【摘要】 目的 设计具有体内长循环能力和肿瘤细胞微环境刺激触发药物释放的双氢青蒿素(DHA)前药，提高肿瘤部位的药物蓄积，增强药物抗肿瘤疗效。方法 采用DHA为模型药物，十六胺(C16)为载体，二硫键(-SS-)和碳碳键(-CC-)为连接臂，合成2种DHA/C16偶联前药(DHA-SS-C16和DHA-CC-C16)。采用纳米沉淀法制备DHA/C16偶联前药自组装纳米粒(DHA-SS-C16 NPs和DHA-CC-C16 NPs)。体外细胞研究评价NPs对4T1细胞的增殖抑制能力；采用大鼠和小鼠分别研究NPs在大鼠体内的药动学特征及在4T1荷瘤小鼠体内的抗肿瘤活性。结果 成功合成了2种DHA/C16偶联前药，制备的DHA-SS-C16 NPs和DHA-CC-C16 NPs的粒径和Zeta电位分别为(115.7±3.0)(106.6±1.0) nm,(-34.5±0.4)(-21.3±0.5) mV,2种DHA/C16偶联前药的平均包封率和载药量分别大于95%和79%,稳定性良好。NPs可抑制4T1细胞的增殖，降低其迁移能力。药动学和药效学研究结果显示，NPs均不同程度地延长了DHA的平均滞留时间，提高了DHA的曲线下面积(AUC),对4T1荷瘤小鼠的肿瘤抑制效果远高于DHA溶液剂组，且DHA-SS-C16 NPs抗肿瘤效果优于DHA-CC-C16 NPs。结论 本实验设计的以二硫键为连接臂的DHA/C16偶联前药自组装纳米递药系统DHA-SS-C16 NPs能够延长药物在体内的滞留时间，提高药物在肿瘤部位的蓄积能力，实现肿瘤部位微环境响应药物释放，增强了药物抗肿瘤能力，改善了小鼠的生存质量，使其有望成为一种有前景的长效智能纳米递药系统。更多还原

【Abstract】 OBJECTIVE To design and release dihydroartemisinic(DHA) prodrug with long circulation ability in vivo by the stimulation of tumor cell microenvironment and improve drug accumulation in tumor site.METHODS DHA was covalently bonded to cetylamine(C16) carriers via disulfide(-SS-) and carbon-carbon bonds(-CC-) to synthesize two DHA/C16 coupled prodrugs of DHA-SS-C16 and DHA-CC-C16, which were formulated as self-assembled nanoparticles(DHA-SS-C16 NPs and DHA-CC-C16 NPs) by nanoprecipitation method. In vitro cellular studies were performed to assess the NPs′ capacity in inhibiting the proliferation of 4T1 cells. Additionally, the pharmacokinetic behaviors in rats and the anti-tumor activity in 4T1 tumor bearing mice of NPs were also studied. RESULTS DHA-SS-C16 and DHA-CC-C16 were successfully synthesized. The particle size and Zeta potential of DHA-SS-C16 and DHA-CC-C16 NPs were(115.7±3.0) and(106.6±1.0) nm,(-34.5±0.4) and(-21.3±0.5)mV, respectively. The average encapsulation efficiency and drug loading capacity of the two DHA/C16 coupled prodrugs were greater than 95% and 79% respectively, demonstrating good stability. NPs could inhibit the proliferation of 4T1 cells and reduce their migration ability. The pharmacokinetic studies showed that NPs prolonged the average retention time of DHA and enhanced the AUC of DHA to certain extent. The anti-tumor effect of DHA-SS-C16 NPs was better than that of DHA solution and DHA-CC-C16 NPs. CONCLUSION The self-assembled nano-drug delivery system designed in this paper, which utilizes disulfide bonds as connecting arm for DHA/C16-coupled prodrug, is capable of prolonging the retention time of drugs in the body, enhancing the accumulation of drugs at the tumor site, achieving responsive drug release in the tumor microenvironment, and improving anti-tumor effect. Furthermore, it also enhances the quality of life of mice. In conclusion, the nano-drug delivery system presents a promising long-acting and intelligent approach in drug delivery.更多还原