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

• We synthesized PEG–PVL–PVL, new biodegradable triblock copolymers.
• PEG–PVL–PEG exhibit sol–gel transition at physiological temperature.
• PEG–PVL–PEG polymer showed no toxicity at clinical relevant concentrations.
• The gel was loaded with hydrophilic and hydrophobic drugs.
• In vivo the gel integrity was maintained for 7 days and was cleared after 29 days.

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 22 h, whereas only 14% of DEX was released in 24 h. 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.

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