Department of Chemistry, University of North Carolina Charlotte, Charlotte, NC 28223, USA; Nanoscale Science Program, University of North Carolina Charlotte, Charlotte, NC 28223, USA.
Department of Biological Sciences, University of North Carolina Charlotte, Charlotte, NC 28223, USA.
J Control Release. 2022 Jul;347:425-434. doi: 10.1016/j.jconrel.2022.05.019. Epub 2022 May 19.
Therapeutic success in the treatment of pancreatic ductal adenocarcinoma (PDAC) is hindered by the extensive stroma associated to this disease. Stroma is composed of cellular and non-cellular components supporting and evolving with the tumor. One of the most studied mediators of cancer cell-stroma crosstalk is sonic hedgehog (SHh) pathway leading to the intense desmoplasia observed in PDAC tumors. Herein, we demonstrate that the use of mesoporous silica nanoparticles (MSNs) containing an SHh inhibitor, cyclopamine (CyP), and the combination of chemotherapeutic drugs (Gemcitabine (Gem)/cisplatin (cisPt)) as the main delivery system for the sequential treatment led to the reduction in tumor stroma along with an improvement in the treatment of PDAC. We synthesized two versions of the MSN-based platform containing the SHh inhibitor (CyP-MSNs) and the drug combination (PEG-Gem-cisPt-MSNs). In vitro and in vivo protein analysis show that CyP-MSNs effectively inhibited the SHh pathway. In addition, the sequential combination of CyP-MSNs followed by PEG-Gem-cisPt-MSNs led to effective stromal modulation, increased access of secondary PEG-Gem-cisPt-MSNs at the tumor site, and improved therapeutic performance in HPAF II xenograft mice. Taken together, our findings support the potential of drug delivery using MSNs for stroma modulation and to prevent pancreatic cancer progression.
治疗胰腺导管腺癌 (PDAC) 的疗效受到与该疾病相关的广泛基质的阻碍。基质由支持和伴随肿瘤发展的细胞和非细胞成分组成。研究最多的癌症细胞-基质串扰介质之一是 sonic hedgehog (SHh) 途径，导致在 PDAC 肿瘤中观察到强烈的纤维组织增生。在此，我们证明了使用载有 SHh 抑制剂（环巴胺（CyP）的介孔硅纳米粒子（MSNs））和化疗药物（吉西他滨（Gem）/顺铂（cisPt））的组合作为主要递药系统进行序贯治疗可减少肿瘤基质，并改善 PDAC 的治疗效果。我们合成了两种载有 SHh 抑制剂（CyP-MSNs）和药物组合（PEG-Gem-cisPt-MSNs）的 MSN 基平台版本。体外和体内蛋白分析表明 CyP-MSNs 能有效抑制 SHh 通路。此外，CyP-MSNs 序贯给药后再给予 PEG-Gem-cisPt-MSNs 可有效调节基质，增加二级 PEG-Gem-cisPt-MSNs 在肿瘤部位的进入，并提高 HPAF II 异种移植小鼠的治疗效果。总之，我们的研究结果支持使用 MSNs 进行基质调节和预防胰腺癌进展的药物递送的潜力。
