Differences in Nanoparticle Uptake in Transplanted and Autochthonous Models of Pancreatic Cancer

Abstract

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.

Biodegradable Polymer with Effective Near‐Infrared‐II Absorption as a Photothermal Agent for Deep Tumor Therapy

“…Cy7.5‐labeled NPs were intraperitoneally injected, and their distribution was imaged 24 h with an in vivo imaging system (IVIS) after the injection. [ 23 ] As shown in Figure A, the tumors are mainly dispersed in the abdominal region, while the NPs are mainly accumulated within the tumor regions. The tumor region is visualized through bioluminescent imaging (BLI), which is used to guide the choice of irradiation sites.…”

Neutrophil-mimicking therapeutic nanoparticles for targeted chemotherapy of pancreatic carcinoma

“…Due to the malignancy nature of pancreatic cancer and the difficulty to diagnose at an early stage of tumor progression, pancreatic carcinoma remains a leading cause of cancer-related mortality worldwide. Despite advances in cancer chemotherapy, limited treatment options are available for pancreatic cancer, which often result in severe adverse effects and poor patient response 45 . As part of the innate immune defense system, neutrophils are the early cell types recruited to the site of injury through tethering, rolling, crawling and transmigration 46 .…”

Microneedles loaded with anti-PD-1–cisplatin nanoparticles for synergistic cancer immuno-chemotherapy

“…[10][11][12] The clonal expansion of T-cells in the tumor microenvironment correlates with a better response to chemotherapy; 13 therefore, the effectiveness of chemotherapy relies on the induction of a durable anticancer immune response. 14,15 Pre-existing CD8+ T-cells in the tumor microenvironment also predict the efficacy of aPD-1 therapy. This represents a novel treatment strategy in which the outcome of chemotherapy and immunotherapy can be improved by altering the tumor microenvironment.…”