Remote-controlled release of therapeutics from multifunctional glycoplexes inhibit melanoma cells

Abstract

Delivery system-based phototherapies such as photodynamic therapy (PDT) and photoactivated chemotherapy have been widely used for curative and palliative cancer treatment due to their selectivity and remote controllability. In this study, biocompatible glycopeptide based multifunctional nanoplexes were fabricated for targeted PDT-chemo-/gene therapy of melanoma. Multifunctional protoporphyrin IX (PpIX)-conjugated polymers were synthesized by reversible addition–fragmentation chain transfer polymerization and ring-opening polymerization from glucose transporter (GLUT1) targeted sugar (glucose/mannose) or non-targeted OEGMEMA monomers, pH-responsive lysine monomer, and pH/singlet oxygen-responsive imidazole functionalized glutamate monomer. The resulting photosensitizer-conjugated amphiphiles were able to self-assemble into spherical micelles with paclitaxel (PTX) to form dual therapeutic nanoformulations (NP1-/NP2-/NP3-PpIX/PTX). The nanoplex systems were then prepared by complexation of micelles with miR-21 inhibitor to form triple therapeutic modality nanoplatforms (NP1-/NP2-/NP3-PpIX/PTX/miR21i). The nanoplexes can readily co-deliver cargo molecules via size expansion facilitated by sequential disassembly triggered by the acidic tumor microenvironment and near infrared (NIR) light exposure. The pH/NIR light-triggered release and combined anticancer efficacy of dual or triple modal nanoformulations were investigated in melanoma (SK-MEL-28) and skin fibroblast (CCD-1079-Sk) cell lines. Glycoplexes exhibited significantly higher cytotoxicity, suppression of melanoma cell growth, efficient downregulation of miR-21, and inhibition of migration/invasion in triple-modal therapy (PDT/chemo/gene) compared to mono or dual-modal therapeutic nanoformulations.