Pancreatic ductal adenocarcinoma (PDAC) accounts for over 90% of the pancreatic cancer cases and is the fourth-leading cause of cancer-related mortality. Therapeutic success in the treatment of 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 growth. 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. Nanoparticle-based drug delivery using mesoporous silica nanoparticles (MSNs) can be a potential alternative for the treatment of PDAC owing to their outstanding properties such as high surface area, tunable pore diameters, external and internal surface, which make this platform suitable for high drug loading and functionalization. Herein, we demonstrate that the use of 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 reduction in the 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 MSN nanoparticles for stroma modulation and to prevent pancreatic cancer progression.

Nano-based strategy for precise tumor stroma modulation and improved therapeutic efficacy to treat pancreatic cancer

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ACS Fall 2022

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.