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.