超声响应的载紫杉醇纳米粒抑制自噬逆转卵巢癌耐药机制研究

大量研究证实超声响应载药纳米粒具有显著的抗肿瘤效果，但生物学机制不清，同时载药纳米粒的控释技术有待优化。紫杉醇为卵巢癌常用化疗药物，但毒性和耐药问题限制了其临床应用。前期研究发现紫杉醇耐药的卵巢癌细胞内自噬水平明显增高，我们的预实验结果显示利用声动力学效应（SDT）可以抑制卵巢癌自噬并逆转紫杉醇耐药，提示SDT在逆转耐药中的潜在价值。基于此，本研究拟合成介孔二氧化钛纳米粒（MTN）为药物载体，利用自主研发的球面自聚焦超声治疗仪为控释手段，实现药物精准控释；利用超声的生物学效应对卵巢癌进行声敏剂和紫杉醇的协同治疗，验证其可以通过抑制自噬促进耐药卵巢癌细胞死亡；利用高通量方法筛选出紫杉醇MTN抑制自噬的关键分子通路，并进一步在小鼠卵巢癌模型上验证其逆转紫杉醇耐药的效应及机制。本研究将为探寻逆转卵巢癌耐药的潜在治疗新方法提供理论基础与实验依据。

A large number of studies have confirmed that acoustic stimuli-responsive drug-loaded nanoparticles have significant anti-tumor effects, but the biological mechanism is unclear. At the same time, the controlled-release technology of drug-loaded nanoparticles need to be optimized. As a common chemotherapeutic drug for ovarian cancer, the toxicity and drug resistance of paclitaxel limit its clinical application. Previous studies found that the autophagy level of paclitaxel-resistant ovarin cancer cells increased significantly. Our preliminary results shows that the sonodynamic effect (SDT) can inhibit autophagy and reverse paclitaxel resistance in ovarian cancer, suggesting the potential value of SDT in reversing drug resistance. Based on this, this study intends to synthesize mesoporous titanium dioxide nanoparticles(MTN) as drug carrier, using self-developed spherical focused ultrasound therapy instrument as a controlled release means to achieve accurate contrlled drug release; The biological effects of ultrasound were combined with paclitaxel and sonosensitizer in the treatment of ovarian cancer, which proved that it could promote the death of drug-resistant ovarian cancer cells by inhibiting autophagy. The key molecular pathway of MTN@ PTX inhibiting autophagy was screened by high-throughput method, and the effect and mechanism of its reversal of paclitaxel resistance were further verified in mouse ovarian cancer model. This study will provide a theoretical and experimental basis for the exploration of a potential new treatment method to reverse the drug resistance in ovarian cancer.