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

• Published in: Journal of controlled release 2013-03, Vol.166 (3), p.203-210
• Main Authors: Xu, Keming, Lee, Fan, Gao, Shu Jun, Chung, Joo Eun, Yano, Hirohisa, Kurisawa, Motoichi
• Format: Article
• Language: English
• Subjects: angiogenesis; Animals; Antineoplastic Agents - administration & dosage; Antineoplastic Agents - pharmacokinetics; Antineoplastic Agents - pharmacology; Antineoplastic Agents - therapeutic use; apoptosis; Apoptosis - drug effects; Cell Line, Tumor; Cell Proliferation - drug effects; Drug Carriers - chemical synthesis; Drug Carriers - chemistry; Female; Humans; Hyaluronic acid; Hyaluronic Acid - chemistry; hydrocolloids; Hydrogel; Hydrogels - chemistry; hydrogen peroxide; Injectable; Injections, Subcutaneous; Interferon; Interferon-alpha - administration & dosage; Interferon-alpha - pharmacokinetics; Interferon-alpha - pharmacology; Interferon-alpha - therapeutic use; liver neoplasms; Liver Neoplasms - drug therapy; Liver Neoplasms - pathology; Mice; Mice, Inbred BALB C; neoplasm cells; peroxidase; pharmacokinetics; Protein delivery; Recombinant Proteins - administration & dosage; Recombinant Proteins - pharmacokinetics; Recombinant Proteins - pharmacology; Recombinant Proteins - therapeutic use; remission; rheological properties; Solubility; therapeutics; tissues; Tyramine - chemistry; Xenograft Model Antitumor Assays
• ISSN: 0168-3659; 1873-4995
• DOI: 10.1016/j.jconrel.2013.01.008

We report an injectable hydrogel system that incorporates interferon-α2a (IFN-α2a) for liver cancer therapy. IFN-α2a 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-α2a-incorporated HA-Tyr hydrogels of varying stiffness were formed by changing the H2O2 concentration. The incorporation of IFN-α2a did not affect the rheological properties of the hydrogels. The activity of IFN-α2a was furthermore well-maintained in the hydrogels with lower stiffness. Through the caspase-3/7 pathway in vitro, IFN-α2a 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-α2a was shown in the plasma of mice treated with IFN-α2a-incorporated hydrogels after 4h post injection, with a much higher amount of IFN-α2a delivered at the tumor tissue comparing to that of injecting an IFN-α2a solution. The tumor regression study revealed that IFN-α2a-incorporated HA-Tyr hydrogels effectively inhibited tumor growth, while the injection of an IFN-α2a solution did not demonstrate antitumor efficacy. Histological studies confirmed that tumor tissues in mice treated with IFN-α2a-incorporated HA-Tyr hydrogels showed lower cell density, with more apoptotic and less proliferating cells compared with tissues treated with an IFN-α2a solution. In addition, the IFN-α2a-incorporated hydrogel treatment greatly inhibited the angiogenesis of tumor tissues. [Display omitted]