Document Type

Article

Journal Title

Molecular Pharmaceutics

Publication Date

2020

Volume

17

Abstract

In pancreatic ductal adenocarcinoma (PDAC), early onset of hypoxia triggers remodeling of the extracellular matrix, epithelial-to-mesenchymal transition, increased cell survival, the formation of cancer stem cells, and drug resistance. Hypoxia in PDAC is also associated with the development of collagen-rich, fibrous extracellular stroma (desmoplasia), resulting in severely impaired drug penetration. To overcome these daunting challenges, we created polymer nanoparticles (polymersomes) that target and penetrate pancreatic tumors, reach the hypoxic niches, undergo rapid structural destabilization, and release the encapsulated drugs. In vitro studies indicated a high cellular uptake of the polymersomes and increased cytotoxicity of the drugs under hypoxia compared to unencapsulated drugs. The polymersomes decreased tumor growth by nearly 250% and significantly increased necrosis within the tumors by 60% in mice compared to untreated controls. We anticipate that these polymer nanoparticles possess a considerable translational potential for delivering drugs to solid hypoxic tumors.

MeSH Headings

Animals, Antineoplastic Agents, Carcinoma, Pancreatic Ductal, Cell Line, Tumor, Female, Humans, Hypoxia, Male, Mice, Mice, Nude, Nanoparticles, Neoplastic Stem Cells, Pancreatic Neoplasms, Polymers

ISSN

1543-8392

Comments

Mol Pharm. Author manuscript; available in PMC 2021 May 12. Published in final edited form as: Mol Pharm. 2020 Aug 3; 17(8): 2849–2863.

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