In situ gelling polyvalerolactone-based thermosensitive hydrogel for sustained drug delivery

Abstract

Biodegradable poly(ethyleneglycol)–poly(valerolactone)–poly(ethyleneglycol) [PEG–PVL–PEG] copolymers were synthesized through ring opening polymerization of δ-valerolactone (VL) followed by the coupling of monomethoxy poly(ethyleneglycol–poly(valerolactone) (mPEG–PVL) with hexamethylene diisocyanate (HDI). The copolymers were characterized by 1H NMR, FT-IR, and GPC. Block copolymers of PEG and PVL with different VL/PEG molar ratios were successfully synthesized. One of the copolymers (Copolymer 2, PEG550–PVL6768–PEG550) displayed a sol–gel transition at a physiological temperature based on the test tube inverting method and rheological studies. The thermogelling copolymer demonstrated a characteristic crystalline peak for PVL block as determined by DSC and XRD analysis. In vitro release from the copolymer hydrogel matrix indicated that dexamethasone (DEX), a hydrophobic model drug, released comparatively slower than 5-fluoruracil (5-FU), a hydrophilic model drug, due to the potential partitioning of DEX into the PVL core. 5-FU in vitro release from copolymer 2 was 86% in 22h, whereas only 14% of DEX was released in 24h. Cell viability studies confirmed that hydrogels composed of block copolymers are biocompatible. Copolymer 2 showed more than 80% relative cell viability at all concentrations, including concentrations greater than 200 fold CMC. In vivo gel formation studies indicate that gel integrity was maintained for 7days upon subcutaneous injection into mice. These results indicate that PEG–PVL–PEG copolymers are suitable for drug delivery applications.