Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest cancer. It has an excessive desmoplastic stroma that can limit the intratumoral delivery of chemotherapy drugs, and protect tumor cells against radiotherapy. Therefore, both stromal and tumor compartments need to be addressed in order to effectively treat PDAC. We hereby co-deliver a sonic hedgehog inhibitor, cyclopamine (CPA), and a cytotoxic chemotherapy drug paclitaxel (PTX) with a polymeric micelle formulation (M-CPA/PTX). CPA can deplete the stroma-producing cancer-associated fibroblasts (CAFs), while PTX can inhibit tumor proliferation. Here we show that in clinically relevant PDAC models, M-CPA effectively modulates stroma by increasing microvessel density, alleviating hypoxia, reducing matrix stiffness while maintaining the tumor-restraining function of extracellular matrix. M-CPA/PTX also significantly extends animal survival by suppressing tumor growth and lowering the percentages of poorly to moderately differentiated tumor phenotypes. Our study suggests that using multifunctional nanoparticles to simultaneously target stromal and tumor compartments is a promising strategy for PDAC therapy.

胰腺导管腺癌（PDAC）是最致命的癌症之一。它具有过量的促纤维增生基质，可以限制化疗药物的瘤内输送，并保护肿瘤细胞免受放射治疗。因此，为了有效治疗 PDAC，需要解决基质和肿瘤区室的问题。我们特此共同提供声波刺猬抑制剂环巴明 (CPA) 和细胞毒性化疗药物紫杉醇 (PTX) 与聚合物胶束制剂 (M-CPA/PTX)。 CPA 可以消耗产生基质的癌症相关成纤维细胞 (CAF)，而 PTX 可以抑制肿瘤增殖。在这里，我们表明，在临床相关的 PDAC 模型中，M-CPA 通过增加微血管密度、缓解缺氧、降低基质硬度，同时维持细胞外基质的肿瘤抑制功能来有效调节基质。 M-CPA/PTX 还可以通过抑制肿瘤生长和降低低分化至中分化肿瘤表型的百分比来显着延长动物的生存期。我们的研究表明，使用多功能纳米粒子同时靶向基质和肿瘤区室是 PDAC 治疗的一种有前景的策略。