还原响应型透明质酸/聚己内酯纳米粒子的制备及其体外抗肺癌效应研究

目的： 构建一种具有良好生物安全性、肿瘤主动靶向性及能实现药物快速释放的药物纳米载体。方法： 通过点击化学反应制备由二硫键连接的两亲性透明质酸/聚己内酯接枝聚合物；采用动态光散射、透射电镜对聚合物的自组装行为进行研究；通过体外药物释放实验探究药物载体还原响应控制释放特性；通过流式细胞术、激光共聚焦显微镜等技术对A549细胞内吞噬载药纳米粒子的机制进行研究；结果： 所制备的含二硫键的接枝聚合物可自组装形成粒径大约为75 nm的球形纳米粒子；该纳米粒子在质量浓度为200 μg·mL^-1时仍具有较好的生物安全性；当纳米粒子包载阿霉素后其粒径增大至128 nm，且药物在还原性条件下可实现快速释放；载药后的纳米粒子经透明质酸/CD44受体间的相互作用快速进入肿瘤细胞内，并能显著抑制肿瘤细胞生长。结论： 本研究合成的含二硫键的透明质酸/聚己内酯接枝聚合物具有良好生物相容性、肿瘤靶向性及药物控制释放特性，作为抗肿瘤药物载体具有一定优势。

Preparation and in vitro anti-lung cancer effect of redox-responsive nanoparticles from hyaluronic acid/polycaprolactone grafted polymer

OBJECTIVE To construct a drug nanocarrier with good biosafety, active tumor targeting and rapid drug release.METHODS The amphiphilic hyaluronic acid/polycaprolactone graft polymer (HA-SS-PCL) with disulfide bond was synthesized by clicking chemical reaction. The self-assembly behavior of the copolymer was studied by dynamic light scattering (DLS) and transmission electron microscope (TEM). The in vitro release of doxorubicin (DOX) triggered by reductant was studied by drug release experiment in vitro. Confocal laser scanning microscopy (CLSM) analysis was performed to reveal the cellular uptakes of the doxorubicin loaded HA-SS-PCL nanocarrier.RESULTS The prepared grafted polymers containing disulfide bonds could self-assemble to form spherical nanoparticles with a particle size of approximately 75 nm; the nanoparticles were at a concentration of 200 μg·mL^-1, it still has good biosafety; when nanoparticles are encapsulated with doxorubicin, their particle size increases to 128 nm, and the drug can be rapidly released under reducing conditions; the loaded nanoparticles rapidly enter the tumor cells through the interaction between hyaluronic acid/CD44 receptor, and can significantly inhibit the growth of tumor cells.CONCLUSION The hyaluronic acid/polycaprolactone graft polymer containing disulfide bonds synthesized in this study has good biocompatibility, tumor targeting and drug controlled release characteristics, and has certain advantages as an anti-tumor drug carrier.