靶向CXCL12/CXCR4轴的AMD3100修饰纳米递药系统调控肿瘤微环境抗卵巢癌的作用及机制研究

Recurrence and metastasis of ovarian cancer were the leading cause of death. On the one hand, surgical resection was difficult to remove small lesions, on the other hand, tumor cell resistance and systemic side effects produced during conventional chemotherapy limited tumor therapy. It was a good strategy to find a suitable site on tumor cells for targeted delivery of chemotherapy drugs while regulating the tumor microenvironment. So we first selected AMD3100, an antagonist with high affinity to CXCR4 receptor which highly expressed on ovarian cancer cells as the targeting head group, then built a new type of AMD-PEG-BSA-Gd nano-drug delivery system, in order to deliver paclitaxel to tumor cells, at the same time, inhibit tumor growth and metastasis, reverse recruitment of immunosuppressive cells and increase sensitivity to chemotherapy drug through blocking the CXCL12/CXCR4 axis. Our previous work had confirmed that the delivery system could selectively target ovarian cancer cells which expressed CXCR4 receptor, while couldn't target normal ovarian cells, and initially revealed its anti-ovarian cancer activity in vitro. In the next study, we will use flow analysis, 51Cr Release assay, gene chip and other techniques to in-depth uncover the anti-tumor effect and mechanism of the drug delivery system, including selectively reducing the immunosuppressive cells Treg, MDSC at the tumor site to promote the activity of killer immune cells, inhibiting tumor growth and metastasis. In all, our research in this project will provide a new idea of treatment to reduce the recurrence and metastasis of ovarian cancer.

卵巢癌手术切除难以清除微小病灶，而化疗的肿瘤细胞耐药性及全身毒副作用限制肿瘤治疗，导致肿瘤复发和转移。寻找合适的肿瘤位点靶向递送化疗药物同时调控肿瘤微环境是很好的策略。我们首次选用与选择性高表达于卵巢癌细胞的CXCR4受体具有高度亲和力的拮抗剂AMD3100为靶向头基，构建AMD-PEG-BSA-Gd新型纳米递药系统，以期在靶向递送紫杉醇至肿瘤部位的同时阻断CXCL12/CXCR4轴，逆转其招募免疫抑制细胞，促进肿瘤细胞生长转移的作用，增大化疗药物敏感性。前期工作已证实该递药系统可选择性靶向于表达CXCR4受体的卵巢癌细胞，而不靶向正常卵巢细胞，并初步明确其体外抗肿瘤活性，进一步研究将通过流式分析、51Cr释放实验、基因芯片等技术探讨该递药系统选择性减少肿瘤部位免疫抑制细胞Treg、MDSC，促进杀伤性免疫细胞的活性，及其抗卵巢癌生长转移的具体作用和机制，为减少卵巢癌复发转移提供新的思路。

卵巢癌是女性常见恶性肿瘤，且死亡率较高，探索新的有效的治疗策略对提高卵巢癌患者生存率具有重要意义。既往研究表明，CXCL12/CXCR4轴不仅在卵巢癌细胞增殖、凋亡、迁移过程中发挥重要作用，还可在卵巢癌小鼠肿瘤部位招募免疫抑制细胞Treg、MDSC，促进肿瘤进展和转移。为此我们首次选用与选择性高表达于卵巢癌细胞的CXCR4受体具有高度亲和力的拮抗剂AMD3100为靶向头基，成功构建了包载化疗药物紫杉醇（PTX）的AMD-PEG-BSA-Gd新型纳米递药系统（AMD-NP-PTX），以具有靶向性的纳米系统为载体，实现了免疫疗法与传统化疗的结合。体外实验和体内实验均显示其具有良好的肿瘤靶向性和安全性，并且可以显著抑制肿瘤生长和转移，促进肿瘤细胞凋亡。此外，C57BL/6卵巢癌小鼠实验结果表明，该递药系统选择性减少了肿瘤部位免疫抑制细胞Treg、MDSC，而不影响CD8+T细胞，显著增加了T细胞介导的抗肿瘤免疫效应，并证明了该选择性作用与肿瘤部位Treg、MDSC对CXCL12的高度趋化性和AMD-NP-PTX对该作用的选择性阻断有关。我们还证实了该递药系统通过靶向CXCL12/CXCR4轴发挥作用，从而干扰其下游信号通路，抑制上皮间质转化（EMT）过程的N-cadherin、vimentin和核因子κB（NF-κB）途径，并增加E-cadherin蛋白的表达。综上，我们成功地构建了一种纳米递药系统，可同时发挥化疗、免疫治疗、主动靶向和递释系统的多重优势，综合调控肿瘤微环境，为卵巢癌多功能一体化治疗提供了一种新的思路。相关成果已发表标注基金号的SCI论文3篇。