pH敏感型mPEG-Hz-PLA聚合物纳米载药胶束的制备

Preparation of m PEG-Hz-PLA Polymeric Micelles for pH Controlled Drug Delivery

以合成的含有腙键的聚乙二醇大分子(mPEG-Hz-OH)为引发剂,以丙交酯为单体引发开环聚合反应,并通过调整投料比,制备出3种不同分子量的含腙键的生物可降解嵌段聚合物(mPEG-Hz-PLA).将腙键引入到聚合物的骨架中,以此构建聚合物胶束并作为pH敏感型纳米药物载体.制备的pH敏感型胶束的CMC值等于或低于5.46×10-4 mg/m L,DLS和TEM显示粒径均小于100 nm,且粒径分布均匀.非pH敏感型胶束在不同pH下的粒径变化不明显,而pH敏感型胶束在酸性环境下(pH=4.0和pH=5.0)胶束粒径出现了明显变化.以阿霉素为模型药物制备了pH敏感型载药胶束,其粒径比空白胶束大(100~200 nm),且粒径分布均匀.药物释放实验表明pH敏感型载药胶束随着释放介质pH降低累积释药量增高.MTT实验表明空白胶束对HeLa细胞和RAW264.7细胞几乎没有抑制作用,而载阿霉素的胶束对2种细胞的抑制作用都随着剂量的增大和时间的延长而增强.

In some pH-sensitive drug delivery systems, hydrazone bonds frequently appeared in the side chains of the polymers as connections to doxorubicin（DOX）. Introducing hydrazone bond onto the backbone of an amphiphilic copolymer to form pH-responsive hydrazone-containing micelles will realize the encapsulation of a broad spectrum of hydrophobic drugs. As a proof of concept, this work began with rational designing of mPEG-based macro-initiators and followed by ring-opening polymerization to construct hydrazone-containing biodegradable block polymers. A series of hydrazone-containing biodegradable copolymers（mPEG-Hz-PLA） of different molecular weights were synthesized. The diblock copolymers bear both hydrophilic PEG chain of fixed length and hydrophobic PLA chain of varied lengths. The resulting copolymers then self-assembled to form stable micelles with mean diameters below 100 nm. The study showed that these pH-sensitive polymeric micelles has a critical micelle concentration（CMC） of 5.46 × 10^-4 mg/m L or less. Notable size change of the hydrazone-containing micelles were found after incubation in acidic media（pH = 4.0 and 5.0）, while no size changes were observed for the polymeric micelles without hydrazone bonds. Doxorubicin（DOX） was used as the model drug and loaded into the core of micelles, leading to the micelles with a larger size（100 - 200 nm） than the blank ones. The drug loading content（DLC） and drug loading efficiency（DLE） of the micelles increased slightly along with the length of PLA. In vitro drug release study showed that DOX loaded in mPEG-Hz-PLA micelles were released more rapidly and more sufficiently under acidic conditions compared with non pH-sensitive micelles. Under pH = 7.4, DOX released from both pH sensitive micelles and non-sensitive ones were less than 30% in 24 h. At pH 4.0, more than 70% of DOX was released from the pH-sensitive micelles while less than 45% of DOX released from the non-sensitive micelles in 24 h. MTT assay in He La and RAW264.7 cells lines showed enhanced antitumor ability for the DOX loaded pH sensitive micelles following 48 h incubation, compared with free DOX or non-sensitive micelles, while no obvious cytotoxicity was detected for the blank micelles. The hydrazone-containing micelles have great promise as a safe and effective carrier for antitumor drug delivery.