Markedly enhanced permeability and retention effects induced by photo-immunotherapy of tumors.

Abstract

A major barrier to cancer treatment is the inability to deliver sufficient concentrations of drug to the tumor without incurring systemic toxicities. Nanomaterials are appealing because they can carry a large drug payload; however, tumor delivery is limited by modest leakage and retention in most tumors. We observed that after photoimmunotherapy (PIT), which is a light-mediated treatment based on an antibody-photosensitizer conjugate, there was surprisingly high leakage of nanosized (10-200 nm) agents into the tumor bed. PIT rapidly induced death in perivascular cancer cells, leading to immediate and dramatic increases in vascular permeability, resulting in up to 24-fold greater accumulation of nanomaterials within the PIT-treated tumor compared with controls, an effect termed "super-enhanced permeability and retention". In a treatment study, PIT followed by liposome-containing daunorubicin, DaunoXome (diameter 50 nm), resulted in greater survival in tumor-bearing mice than either PIT or DaunoXome alone. Thus, PIT greatly enhances delivery of nanosized reagents and thus holds promise to improve therapeutic responses.