Hyaluronic acid-coated pH sensitive poly (β-amino ester) nanoparticles for co-delivery of embelin and TRAIL plasmid for triple negative breast cancer treatment

Triple negative breast cancer (TNBC) still lacks an effective targeted treatment. In this study, hyaluronic acid (HA)-mediated tumor targeting and pH-sensitive amphiphilic polymeric nanoparticles were designed and prepared to co-deliver the anticancer drug embelin (EMB) and tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) plasmid (pTRAIL) (EMB/TRAIL-HA/PBAE-PEI) for synergistic anti-breast cancer efficacy. These pH-sensitive amphiphilic polymeric nanoparticles were formed using the amphiphilic polymers polyethyleneimine (PEI)-poly[(1,6-hexanediol)-diacrylate-beta-5-hydroxyamylamine] (PBAE), which was synthesized via Michael addition polymerization. Taking advantage of the specific binding between HA and CD44, which is highly expressed in MDA-MB-231 TNBC cells, the HA-coated nanoparticles increased drug uptake in MDA-MB231 TNBC cells compared with MCF-7 non-TNBC cells with lower CD44 expression. Moreover, EMB/TRAIL-HA/PBAE-PEI exhibited enhanced cytotoxic and pro-apoptotic effects against MDA-MB-231 cells compared with free EMB and EMB- or pTRAIL-loaded nanoparticles via activation of caspase 3/7, an increase in reactive oxygen species levels, and inhibition of the expressions of apoptosis-related proteins. These results demonstrated that EMB/TRAIL-HA/PBAE-PEI exerted enhanced cytotoxic and pro-apoptotic effects against MDA-MB-231 cells and showed great potential for TNBC treatment.