环境响应性多靶点基因-药质体对“疏而不漏”型肿瘤间质的重塑及其用于胰腺导管腺癌的治疗

胰腺导管腺癌（PDAC）是最具侵袭性的恶性肿瘤之一。目前临床治疗方法效果不佳，这主要是因为其异常增生且致密的肿瘤间质限制了药物的渗透和治疗。直接耗竭肿瘤间质又会破坏抑制肿瘤转移的物理屏障。因此，对肿瘤间质重塑实现“疏而不漏”（允许治疗分子通过且限制肿瘤细胞转移）是有希望提高PDAC治疗效果的重要手段。本项目拟设计构建一种环境响应性（pH/氧化还原）多靶点（肿瘤相关成纤维细胞/肿瘤细胞）基因-药质体。该基因-药质体可以突破多种递送屏障，延长体内循环时间，利用肿瘤组织外围及中心的pH差异实现载体的渗透和靶向、微环境逐级响应和基因/药物精准释放。药质体降解释放的药物能使肿瘤间质主要成分肿瘤相关成纤维细胞恢复至静止状态进而重塑肿瘤间质，所递送的PDAC肿瘤细胞特异性突变基因的siRNA能特异性杀死肿瘤细胞。此联合策略能在杀死肿瘤细胞的同时保持肿瘤组织外围间质的完整性，从而抑制PDAC的生长和转移。

Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive solid malignancies along with poor therapeutic outcome in clinic. The poor response of current PDAC therapies is majorly contributed to unusually proliferous and tough tumor stroma, which reduces drug diffusion and mediates drug resistance. However, direct tumor stroma depletion can disrupt the physical barrier for preventing tumor metastasis. Therefore, it is of great potential to enhance anti-primary PDAC efficacy by remodeling tumor stroma to achieve “omission without leakage” (enhancing drug penetration while preventing cancerous metastasis). This project proposes to fabricate a tumor microenvironment responsive (pH/redox) and mutil-target (cancer associated fibroblasts/tumor cells) gene-pharmacosome. This novel developed gene-pharmacosome can overcome the therapeutic barriers of PDAC, prolong circulation time, enhance gene-pharmacosome penetration/targeting based on the pH difference between the periphery and the center of the tumor tissue, realize cascaded multi-responsive function, and release gene/drug precisely. The released drug by the degradation of the gene-pharmacosomes can remodel tumor stroma by making cancer associated fibroblasts, the main component of tumor stroma, return to the quiescent state. Meanwhile, the co-delivered siRNA could selectively knockdown the targeted oncogene and kill tumor cells. As a result, our combination therapy could specifically kill tumor cells while preserving the external stroma, thereby both inhibiting the growth and metastasis of PDAC.