Biodegradable block copolymers as injectable drug-delivery systems

Abstract

Polymers that display a physicochemical response to stimuli are widely explored as potential drug-delivery systems^1,2,3,4. Stimuli studied to date include chemical substances and changes in temperature, pH and electric field. Homopolymers or copolymers of N-isopropylacrylamide⁵,⁶ and poly(ethylene oxide)–poly(propylene oxide)–poly(ethylene oxide) (known as poloxamers)⁷ are typical examples of thermosensitive polymers, but their use in drug delivery is problematic because they are toxic and non-biodegradable. Biodegradable polymers used for drug delivery to date have mostly been in the form of injectable microspheres or implant systems, which require complicated fabrication processes using organic solvents⁸. Such systems have the disadvantage that the use of organic solvents can cause denaturation when protein drugs are to be encapsulated. Furthermore, the solid form requires surgical insertion, which often results in tissue irritation and damage. Here we report the synthesis of a thermosensitive, biodegradable hydrogel consisting of blocks of poly(ethylene oxide) and poly(L-lactic acid). Aqueous solutions of these copolymers exhibit temperature-dependent reversible gel–sol transitions. The hydrogel can be loaded with bioactive molecules in an aqueous phase at an elevated temperature (around 45 °C), where they form a sol. In this form, the polymer is injectable. On subcutaneous injection and subsequent rapid cooling to body temperature, the loaded copolymer forms a gel that can act as a sustained-release matrix for drugs.