Department of Cancer Systems Imaging, The University of Texas MD Anderson Cancer Center, Houston, TX 77054, USA.
Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX 77054, USA.
Biomaterials. 2018 Mar;159:215-228. doi: 10.1016/j.biomaterials.2018.01.014. Epub 2018 Jan 9.
Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest cancers. 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。它具有过度的促结缔组织增生性基质，这可能会限制化疗药物在肿瘤内的输送，并保护肿瘤细胞免受放疗的影响。因此，为了有效地治疗 PDAC，需要同时解决基质和肿瘤两部分。我们通过聚合物胶束制剂 (M-CPA/PTX) 联合递送一种 Sonic Hedgehog 抑制剂——环巴胺 (CPA) 和细胞毒性化疗药物紫杉醇 (PTX)。CPA 可以耗尽产生基质的癌相关成纤维细胞 (CAFs)，而 PTX 可以抑制肿瘤增殖。在这里，我们在临床相关的 PDAC 模型中证明，M-CPA 通过增加微血管密度、缓解缺氧、降低基质硬度，同时保持细胞外基质的肿瘤抑制功能，有效地调节基质。M-CPA/PTX 通过抑制肿瘤生长和降低分化不良至中度分化肿瘤表型的比例，显著延长了动物的生存时间。我们的研究表明，使用多功能纳米颗粒同时靶向基质和肿瘤两部分是 PDAC 治疗的一种有前途的策略。
