Enhancing the Accumulation of Polymer Micelles by Selectively Dilating Tumor Blood Vessels with NO for Highly Effective Cancer Treatment

A tumor vascular‐targeted multifunctional hybrid polymeric micelle, which is capable of augmenting the EPR effect of nanoparticles by in situ production of NO to selectively dilate tumor blood vessels, is successfully fabricated. The augmented EPR effect can significantly enhance the accumulation of the micelles in tumors, with a high cumulative content of DOX, causing a highly effective cancer treatment.

Abstract

The accumulation of nanoparticles in tumors by the enhanced permeability and retention (EPR) effect is effective and well known. However, how to maximize accumulation is still a bottleneck in the development of nanomedicine. Herein, a tumor vascular‐targeted hybrid polymeric micelle, which has a great capacity to selectively augment the EPR effect of nanoparticles by dilating tumor blood vessels via the activity of nitric oxide (NO), is presented. Under neutral conditions, the micelle is stable, with a long blood circulation half‐life due to the carboxylated poly(ethylene glycol) (PEG) layer; in mildly acidic tumor tissues, the micelle can selectively target the tumor blood vessels by the exposed cyclic Arg‐Gly‐Asp peptide (cRGD) peptides, which is realized with a pH‐dependent hydrolysis of the monomethoxy PEG layer. Simultaneously, exposed copper ions catalyze the decomposition of endogenous NO donors, which generates NO in situ, leading to vasodilation and increased tumor vascular permeability. As a result, the accumulation of nanoparticles is significantly enhanced, and a high accumulation of doxorubicin in tumors is achieved at 48 h after injection. This high dose of therapeutic agent produces a large inhibition of tumor growth (94%) in cancer treatment, and shows no general toxicity, with 100% of the mice surviving the treatment regimen.

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