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

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 (1)H 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 22 h, 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 7 days upon subcutaneous injection into mice. These results indicate that PEG-PVL-PEG copolymers are suitable for drug delivery applications.