Enhancement of the fraction of the active form of an antitumor drug topotecan via an injectable hydrogel

Poly(D,L-lactic acid-co-glycolic acid)-b-poly(ethylene glycol)-b-poly(D,L-lactic acid-co-glycolic acid) (PLGA–PEG–PLGA) hydrogels were tried as implants to encapsulate antitumor drug topotecan (TPT), a derivative of camptothecin (CPT). Despite of water solubility of TPT, the in vitro release of this low-molecular-weight drug from hydrogels sustained for 5 days with only a mild initial burst. The antitumor efficacy of the released TPT was further validated in S180-bearing mice. Surprisingly, the fraction of the active lactone form of TPT was increased to above 50% in the hydrogel matrix, while the fraction was just about 10% in phosphate buffer saline under physiological pH at 37 °C. This significant effect was interpreted not by the local acidic pH within the hydrogel, but by the increase of pKa of the carboxylate group of the open-ring form due to the hydrophobic interaction between the amphiphilic polymer and TPT. Theoretical analysis via a pKa-related mechanism was also performed, which was consistent with our experimental measurements. Hence, this study has revealed that an appropriate biomaterial could, via drug-material interactions, enhance the drug efficacy by increasing the active fraction of some drugs which exhibit a reversible conversion between the active and inactive structures.

A thermoreversible hydrogel composed of copolymer PLGA–PEG–PLGA was found to enhance the equilibrium fraction of the lactone form of topotecan via elevation of the carboxylate pKa due to drug-material interactions.Figure optionsDownload as PowerPoint slide