同轴电喷-去模板法制备具有金属基质蛋白酶响应性的纳米载体

Fabrication of MMP-2 Rresponsive Nanoparticles by Coaxial Electrospray-template Removal

通过化学键偶联的形式在聚乳酸(PLA)分子链中引入了可被金属基质蛋白酶(MMP-2)特异性降解的多肽peptide(GPLGIAGQ)单元,得到具有金属基质蛋白酶响应性的聚合物PLA-b-peptide-b-PLA.通过同轴电喷方法制备得到以PLA-b-peptide-b-PLA和抗肿瘤药物DOX的混合物作为内核,亲水性聚乙二醇(PEG)作为外壳的,具有核-壳结构的载药微球.其中水溶性的PEG壳层可在水环境中迅速脱除,将载药微球的尺寸从微米级减小到纳米尺度,可以达到药物载体系统在输运的循环过程中的尺寸递减.制备的纳米载体可在金属基质蛋白酶存在的环境中,响应性释放所包载的抗肿瘤药物,实现药物的控制释放.

Peptide（Gly-Pro-Leu-Gly-Ile-Ala-Gly-Gln）, which can be specifically degraded by matrix metalloproteinases 2（MMP-2）, was conjugated into polylactic acid（PLA）, constructing therefore a new type of MMP-responsive drug delivery system（DDS）. Microparticles with core-shell structure were fabricated using coaxial electrospray. PEG was used as the shell and PLA-b-peptide-b-PLA as the core material. The water-soluble PEG shell was quickly removed from aqueous environment and the size of the microspheres was reduced from micron to nanometer scale. Eventually, MMP-2 responsive nanoparticles with a diameter of about 100 nm were obtained through coaxial electrospray-template removal method. MMP-2 response of the nanoparticles was investigated by the change of particle size and morphology with DLS and TEM. After coculturing with MMP-2 protease, the spherical skeleton of the nanoparticles was partly degraded. Meanwhile, part of the degraded particles got aggregated. This is because MMP-2 protease specifically cleave the peptide, resulting in the partly disassembly of the nanoparticles and random reassembling of PLA. Doxorubicin（DOX） was used as a model chemotherapeutic drug and loaded in the core of the nanoparticles. The drug loading content and entrapment efficiency of DOX were 0.326% and 75.3%,respectively. The in vitro release profile of DOX from the electrosprayed particles was studied. It was found that the encapsulated DOX was released from the nanoparticles, and the release was controlled by the stimulus of overexpressed MMP-2 protease, and the process lasted more than 20 days. The results show that coaxial electrospray-template removal method did not affect the matrix metalloproteinases response of the peptide, and thus the nanoparticles prepared have good MMP-2 responsiveness. Meanwhile, the size of the particles can be modulated by the coaxial electrospray-template removal method, and the nano-sized particles can be simply and effectively achieved. The study suggests that the coaxial electrospray-template removal method is a promising route to the preparation of stimuli-responsive drug delivery system.