Injectable Thermo-sensitive Hydrogel For Sustained Release Carrier Of Doxorubicin Hydrochloride

Doxorubicin has been one of the most effective antitumor drugs since it was applied in clinical tumor treatment in 1970's. However, it causes acute or chronic side effects such as cardiotoxicity, hepatic dysfunction. In addition, the stability of doxorubicin is poor and it is rapidly metabolized to inactive derivatives by liver. So the efficacy of doxorubicin therapy is restricted. To reduce the side effect and increase the therapeutic effect, a biodegradable and injectable hydrogel was tried as a carrier of doxorubicin in this thesis. The drug-loading formulation has characteristics of passive target and site-specific sustained release through direct injection into the tumor site.In this study, a ABA type thermogelling triblock copolymer composed of poly(lactic acid-co-glycolic acid) (PLGA) and poly(ethylene glycol) (PEG) was synthesized. The polymer/water mixture was a low-viscosity solution (free-flowing) at room temperature, and turned into a gel with increasing the temperature. Therefore, active substances were conveniently incorporated in a sol state and then the polymer aqueous solution becomes a semisolid gel by injection into a target site of body due to the physiological heat at 37℃. Here, doxorubicin was successfully encapsulated and released from the polymer depot. In vitro studies showed that the release of drug last for over 3 weeks. The accumulative release amount was as high as 90% and the release profile was diffusion-controlled as described by Higuchi equation. Furthermore, in vivo antican-cer tests based on a mouse model exhibited the high efficacy against S-180 tumor. No severe cardiotoxicity was observed.