基于前药构建混合胶束实现紫杉醇/阿霉素共递送

为了达到靶向递送,实现肿瘤的联合治疗,制备两亲性紫杉醇-聚乙二醇前药以及小分子阿霉素前药,两者共同构成混合胶束实现共递送。合成还原敏感性的聚乙二醇-紫杉醇前体药物(m PEG-SS-PTX)和靶向性叶酸修饰的聚乙二醇-紫杉醇前体药物(FA-PEG-SS-PTX)。同时合成p H敏感阿霉素-乌头酸酐(CAD)小分子前药,采用透析法制备了靶向性混合胶束。对胶束的氧化还原敏感性和p H敏感性、靶向能力以及抗肿瘤效果进行了评价。所制备胶束具有还原敏感性和p H敏感性。叶酸修饰的混合胶束具有一定的靶向作用。体内外试验结果表明,混合胶束具有较好的治疗效果和较低的毒性。与紫杉醇/阿霉素混合溶液相比,m PEG-SS-PTX/FA-PEGSS-PTX/CAD混合胶束具有更高的抗肿瘤功效和更低的全身毒性。

Co-Delivery of Paclitaxel and Doxorubicin through Mixed Micelles Formed by Paclitaxel and Doxorubicin Prodrugs for Tumor Therapy

In order to achieve the targeted delivery of the two drugs and realize the combination therapy of tumor,the amphiphilic redox-sensitive paclitaxel-polymer prodrug and small molecule doxorubicin prodrug were prepared in this paper,and the mixed micelles were formed using two prodrugs together to achieve the co-delivery of many drugs.Redox-sensitive polyethylene glycol-paclitaxel prodrug( m PEG-SS-PTX) and folate modified prodrug( FA-PEG-SS-PTX) were synthesized using disulfide containing linker.The p H-sensitive doxorubicin-aconitic anhydride prodrug( CAD) was also synthesized by amidation of doxorubicin and aconitic anhydride. Afterwards,mixed micelles were prepared by dialysis method using these prodrugs.The morphology,particle size and critical micelle concentration of the mixed micelles were measured.By the release of drugs in a thermostatic shaker,the redox sensitivity of PTX and p H sensitivity of DOX were evaluated.The targeting ability was also evaluated using MCF-7 cells with high folate receptor expression and A549 cells with low folate receptor expression. And antitumor effect of mixed micelles and synergistic effect in the combination therapy were evaluated by MTT method.By adjusting the mass ratio of FA-PEG-SS-PTX,m PEG-SS-PTX and CAD,the mixed micelles were successfully prepared with the redox sensitive release and p H sensitive release.In physiological environment,the release rate of paclitaxel is 35%,but in 10 mmol/L glutathione,the release of PTX triggered by glutathione can reach a maximum of65% within 96 h.Also doxorubicin release was significantly faster at p H5.0 than at p H7.4.After incubation for 72 h,the cumulative release of doxorubicin at p H 5. 0 was 99%,significantly higher than that at p H 7. 4. The cell experiment also showed that folate modifying mixed micelles had a certain targeting effect in MCF-7 cells with high folate receptor expression. Moreover,the mixed micelles displayed synergistic effect in vitro and the combination therapy in micellar dosage-form led to reduced systematic toxicity and enhanced antitumor efficacy in vivo. In general,m PEG-SS-PTX/FA-PEG-SS-PTX/CAD mixed micelles had better therapeutic effects and lower toxicity.Compared with paclitaxel and doxorubicin mixture solution,m PEG-SS-PTX/FA-PEG-SS-PTX/CAD mixed micelles had higher antitumor efficacy and lower systemic toxicity.