靶向纳米颗粒调控HIF-1α通路抑制缺氧三阴性乳腺癌耐药和转移的研究

For the lack of specific therapeutic targets, chemotherapy is still the main practice of three negative breast cancer (TNBC) in clinic. However, hypoxic microenvironment induces overexpression of hypoxia-inducible factor-1α (HIF-1α) in TNBC, which not only activates multidrug resistance genes to produce drug resistance, but also regulates target genes such as vascular endothelial growth factor to promote metastasis. In the early stage, we used human serum albumin (HSA) to synthesize targeted oxygen nanocarrier. By downregulating the expression of HIF-1α in hypoxic breast cancer through oxygen supply, the chemoresistance induced by hypoxia was improved to some extent. But the oxygen supply mode had limited ability to alleviate hypoxia, which failed to inhibit HIF-1α in a long-term manner and was difficult to be applied clinically. To further overcome hypoxia-induced chemoresistance and metastasis of TNBC, this project proposes to construct tumor-targeted nanoparticles by loading berberine and DOX in HSA. Berberine's non-oxygen-dependent inhibition of HIF-1α synthesis is used to improve the drug resistance and metastasis induced by hypoxia in TNBC. Meanwhile, berberine can also reduce the toxic side effects of DOX, and ultimately achieve more efficient and safe treatment of TNBC. The completion of this project will provide an accurate strategy of nanomedicine for hypoxic TNBC.

阴性乳腺癌（TNBC）缺乏特异性治疗靶点，目前临床上仍以化疗为主。然而缺氧微环境会诱导TNBC过表达缺氧诱导因子-1α（HIF-1α），不仅激活多药耐药基因产生耐药性，还会调控血管内皮因子等靶基因促进转移。前期我们采用人血清白蛋白（HSA）合成靶向纳米氧载体，通过对缺氧乳腺癌输氧下调HIF-1α的表达，在一定程度上改善了缺氧诱导的耐药性。但供氧方式缓解缺氧能力有限，不能长期高效抑制HIF-1α，且难以在临床上应用。为进一步克服TNBC缺氧诱导的化疗耐药和转移，本项目拟用HSA包载小檗碱（Berberine）和阿霉素（DOX）构建肿瘤靶向纳米颗粒，利用Berberine非氧依赖性抑制HIF-1α合成的特性改善TNBC缺氧诱导的化疗耐药和转移。同时Berberine还可以降低DOX的毒副反应，最终实现更高效安全的TNBC治疗。本项目的完成将为缺氧TNBC提供一种精准的纳米医疗方案。

恶性肿瘤在全球范围内发展态势异常严峻，已成为危害人类健康，阻碍社会发展的首要疾病之一。纳米技术的快速发展为肿瘤诊疗带来了新的机遇，但传统纳米材料缺乏动力来源，只能依赖被动扩散，难以实现真正意义上的主动靶向。为解决该问题，本项目在研究设计基础上，聚焦肿瘤微环境，以白蛋白为载体交联脲酶，并负载药物构建蛋白纳米马达。在富含尿素的膀胱微环境中，蛋白马达将尿素分解为二氧化碳和氨，从而实现自主运动，延长在体内的滞留时间，并增加对肿瘤的渗透能力。负载的药物进一步抑制产物氨的生物转化，从而放大氨对肿瘤细胞的毒性作用，实现对肿瘤的主动高效治疗。此外，本项目负为了进一步深入研究纳米马达在肿瘤微环境中应用，还构建了生物可降解的新型二氧化锰纳米马达。该纳米马达通过催化肿瘤微环境中的过氧化氢实现自主运动，增强肿瘤渗透及缓解缺氧环境，并消耗细胞内高浓度的谷胱甘肽释放出具有类芬顿反应的锰离子，增强了化学动力疗法的效果。本项目基于研究基础并紧跟科学前沿热点，同时开发具有运动特性的蛋白和二氧化锰纳米颗粒，利用肿瘤微环境增强药物渗透和主动递送，从而实现更精准高效的肿瘤治疗，为纳米材料的主动靶向癌症治疗提供了一种新的研究思路。