pH敏感型脂质体靶向调控CAFs协同PD-1抑制剂在tamoxifen耐药乳腺癌治疗中的研究

肿瘤相关成纤维细胞(CAFs)与乳腺癌tamoxifen耐药密切相关。GPR77高表达的CAFs亚群，通过分泌IL-6和IL-8，促使肿瘤干细胞富集，诱发乳腺癌治疗耐药。阻断GPR77可抑制CAFs，增强药物疗效，抑制肿瘤生长。程序性死亡分子-1（PD-1）抑制剂联合化疗药物，已应用于实体肿瘤的临床治疗，具有一定疗效，而CAFs可诱发抗PD-1治疗耐药。联合应用GPR77抗体与PD-1抑制剂，对CAFs及肿瘤细胞进行双重干预，有望协同治疗tamoxifen耐药乳腺癌。本项目拟在前期制备出长循环含COOH纳米靶向脂质体微泡及微环境响应型脂质体微泡的基础上，制备pH敏感型载GPR77抗体/PD-1抑制剂靶向脂质超声造影剂，在超声空化的辅助下促进药物靶向释放，通过抑制CAFs，降低组织间质压，增加PD-1抑制剂的弥散距离以增强其疗效。本项目有望为tamoxifen耐药乳腺癌提供一种新疗法。

Relevant studies have shown that, tumor associated fibroblasts (CAFs) are closely related to tamoxifen-resistance breast cancer. CAFs and their products can promote tumor progression, and the mechanical pressure they form can affect drug delivery, leading to drug resistance. GRP77+ CAFs promote tumor formation and chemoresistance, and targeting these CAFs with a neutralizing anti-GPR77 antibody abolishes tumor formation and restores tumor chemosensitivity. Programmed death 1(PD-1) inhibitors combined with chemotherapeutic agents have been proved to be useful in various clinical studies of solid tumor therapies. FAP high expression CAFs are reported to be able to induce anti-PD-1 resistance. Therefore, targeted liposome combined anti-GPR77 antibody with PD-1 inhibitors to modulate CAFs and cancer cells at the same time, is supposed to achieve effective treatment of tamoxifen-resistance breast cancer. In this project, based on the experience of preparing targeted nano-lipid microbubble connected with -COOH and folate acid-decorated NaHCO3-encapsulated liposome before, we prepared a pH sensitive targeted lipid ultrasound contrast agent carried anti-GPR77 antibody/PD-1 inhibitor co-delivery complex. This contrast agent can achieve targeted release with ultrasonic cavitation effect. It can not only interfere with the expression of GPR77 in breast cancer CAFs, but also enhance the curative effect by decreasing CAFs, reducing tissue interstitial pressure and increasing the diffusion distance of PD-1 inhibitor. This project is expected to provide a new therapy for tamoxifen-resistance breast cancer.