pH-Responsive Biodegradable Micelles Based on Acid-Labile Polycarbonate Hydrophobe: Synthesis and Triggered Drug Release
pH-Responsive Biodegradable Micelles Based on Acid-Labile Polycarbonate Hydrophobe: Synthesis and Triggered Drug Release
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基于酸不稳定聚碳酸酯疏水物的 pH 响应型可生物降解胶束：合成和触发药物释放
DOI：
10.1021/bm900074d
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发表时间：
2009-07-01
影响因子：
6.2
通讯作者：
Zhong, Zhiyuan
中科院分区：
文献类型：
--
作者：
Chen, Wei;Meng, Fenghua;Zhong, Zhiyuan
由一种新型的酸不稳定的聚碳酸酯疏水物和聚乙二醇（PEG）组成的嵌段共聚物制备了pH响应性可生物降解胶束。设计并通过两步反应成功合成了两种新型环状脂肪族碳酸酯单体：单-2，4，6-三甲氧基亚苄基季戊四醇碳酸酯（TMBPEC，2a）和单-4-甲氧基亚苄基季戊四醇碳酸酯（MBPEC，2b）。2a或2b在甲氧基PEG存在下在二氯甲烷中在50 ℃下使用双[双（三甲基甲硅烷基）氨基]锌作为催化剂的开环聚合产生具有低多分散性（PDI 1.03-1.04）的相应嵌段共聚物PEG-PTMBPEC（3a）或PEG-PMBPEC（3b）。在其它条件相同的情况下，D，L-丙交酯（DLLA）与2a的共聚也能顺利进行，得到PEG-P（TMBPEC-co-DLLA）（3c）嵌段共聚物。这些嵌段共聚物容易在水中形成胶束，通过动态光散射（DLS）测定其尺寸为约120 nm。使用UV/维斯光谱研究聚碳酸酯的缩醛的水解。结果表明，胶束3a的缩醛，而稳定的pH值为7.4，易于迅速水解，在温和的酸性pH值为4.0和5.0，与半衰期分别为1和6.5小时。缩醛水解导致胶束的显着溶胀，作为疏水聚碳酸酯的亲水聚碳酸酯的变化的结果。相比之下。胶束3b的PMBPEC的缩醛在相同pH下表现出明显较慢的水解。紫杉醇和阿霉素都可以有效地包封到胶束3a中，实现高载药量（分别为13.0和11.7wt%）。体外释放研究表明，清楚的pH依赖性的释放行为，即，显着更快的药物释放在温和的酸性pH值为4.0和5.0相比，生理pH值。这些pH值响应的生物可降解胶束是有前途的智能纳米载体的抗癌药物的靶向输送。
pH-responsive biodegradable micelles were prepared from block copolymers comprising of a novel acid-labile polycarbonate hydrophobe and poly(ethylene glycol) (PEG). Two new cyclic aliphatic carbonate monomers, mono-2,4,6-trimethoxybenzylidene-pentaerythritol carbonate (TMBPEC, 2a) and mono-4-methoxybenzylidene-pentaerythritol carbonate (MBPEC, 2b) were designed and successfully synthesized via a two-step procedure. The ring-opening polymerization of 2a or 2b in the presence of methoxy PEG in dichloromethane at 50 degrees C using zinc bis[bis(trimethylsilyl)amide] as a catalyst yielded the corresponding block copolymers PEG-PTMBPEC (3a) or PEG-PMBPEC (3b) with low polydispersities (PDI 1.03-1.04). The copolymerization of D,L-lactide (DLLA) and 2a under otherwise the same conditions Could also proceed smoothly to afford PEG-P(TMBPEC-co-DLLA) (3c) block copolymer. These block copolymers readily formed micelles in water with sizes of about 120 nm as determined by dynamic light scattering (DLS). The hydrolysis of the acetals of the polycarbonate was investigated using UV/vis spectroscopy. The results showed that the acetals of micelles 3a, while stable at pH 7.4 are prone to rapid hydrolysis at mildly acidic pH of 4.0 and 5.0, with a half-life of 1 and 6.5 h, respectively. The acetal hydrolysis resulted in significant swelling of micelles, as a result of change of hydrophobic polycarbonate to hydrophilic polycarbonate. In comparison. the acetals of PMBPEC of micelles 3b displayed obviously slower hydrolysis at the same pH. Both paclitaxel and doxorubicin could be efficiently encapsulated into micelles 3a achieving high drug loading content (13.0 and 11.7 wt %, respectively). The in vitro release studies showed clearly a pH dependent release behavior, that is, significantly faster drug release at mildly acidic pH of 4.0 and 5.0 compared to physiological pH. These pH-responsive biodegradable micelles are promising as smart nanovehicles for targeted delivery of anticancer drugs.