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Simultaneous inhibition of hedgehog signaling and tumor proliferation remodels stroma and enhances pancreatic cancer therapy
- Source :
- Biomaterials. 159:215-228
- Publication Year :
- 2018
- Publisher :
- Elsevier BV, 2018.
-
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.
- Subjects :
- 0301 basic medicine
Stromal cell
Paclitaxel
Cyclopamine
Polymers
Biophysics
Mice, Nude
Bioengineering
Article
Biomaterials
Extracellular matrix
Mice
03 medical and health sciences
chemistry.chemical_compound
0302 clinical medicine
Stroma
Pancreatic cancer
medicine
Animals
Sonic hedgehog
Micelles
Cell Proliferation
biology
medicine.disease
Hedgehog signaling pathway
Pancreatic Neoplasms
030104 developmental biology
chemistry
Mechanics of Materials
030220 oncology & carcinogenesis
cardiovascular system
Ceramics and Composites
biology.protein
Cancer research
Female
Signal Transduction
Subjects
Details
- ISSN :
- 01429612
- Volume :
- 159
- Database :
- OpenAIRE
- Journal :
- Biomaterials
- Accession number :
- edsair.doi.dedup.....c3c01d4eb08fde27b04e4b2929288349
- Full Text :
- https://doi.org/10.1016/j.biomaterials.2018.01.014