Thioester platform to develop potential nanomedicines for breast cancer therapy

PurposeThe purpose of this study was to develop thioester based novel crosslinker and utilized them to synthesize duel responsive thioester (tt-) crosslinked polyethyleneimine (PEI) based cationic polymer (PEI-tt) for the delivery of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) plasmid (pTRAIL) to different breast cancer cells.MethodsThioester crosslinkers were prepared by substitution of 2-mercaptopropionic acid onto aliphatic lipid chlorides (e.g. Glutaryl Chloride: C5, Pimeloyl Chloride: C7, and Azelaoyl Chloride: C9) and utilized to crosslink low molecular weight (MW 0.6, 1.2, 2.0, kDa) branched and linear (MW 2.5 kDa) polyethyleneimine (PEIs). All the products were analyzed by matrix-assisted laser desorption-time of flight (MALDI-TOF) mass spectroscopy and 1H-NMR spectroscopy. DNA delivery efficiency and subsequent anticancer activity of PEI-tt polymers in different breast cancer cells were studied through cellular uptake, transfection efficiency and MTT assay, respectively.ResultsThese polymers showed enough buffering and pDNA binding capacity that results the formation of polyplexes of variable hydrodynamic sizes (150 to 200 nm) and surface charges (+ 20 to + 50 mV). The optimized PEI-tt polymer showed significantly higher transfection efficiency (40 to 90%) in 293T, MBA-MB-231, MDA-MB-436 and SUM-149 cell which was competitive with or higher than the commercial transfection reagent, linear PEI40kDa. With the delivery of pTRAIL, these polymers generate substantial anticancer activity (40 to 80% cell death) in triple negative breast cancer cell line (SUM-197 cells) though the effect was dependent on cell types, and it was typically based on available death receptors.ConclusionOur results showed that aliphatic lipid-based thioester linkers are potential moieties to crosslink low molecular weight PEIs which shows promising DNA transfection efficiency and anticancer activity in triple negative breast cancer cell lines, though the improvement is always dependent on the type of crosslinking reagent, e.g., carbon chain length, and building blocks of the polymer, e.g., molecular weight, topology and cell types.