Conventional
cancer targeting with nanoparticles has been based on the assumed enhanced permeability and retention (EPR) effect. The data obtained in clinical trials to date, however, have rarely supported the presence of such an effect. To address this challenge, we formulated intracellular
nitric oxide-generating nanoparticles (NO-NPs) for the
tumor site-specific delivery of NO, a well-known
vasodilator, with the intention of boosting EPR. These nanoparticles are self-assembled under aqueous conditions from amphiphilic copolymers of poly(
ethylene glycol) and nitrated
dextran, which possesses inherent NO release properties in the reductive environment of
cancer cells. After systemic administration of the NO-NPs, we quantitatively assessed and visualized increased
tumor blood flow as well as enhanced vascular permeability than could be achieved without NO. Additionally, we prepared
doxorubicin (DOX)-encapsulated NO-NPs and demonstrated consequential improvement in therapeutic efficacy over the control groups with considerably improved DOX intratumoral accumulation. Overall, this proof of concept study implies a high potency of the NO-NPs as an EPR enhancer to achieve better clinical outcomes.