双重pH敏感的聚合物-阿霉素偶联物胶束的制备与表征

摘要

In the present study,we designed and fabricated pH-sensitive polymeric micelles based on the conjugate of poly(2-ethyl-2-oxazoline)-poly(D,L-lactide) (PEOz-PLA) with doxorubicin (PEOz-PLA-imi-DOX) to efficiently inhibit tumor cell growth.Hence,PEOz-PLA-imi-DOX was successfully synthesized by connecting DOX to the hydrophobic end of pH-sensitive PEOz-PLA via acid cleavable benzoic imine linker and characterized by 1H NMR spectrum and thin layer chromatography.The critical micelle concentration of PEOz-PLA-imi-DOX was determined to be (14.84±3.85) mg/L.The conjugate micelles (denoted as PP-DOX-PM) formed by PEOz-PLA-imi-DOX using film-hydration method were characterized to have a nano-scaled size of about 21 nm in diameter,and the drug loading content was 1.67％.PP-DOX-PM showed pH-dependent drug release behavior with gradually accelerated release of DOX with decrease of pH value,illustrating the micelles' distinguishing feature of endo/lysosomal pH from physiological pH by accelerating drug release.As anticipated,PP-DOX-PM maintained the cytotoxicity of DOX against MDA-MB-231 cells.Collectively,PP-DOX-PM might have great potential for effective suppression of tumor growth.%为了有效抑制肿瘤生长并降低抗肿瘤药物的毒副作用,本研究设计并构建了基于阿霉素(DOX)与聚(2-乙基-2-嗯唑啉)-聚乳酸(PEOz-PLA)偶联物(PEOz-PLA-imi-DOX)的双重pH敏感聚合物胶束.成功合成了DOX与pH敏感的PEOz-PLA经酸敏感的安息香亚胺键偶联的PEOz-PLA-imi-DOX,并用1H NMR和薄层色谱进行了确证,芘荧光探针法测定其临界胶束浓度为(14.84±3.85) mg/L.由PEOz-PLA-imi-DOX经薄膜水化法制备的偶联物胶束(PP-DOX-PM)的粒径约为21 nm,载药量为1.67％.体外释放实验表明,PP-DOX-PM具有随着pH的降低而释放逐渐加快的pH依赖性释放行为,说明该胶束能识别正常生理环境和胞内的pH差异,预示该胶束具有胞内快速释药的特征.此外,PP-DOX-PM保持了DOX对MDA-MB-231细胞的毒性.因此,PP-DOX-PM胶束在抗肿瘤方面具有潜在的优势.