Enhancing Tumor Perfusion and Nanomedicine Delivery by Modulating Vascular Tone with Methyl Palmitate Nanoparticles

Despite a few clinical successes, the efficacy of cancer nanomedicines remains limited by rapid clearance by the mononuclear phagocytic system and poor permeation across the abnormal tumor vasculature. We previously showed that methyl palmitate nanoparticles (MPN) can safely and reversibly inhibit the phagocytic activity of immune cells for several hours, thereby improving tumor accumulation and the efficacy of systemically administered nanomedicines. Here, we demonstrate that, on a shorter time scale, MPN can induce vasodilation, introducing an additional mechanism to enhance the accumulation of therapeutic agents within malignant tissue. Upon internalization by macrophages and endothelial cells, MPN could potentially trigger the release of endogenous nitric oxide (NO), a key mediator of vasodilation, in a concentration-, and time-dependent manner. Following MPN administration, raster-scanning optoacoustic mesoscopy (RSOM) revealed vasodilation across multiple tissues, with a strong effect observed in tumors. To assess enhanced tumor accumulation, we injected 70 kDa fluorescent dextran and demonstrated via histology a markedly increased fluorescence signal exclusively in MPN-treated tumors compared to controls 24 h later. In addition, positron emission tomography (PET) imaging of 89Zr-labeled Feraheme nanoparticles showed significantly greater tumor accumulation after a 15 min MPN pretreatment. Finally, general serum biochemistry panels and histological analyses of major organs in healthy mice revealed that MPN did not induce observable short-term toxicity under the tested conditions (single or repeated MPN dosing). Overall, this study demonstrates that MPN-induced vasodilation occurring within minutes enhances intratumoral deposition of macromolecules and small nanoparticles. Together with their longer-term effects on phagocytosis inhibition, these findings indicate that MPN can improve therapeutic delivery through complementary, time-dependent mechanisms that increase tumor perfusion and vascular permeability.