tLyp-1-conjugated GSH-sensitive biodegradable micelles mediate enhanced pUNO1-hTRAILa/curcumin co-delivery to gliomas

The successful treatment of gliomas relies on two important factors, namely therapeutic genes/drugs and efficient delivery vehicles to cross the blood-brain barrier. In this work, a new gene vector was constructed based on polycaprolactone (PCL), glutathione (reduced; GSH)-sensitive polyethylenimine (PEI-SS) and polyethylene glycol (PEG), and modified with a cell-penetrating peptide (tLyp-1); this yielded tLyp-1-conjugated GSH-sensitive biodegradable micelles (PPPt) that mediated enhanced tumour necrosis factor (TNF)-related apoptosis-inducing ligand (pUNO1-hTRAILa) and curcumin (CUR) co-delivery to gliomas. The sensitisation function of CUR was used to explore whether CUR and genes have a synergistic antitumour effect. The results showed that the drug loading efficiency of PPPt was about 8.6%. The PPPt possessed good cytocompatibility and blood compatibility when the concentration was less than 0.06 mg/mL. PPPt strongly condensed pUNO1-hTRAILa to form a nanocomplex and efficiently transfected C6 cells. The drug-release behaviour of PPPt/CUR/pUNO1-hTRAILa was reduction-sensitive and the cellular uptake results indicate that modification of tLyp-1 promoted the internalisation of micelles. The PPPt/CUR/pUNO1-hTRAILa complexes exhibited much better in vitro and in vivo antitumour effects than micelles loaded with CUR or pUNO1-hTRAILa alone. We also used magnetic resonance imaging for in vivo monitoring of the transcranial drug delivery and therapeutic effect of the tumour on rats bearing in situ glioma.