Thermoresponsive and biodegradable linear-dendritic nanoparticles for targeted and sustained release of a pro-apoptotic drug
Ceramide is a bioactive sphingolipid-derived second messenger that has been demonstrated to induce apoptosis and cell cycle arrest in various cancer cell culture systems. Although in vitro tumor cell culture models have illuminated the potential therapeutic utility of a cell-permeable analog of ceramide, C6, in vivo delivery is impeded by the extreme hydrophobicity and physical-chemical properties of this bioactive lipid. Previously, we have demonstrated that the incorporation of C6 into pegylated liposomal vesicles is an effective anti-cancer drug delivery strategy in vitro and in vivo. Here, we report the utilization of a novel multi-functional polymeric drug delivery system designed to therapeutically target C6 to solid tumor tissue. This delivery system is a hydrolytically degradable and temperature-sensitive linear-dendritic nanoparticle with a lower critical solution temperature (LCST) of 30 °C. C6 was effectively loaded into the nanoparticles, and released continuously for at least 1 month in vitro, measured by mass spectroscopy. The preferential uptake of fluorescein isothiocyanate-labeled linear-dendritic nanoparticles into human MDA-MB-231 breast adenocarcinoma cells at temperature above the LCST (37 °C) was confirmed by confocal microscopy and quantified by flow cytometry. The accumulation of NBD-C6 into MDA-MB-231 cells was highly enhanced by the thermoresponsive linear-dendritic nanoparticles, but not by non-thermoresponsive liposome and PEG-dendritic polymer, at temperature above the LCST (37 °C). The linear-dendritic nanoparticles alone were not toxic, but their complexes with C6 caused significant growth inhibition and apoptosis to MDA-MB-231 cells at 37 °C. The designed thermoresponsive and biodegradable linear-dendritic nanoparticles have great potential for thermally targeted and sustained release of C6 for the treatment of solid tumors with hyperthermia.
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