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
