位进行测定;采用透析法测定载药胶束在不同pH条件下的体外释药行为。结果 PHis-PLA-mPEG临界胶束质量浓度为8.9 mg·L-1,胶束载药量质量分数为8%;包封率可达90%以上;载药胶束的平均粒径为150.2nm,PDI为0.097,粒度分布较窄,Zeta电位为-14.3 mV;载药胶束在弱酸性条件下,药物释放行为明显加快。结论 PHis-PLA-mPEG聚合物载体材料具有较好的pH敏感释药行为,其作为抗肿瘤药物的靶向传递系统具有较好的应用前景。     

多西他赛pH敏感嵌段共聚物胶束的制备

本文在合成pH敏感两亲性嵌段共聚物聚(2-乙基-2-噁唑啉)-聚乳酸(PEOz-PDLLA)的基础上，采用薄膜分散法制备多西他赛pH敏感嵌段共聚物胶束，利用芘荧光探针技术测定胶束的临界胶束浓度(CMC)；通过高效液相色谱测定胶束的载药量及包封率；分别利用透射电镜、动态光散射法和zeta电位分析仪对胶束的形态、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。结果表明，胶束的临界胶束浓度值为1.0×10^-3 g·L^-1；载药量可达15.0%，包封率为91.1%；胶束的粒度分布很窄，平均粒径为28.7nm；胶束粒子为圆球形且分散良好，其表面zeta电位值为(1.19±0.12)mV；在pH 7.4释放介质中，多西他赛胶束具有缓释作用；而在pH 5.0条件下，胶束释药明显加快，体现出PEOz-PDLLA胶束释药行为的pH敏感性。综合上述研究可见，PEOz-PDLLA嵌段共聚物胶束作为疏水性抗肿瘤药物的给药系统具有很好的应用前景。     

pH敏感聚(2-乙基-2-噁唑啉)-壳聚糖-阿霉素共聚物胶束的制备及性质考察

目的合成pH敏感两亲性接枝共聚物聚(2-乙基-2-噁唑啉)-壳聚糖-阿霉素(PEOz-g-CS-HyzDOX),采用透析法制备阿霉素pH敏感两亲性共聚物胶束并对其相关的制剂学性质、细胞抑制及细胞摄取行为进行考察。方法分别利用透射电镜(TEM)、动态光散射法(DLS)和zeta电位分析仪对胶束的形态、粒径和表面电位进行表征;采用透析法考察载药聚合物胶束的体外释放行为;采用MTT法考察聚合物胶束的细胞抑制作用。结果反应产物使用红外及核磁表征,确定为目标产物;PEOz-g-CS-Hyz-DOX聚合物胶束载药量为4.2%。采用透析法制备的载阿霉素聚(2-乙基-2-噁唑啉)-壳聚糖丁二酸单甲酯胶束(PEOz-g-CSMS/DOX)载药量可达5.62%,包封率为59.35%;两种胶束的粒径均较小且粒径分布很窄,胶束粒子为类球形且分散良好;两种胶束释药行为体现pH敏感性;PEOz-g-CS-Hyz-DOX聚合物胶束体外细胞毒作用及细胞摄取均优于PEOz-g-CSMS/DOX胶束和阿霉素溶液。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药物传递系统具有可行性及良好的应用前景。     

紫杉醇pH敏感聚合物胶束的制备与评价

摘 要 目的：合成双嵌段共聚物材料聚（2-乙基-2-噁唑啉）-聚乳酸（PEOz-PLA）,制备紫杉醇pH敏感嵌段共聚物胶束,并对其体外性质进行评价。方法: 用¹ HNMR和红外光谱对聚合物结构进行表征,采用透析法制备紫杉醇载药胶束,对冻干胶束的冻干保护剂种类进行筛选,芘荧光探针法测定胶束的临界胶束浓度（CMC）,动态光散射法（DLS）对胶束的粒径分布进行测定,透析法测定载药胶束在不同pH条件下的体外释药行为。结果: 胶束的临界胶束浓度为25.63 mg·ml^-1,以10% 聚乙二醇4000作为冻干保护剂胶束复溶性好,粒径分布窄,胶束载药量为8.12%,包封率为69.33%,冻干胶束平均粒径为183.7 nm;在 pH 7.4释放介质中,胶束释药缓慢,而在pH 5.0条件下,胶束释药速率明显加快,体现出胶束释药行为的pH敏感性。结论: PEOz PLA 聚合物胶束制备工艺简单,其粒径、包封率和载药量可控,具有一定的缓释作用,为其进一步的药理与临床应用提供依据。     

pH敏感释药两亲性壳聚糖共聚物胶束的制备及其性质考察

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。     

阿霉素-五味子乙素pH敏感聚合物胶束的制备与制剂学性质

目的以p H敏感聚合物聚乙二醇-聚乳酸-聚组氨酸[poly(ethyleneglyco1)-poly(D,L-lactide)-poly(L-histidine),m PEG-PLA-PHis]胶束为载体,联合包载抗肿瘤药物阿霉素与多药耐药逆转剂五味子乙素制备聚合物胶束,并对其制剂学性质进行研究。方法采用薄膜分散法制备阿霉素-五味子乙素p H敏感聚合物胶束,以包封率、载药量和稳定性(载药胶束24 h的包封率和载药量变化)为评价指标,采用单因素试验及Box-Behnken效应面法筛选最优处方;应用透射电子显微镜观察载药胶束的外观形态,动态光散射法测定载药胶束的粒径及zeta电位;透析法考察载药胶束在不同p H条件下的释药行为。结果制备的阿霉素-五味子乙素p H敏感聚合物胶束平均粒径为64.73 nm,zeta电位为-8.7 m V。最优处方中阿霉素包封率为95.3%,载药量为8.7%,五味子乙素包封率为76.1%,载药量为3.4%,载药胶束稳定性较好。体外释放结果表明,所制备的阿霉素-五味子乙素p H敏感聚合物胶束在弱酸性条件下,药物释放速率明显加快。结论采用星点设计-效应面法优化处方与制备工艺,所制备的阿霉素-五味子乙素p H敏感聚合物胶束粒径分布均匀,包封率和载药量良好,具有明显的p H响应行为。     

多西他赛pH敏感型聚(2-乙基-2-噁唑啉)-聚(D,L-丙交酯)自组装胶束的制备及其性质

目的利用两亲性嵌段共聚物聚(2-乙基-2-噁唑啉)-聚(D,L-丙交酯)[poly(2-ethyl-2-oxazo-line)-poly(D,L-lactide),PEOz-PDLLA]的自组装性能制备pH敏感型多西他赛胶束,并对其相关性质进行考察。方法运用阳离子开环聚合反应得到PEOz-PDLLA,通过FITR、1H-NMR和凝胶色谱法对其结构进行表征,采用电位滴定法测定共聚物pKa,应用荧光探针技术确定临界胶束浓度(criticalm icelle concentration,CMC)。动态光散射法和Zeta电位测试仪测定胶束的粒径和Zeta电位。以薄膜分散法包载多西他赛,并用透析法研究载药胶束的体外释放度。结果PEOz-PDLLA的亲水/疏水段分子质量比值为0.76,pKa为6.41,CMC为0.8×10-3g.L-1。载药胶束包封率为94.9%、载药量质量分数为8.7%、平均粒径为(35.3±4.9)nm、Zeta电位为(25.51±2.14)mV,在pH5.0的释放介质中释药速度加快。结论PEOz-PDLLA嵌段共聚物可自组装形成胶束,高效包载多西他赛,体外释放具有pH敏感性。     

PEG-I-dC16酸敏释药胶束的制备及体外释放研究

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。     

Brushed Block Copolymer Micelles with pH-Sensitive Pendant Groups for Controlled Drug Delivery

Purpose

To investigate the effects of small aliphatic pendent groups conjugated through an acid-sensitive linker to the core of brushed block copolymer micelles on particle properties.

Methods

The brushed block copolymers were synthesized by conjugating five types of 2-alkanone (2-butanone, 2-hexanone, 2-octanone, 2-decanone, and 2-dodecanone) through an acid-labile hydrazone linker to poly(ethylene glycol)-poly(aspartate hydrazide) block copolymers.

Results

Only block copolymers with 2-hexanone and 2-octanone (PEG-HEX and PEG-OCT) formed micelles with a clinically relevant size (< 50 nm in diameter), low critical micelle concentration (CMC, < 20 μM), and drug entrapment yields (approximately 5 wt.%). Both micelles degraded in aqueous solutions in a pH-dependent manner, while the degradation was accelerated in an acidic condition (pH 5.0) in comparison to pH 7.4. Despite these similar properties, PEG-OCT micelles controlled the entrapment and pH-dependent release of a hydrophobic drug most efficiently, without altering particle size, shape, and stability. The molecular weight of PEG (12 kDa vs 5 kDa) induced no change in pH-controlled drug release rates of PEG-OCT micelles.

Conclusion

Acid-labile small aliphatic pendant groups are useful to control the entrapment and release of a hydrophobic drug physically entrapped in the core of brushed block copolymer micelles.     

蓝萼甲素自组装纳米胶束的制备与性质研究

摘要目的制备蓝萼甲素自组装纳米胶束,并考察其性质。方法以三嵌段聚合物聚酯 聚乙二醇（PLGA PEG PLGA）为载体,采用溶剂蒸发法制备蓝萼甲素胶束,并通过正交实验筛选最佳制备工艺;采用芘荧光探针法测定临界胶束浓度（CMC）,透析法测载药胶束包封率和载药量,Zetasizer nano ZS仪测定其粒径和Zeta电位,透射电镜观察形态,并对其体外释放进行研究。结果胶束的CMC为2.5×10－3 mg&#8226;mL－1;平均粒径（62.49±0.60）nm,电位为（－25.4±0.4） mV;平均包封率（84.85±2.00）%;平均载药量（5.36±1.00）%;体外缓释约12 h,符合Higuchi方程。结论用三嵌段聚合物PLGA PEG PLGA可制备蓝萼甲素纳米胶束,因其缓释和纳米粒度特性而具有良好的应用前景。     

Dual Redox/pH-Sensitive Micelles Self-Assembled From Star-Like Amphiphilic Copolymers Based On Sucrose For Controlled Doxorubicin Delivery

Novel dual redox/pH-sensitive star-like amphiphilic sucrose-oligo(butyl fumarate) (thioglycolic acid conjugate)–SS–poly(ethylene glycol) (Suc-OBF(TGA)–SS–PEG) copolymers and their self-assembled micelles were prepared and utilized for intracellular doxorubicin delivery. Importance of changing the hydrophobic chain length on micelles properties was investigated. Results showed that the micelles with longer hydrophobic chain exhibited smaller size and were more stable in aqueous solution. The redox and pH sensitivity of the micelles was confirmed by the change of micelle diameter/diameter distribution measured by dynamic light scattering and the change of micellar morphology observed by scanning electron microscope. The micelles display a decent doxorubicin loading capacity. In vitro release studies showed that only 14.3% doxorubicin was released from doxorubicin-loaded micelles under physiological conditions in 30 h. The release of doxorubicin was accelerated at pH 5.5 or in the presence of 10 mM glutathione at pH 7.4 (46.9% and 76.9% of doxorubicin was released, respectively, in 30 h). The doxorubicin release was further expedited under pH 5.5 and 10 mM GSH conditions (91.4%). Suc-OBF(TGA)–SS–PEG micelles displayed no cytotoxicity toward HDF cells. MTT assays indicated that doxorubicin-loaded micelles had good cytotoxicity against MCF-7 cells. This work suggested that star-like amphiphilic Suc-OBF(TGA)–SS–PEG copolymer micelles may provide a promising platform for delivering doxorubicin and other hydrophobic anticancer drugs.     

Preparation,characterization, and drug release behaviors of drug nimodipine-loaded poly(epsilon-caprolactone)-poly(ethylene oxide)-poly(epsilon-caprolactone) amphiphilic triblock copolymer micelles

Amphiphilic triblock copolymers, poly(epsilon-caprolactone)-poly(ethylene oxide)-poly(epsilon-caprolactone) (PCL-PEO-PCL), were synthesized by ring opening polymerization of epsilon-caprolactone initiated with the hydroxyl functional groups of poly(ethylene glycol) at both ends of the chain. The micelles composed of this type of copolymer had such a structure that both ends of the PEO chain were anchored to the micelle. The critical micelle concentration of the block copolymer in distilled water was determined by a fluorescence probe technique using pyrene. As the hydrophobic components of the block copolymer increased, the critical micelle concentration value decreased. To estimate the feasibility as novel drug carriers, the block copolymer micelles were prepared by precipitation of polymer from acetone solution into water. From the observation of transmission electron microscopy, the micelles exhibited a spherical shape. Nimodipine was incorporated into the hydrophobic inner core of micelles as a lipophilic model drug to investigate the drug release behavior. The PEO/PCL ratio of copolymer was a main factor in controlling micelle size, drug-loading content, and drug release behavior. As PCL weight ratio increased, the micelle size and drug-loading content increased, and the drug release rate decreased.     

Preparation, pharmacokinetics and tissue distribution of micelles made of reverse thermo-responsive polymers

New reverse thermo-responsive polymers, poly(ethylene oxide)–poly(propylene oxide) multiblock copolymers (poly(ether-carbonate)s) were synthesized. The micelles made of new reverse thermo-responsive polymers were also prepared loaded with the poorly soluble anticancer drug, hydroxycamptothecin (HCPT). The structure characterization of poly(ether-carbonate)s was determined by ¹H NMR and FT-IR analysis. The critical micelle concentration (CMC), critical micelle temperature (CMT), size distribution and drug release in vitro were determined. The pharmacokinetics and tissue distribution in vivo for novel copolymer micelles were studied. The experimental results showed that the micelles was spherical in appearance and dispersed well. The process of HCPT release from micelles in vitro was composed of two steps, abrupt release and sustained release. After i.v. administration (2 h), the drug concentration of poly(ether-carbonate) micelles group in liver in mice was 3.46 μg/g, while that of HCPT injection group was 0.401 μg/g. Compared with HCPT injection, the elimination half-life of poly(ether-carbonate) micelles group was prolonged remarkably from 1.3 to 12.5 h. The poly(ether-carbonate) micelles showed a combination of liver targeting and sustained drug release in experiments on animals.     

Optimization of self-assembling properties of fatty acids grafted to methoxy poly(ethylene glycol) as nanocarriers for etoposide

The objective of this work was to study the effect of fatty acid chain length grafted to methoxy poly(ethylene glycol) (mPEG) on self assembling properties of micelles for etoposide delivery. Three amphiphilic copolymers were synthesized using mPEG, myristic acid, stearic acid and behenic acid through an esteric linkage. The particle size and zeta potential of the micelles were determined by the dynamic light scattering method. Etoposide was loaded into micelles by film casting using various drug/polymer ratios. Drug release was studied by the dialysis method. The structure of copolymers was confirmed by (1)H NMR and FTIR. Central micellar concentration (CMC) measurements showed that the longer hydrophobic chains formed more thermodynamically stable micelles. Among the prepared copolymers, etoposide showed the highest solubility in the mPEG-behenic copolymer. Drug loading efficiency depended on the hydrophobic chain length and drug/polymer ratio. The highest drug loading efficiency was found in mPEG-myristic micelles with 1:20 drug/polymer ratio. Micelles released 80 % of loaded drug within about 5 h.