Tumor vascular permeabilization using localized mild hyperthermia to improve macromolecule transport

The abnormal tumor vasculature presents a major challenge to the adequate delivery of chemotherapeutics, often limiting efficacy. We developed a nanoparticle-based technique to deliver localized mild hyperthermia (MHT) used to transiently alter tumor vascular transport properties and enhance transport of macromolecules into tumor interstitium. The strategy involved administering and localizing accumulation of stealth gold nanorods (GNRs, 103μg of GNRs/g of tumor), and irradiating tumor with a low-photon laser flux (1W/cm²) to generate MHT. The treatment increased vascular permeability within 24h after treatment, allowing enhanced transport of macromolecules up to 54nm in size. A mathematical model is used to describe changes in tumor mass transport properties where the rate of macromolecular exchange between interstitial and vascular region (R) and maximum dye enhancement (Y_max) of 23-nm dextran dye is analytically solved. During enhanced permeability, R increased by 200% while Y_max increased by 30% relative to untreated group in pancreatic CAPAN-1 tumors. MHT treatment also enhanced transport of larger dextran dye (54nm) as assessed by intravital microscopy, without causing occlusive cellular damage. Enhanced vascular transport was prolonged for up to 24h after treatment, but reversible with transport parameters returning to basal levels after 36h. This study indicates that localized mild hyperthermia treatment opens a transient time-window with which to enable and augment macromolecule transport and potentially improve therapeutic efficacy. From the Clinical Editor: In this study, local intra-tumor mild hyperthermia is induced using a nanoparticle-based approach utilizing stealth gold nanorods and irradiating the tumor with low-photon laser flux, resulting in locally increased vascular permeability enabling enhanced delivery of therapeutics, including macromolecules up to 54nm in size. Similar approaches would be very helpful in addressing treatment-resistant malignancies in clinical practice.