Sustained release of PTX-incorporated nanoparticles synergized by burst release of D0XHC1 from thermosensitive modified PEG/PCL hydrogel to improve anti-tumor efficiency

摘要

As drug therapies become increasingly sophisticated, the synergistic benefits of two or more drugs are often required. In this study, we aimed at improving anti-tumor efficiency of paclitaxel (PTX)-incorpo-rated thermo-sensitive injectable hydrogel by the synergy of burst release of doxorubicin hydrochloride (DOXHC1). Thermosensitive injectable hydrogel composed of nanoparticles assembled from amphiphilic copolymer poly(8-caprolactone-co-l,4,8-trioxa[4.6]spiro-9-undecanone)-poly(ethylene glycol)-poly(e-caprolaone-co-l,4,8-trioxa[4.6]spiro-9-undecanone) (PECT) was fabricated. Hydrophobic PTX and hydro-philic D0XHC1 were loaded simultaneously in the thermo-sensitive injectable hydrogel by a two-stage entrapment. Thermosensitive gelling behaviors of drug-loading PECT nanoparticle aqueous dispersions were studied. In vitro release profiles of PTX and DOXHC1 and in vivo anti-tumor effect by dual drugs from PECT hydrogel were investigated. The results showed that hydrophilic and hydrophobic drugs could be successfully entrapped in PECT hydrogel simultaneously without affecting its thermo-sensitive behavior. In vitro release profiles demonstrated the burst release of D0XHC1 and the sustained release of PTX. Anti-tumor effect was improved by a fast and tense attack caused by the burst release of hydrophilic D0XHC1 from hydrogel, which was continued by the sequent sustained release of PTX-incorporated nanoparticles and remnant D0XHC1. Unintentionally, entrapped in PECT hydrogel, hydrophilic DOXHC1 was observed to have a sustained releasing pattern in vitro and in vivo.