PHASE-SEPARATED HYDROGELS WITH TUNABLE DOMAIN SIZE ENABLED LONG-TERM CONTROLLED DELIVERY OF PEGINTERFERON ALFA-2A AND IMPROVED ITS THERAPEUTIC EFFICACY
Ki Hyun Bae, Fan Lee, Keming Xu, Choong Tat Keng, Sue Yee Tan, Yee Joo Tan, Qingfeng Chen, Motoichi
Institute of Bioengineering and Nanotechnology, A*STAR, Singapore
Hepatitis C remains a significant global health problem that affects approximately 130–150 million people and causes over 50 thousand deaths each year. Although new drugs known as direct-acting antivirals have been introduced, Peginterferon alfa-2a is still extensively used for the treatment of hepatitis C. Currently, the standard treatment for hepatitis C consists of weekly injections of Peginterferon alfa-2a together with daily oral administration of antiviral drugs for 12-48 weeks. Such frequent injections not only increase patient discomfort, but also cause serious and sometimes lifethreatening side effects. Hence there is an urgent need to develop a controlled drug delivery system which can improve the therapeutic efficacy of Peginterferon alfa-2a while reducing the need for frequent injections. Herein we report the development of phase-separated hydrogels with tunable domain size for long-term controlled delivery of Peginterferon alfa-2a. These hydrogels were formed by crosslinking-induced phase separation of initially miscible mixtures of dextrantyramine conjugates and polyethylene glycol (PEG). The phase separation of the polymer mixtures led to the formation of micron-sized PEG domains as drug reservoirs. The existence of PEG domains enabled burst-free sustained release of Peginterferon alfa-2a over 3 months without compromising its bioactivity. Moreover, the rate of drug release could be regulated simply by tuning the size of PEG domains with variations in gelation rates. The phase-separated hydrogels prolonged the plasma half-life of Peginterferon alfa-2a up to 10 times, thereby enhancing its therapeutic efficacy in a humanized mouse model of hepatitis C. A one-time administration of the drug-loaded hydrogels prevented hepatitis C virus-induced liver damage as effectively as the clinically relevant formulation that necessitated eight weekly injections of Peginterferon alfa-2a. Our study demonstrated the capability of the phase-separated hydrogels to extend the duration of action of Peginterferon alfa-2a for more effective hepatitis C treatment without the need for frequent dosing.