Collaborative assembly of doxorubicin and galactosyl diblock glycopolymer for targeted delivery of hepatocellular carcinoma
Hepatocellular carcinoma (HCC) patients suffer from severe pain for the serious systemic side effects and low efficiency of chemotherapeutic drugs, and it is significant to develop novel drug delivery systems to circumvent these issues. In this study, a series of galactose-based glycopolymers, poly(N-(prop-2-enoyl)-β-D-galactopyranosylamine)-b-poly(N-isopropyl acrylamide) (pGal(OH)-b-pNIPAA), were prepared through a sequential reversible addition-fragmentation chain transfer (RAFT) polymerization and tetrabutylammonium hydroxide (TBAOH)-mediated removal of acetyl groups. Hydrophilic doxorubicin hydrochloride was induced to undergo collaborative assembly with poly(N-(prop-2-enoyl)-β-D-peracetylated galactosamine)-b-poly(N-isopropyl acrylamide) (pGal(Ac)-b-pNIPAA) via TBAOH treatment. The pGal-b-pNIPAA/doxorubicin (DOX) delivery nanoparticles (GND NPs) formed by collaborative assembly were fully characterized by NMR, TEM and FT-IR, indicating the well-controlled particles with uniform size, and high efficiency in terms of drug loading and encapsulation compared with conventional adsorption methods. Meanwhile, the GND NPs was observed to be rapidly disintegrated under acidic conditions and resulted in an increased release of DOX. Cellular experiments showed that pGal-b-pNIPAA/DOX is apparently an aspiric glycoprotein receptor (ASGPR)-mediated target of HCC, resulting in enhanced cellular uptake to HepG2 cell and anti-tumor efficacy in vitro. Furthermore, GND NPs III imparted more sustainable and effective anti-tumor effects than free DOX on a transgenic zebrafish TO(KrasG12V) model in vivo. These results indicated that the biocompatible nanomaterials developed by collaborative assembly with galactosyl diblock glycopolymers and DOX may serve as a promising strategy for targeting therapy of HCC.