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Biomaterials. 2018 Mar;159:215-228. doi: 10.1016/j.biomaterials.2018.01.014. Epub 2018 Jan 9.

Simultaneous inhibition of hedgehog signaling and tumor proliferation remodels stroma and enhances pancreatic cancer therapy.

Author information

1
Department of Cancer Systems Imaging, The University of Texas MD Anderson Cancer Center, Houston, TX 77054, USA.
2
Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX 77054, USA.
3
Department of Pharmacological and Pharmaceutical Sciences, College of Pharmacy, University of Houston, Houston, TX 77030, USA.
4
Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77054, USA.
5
Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77054, USA.
6
Department of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77054, USA.
7
Department of Imaging Physics, The University of Texas MD Anderson Cancer Center, Houston, TX 77054, USA.
8
Department of Immunology, The University of Texas MD Anderson Cancer Center, Houston, TX 77054, USA.
9
Department of Cancer Systems Imaging, The University of Texas MD Anderson Cancer Center, Houston, TX 77054, USA. Electronic address: cli@mdanderson.org.

Abstract

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.

KEYWORDS:

Cancer-associated fibroblast; Pancreatic cancer; Polymeric micelles; Sonic hedgehog signaling; Stromal modulation

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