Nanoparticle combination for precise stroma modulation and improved delivery for pancreatic cancer.
Nanoparticle combination for precise stroma modulation and improved delivery for pancreatic cancer.
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DOI：
10.1016/j.jconrel.2022.05.019
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发表时间：
2022-05
期刊：
影响因子：
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通讯作者：
M. Tarannum;Katherine Holtzman;D. Dréau;P. Mukherjee;Juan L. Vivero-Escoto
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作者：
M. Tarannum;Katherine Holtzman;D. Dréau;P. Mukherjee;Juan L. Vivero-Escoto
胰腺导管腺癌(PDAC)的广泛间质阻碍了治疗的成功。间质是由支持和随肿瘤进化的细胞和非细胞成分组成的。Sonic Hedgehog(Shh)途径是癌细胞-间质串扰的最重要的介质之一，导致在PDAC肿瘤中观察到强烈的促结缔组织增生。在这里，我们证明使用含有ShH抑制剂环丙胺(CYP)的介孔二氧化硅纳米颗粒(MSN)以及化疗药物(吉西他滨(Gem)/顺铂(Cispt))的组合作为序贯治疗的主要递送系统，可以减少肿瘤间质，同时改善PDAC的治疗。我们合成了两个版本的基于MSN的平台，其中包含Shh抑制剂(CYP-MSNS)和药物组合物(PEG-Gem-cispt-MSNS)。体外和体内蛋白质分析表明，CYP-MSN有效地抑制了Shh途径。此外，CYP-MSN和PEG-Gem-cispt-MSN的顺序组合导致了有效的间质调节，增加了肿瘤部位的二次PEG-Gem-cispt-MSN的通达性，并改善了HPAF II异种移植鼠的治疗效果。综上所述，我们的发现支持了使用MSN进行间质调节和预防胰腺癌进展的药物传递的潜力。
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.