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Differences in Nanoparticle Uptake in Transplanted and Autochthonous Models of Pancreatic Cancer
Name
nihms966630.pdf
Description
Accepted version
Size
1.73 MB
Format
Adobe PDF
Checksum (MD5)
51dfcd8dd0cee9b597d71076068ead41
Author(s)
Tao, Zhimin
Muzumdar, Mandar Deepak
Detappe, Alexandre
Huang, Xing
Xu, Eric S
Yu, Yingjie
Mouhieddine, Tarek H
Song, Haiqin
Jacks, Tyler
Ghoroghchian, P Peter
Date Issued
2018
Journal
Nano Letters
Publisher
American Chemical Society (ACS)
Version
Author's final manuscript
Abstract
© 2018 American Chemical Society. Human pancreatic ductal adenocarcinoma (PDAC) contains a distinctively dense stroma that limits the accessibility of anticancer drugs, contributing to its poor overall prognosis. Nanoparticles can enhance drug delivery and retention in pancreatic tumors and have been utilized clinically for their treatment. In preclinical studies, various mouse models differentially recapitulate the microenvironmental features of human PDAC. Here, we demonstrate that through utilization of different organic cosolvents and by doping of a homopolymer of poly(ϵ-caprolactone), a diblock copolymer composition of poly(ethylene oxide)-block-poly(ϵ-caprolactone) may be utilized to generate biodegradable and nanoscale micelles with different physical properties. Noninvasive optical imaging was employed to examine the pharmacology and biodistribution of these various nanoparticle formulations in both allografted and autochthonous mouse models of PDAC. In contrast to the results reported with transplanted tumors, spherical micelles as large as 300 nm in diameter were found to extravasate in the autochthonous model, reaching a distance of approximately 20 μm from the nearest tumor cell clusters. A lipophilic platinum(IV) prodrug of oxaliplatin was further able to achieve a ∼7-fold higher peak accumulation and a ∼50-fold increase in its retention half-life in pancreatic tumors when delivered with 100 nm long worm-like micelles as when compared to the free drug formulation of oxaliplatin. Through further engineering of nanoparticle properties, as well as by widespread adoption of the autochthonous tumor model for preclinical testing, future therapeutic formulations may further enhance the targeting and penetration of anticancer agents to improve survival outcomes in PDAC.
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DOI of Published Version
10.1021/ACS.NANOLETT.7B04043
