Hybrid Nanocarrier Delivers Immuno-Photothermal Therapy to Modulate Pancreatic Tumor Microenvironment

Pancreatic ductal adenocarcinoma (PDAC) remains one of the deadliest cancers due to its complex tumor microenvironment and limited treatment options. The present study explores a therapeutic strategy that combines immuno- and photothermal therapies (PTT) using hybrid polymer-metal nanoparticles (NPs) to modulate the pancreatic tumor microenvironment, leading to sustained therapeutic efficacy. Core-satellite particles constituted of gold nanorods grafted at the surface of polylactic polyethylene block copolymer particles were designed to encapsulate a potent PI3K-γ inhibitor. The release of the drug from the particles was controlled by near-infrared laser irradiation power and time, offering versatility in controlling dosage profile noninvasively over 96 h. In vitro, 2D cultures of pancreatic cancer cells (KPC) exhibited significantly higher uptake of the hybrid nanoparticles compared to proinflammatory (M1) and anti-inflammatory (M2) macrophages. Consequently, KPC cells were more sensitive to PTT and could be eradicated while maintaining macrophages' viability. Through the photostimulated release of the PI3K-γ inhibitor, the particles effectively repolarized M2 macrophages to the M1 phenotype, enhancing cancer cell eradication. These positive outcomes were further confirmed on 3D cocultures of KPC and macrophage spheroids. Additionally, we showed that macrophages exposed to the nanoparticles exhibited sustained antitumor activity when repeatedly put in contact with cancer cells, confirming the long-term efficacy of the treatment. This study highlights the potential of the present polymer-metal hybrid nanoparticles as a versatile platform for combined immuno- and photothermal therapy in PDAC.