1 research outputs found
Differences in Nanoparticle Uptake in Transplanted and Autochthonous Models of Pancreatic Cancer
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)-<i>block</i>-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