Injectable hyaluronic acid-tyramine hydrogels incorporating interferon-α2a for liver cancer therapy

We report an injectable hydrogel system that incorporates interferon-alpha 2a (IFN-alpha 2a) for liver cancer therapy. IFN-alpha 2a was incorporated in hydrogels composed of hyaluronic acid-tyramine (HA-Tyr) conjugates through the oxidative coupling of Tyr moieties with hydrogen peroxide (H2O2) and horseradish peroxidase (HRP). IFN-alpha 2a-incorporated HA-Tyr hydrogels of varying stiffness were formed by changing the H2O2 concentration. The incorporation of IFN-alpha 2a did not affect the rheological properties of the hydrogels. The activity of IFN-alpha 2a was furthermore well-maintained in the hydrogels with lower stiffness. Through the caspase-3/7 pathway in vitro, IFN-alpha 2a released from HA-Tyr hydrogels inhibited the proliferation of liver cancer cells and induced apoptosis. In the study of the pharmacokinetics, a higher concentration of IFN-alpha 2a was shown in the plasma of mice treated with IFN-alpha 2a-incorporated hydrogels after 4 h post injection, with a much higher amount of IFN-alpha 2a delivered at the tumor tissue comparing to that of injecting an IFN-alpha 2a solution. The tumor regression study revealed that IFN-alpha 2a-incorporated HA-Tyr hydrogels effectively inhibited tumor growth, while the injection of an IFN-alpha 2a solution did not demonstrate antitumor efficacy. Histological studies confirmed that tumor tissues in mice treated with IFN-alpha 2a-incorporated HA-Tyr hydrogels showed lower cell density, with more apoptotic and less proliferating cells compared with tissues treated with an IFN-a2a solution. In addition, the IFN-alpha 2a-incorporated hydrogel treatment greatly inhibited the angiogenesis of tumor tissues. (C) 2013 Elsevier B. V. All rights reserved.