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submitted on 08.08.2020 and posted on 10.08.2020by Song Ding, Christopher L. Hackett, Fang Liu, Ryan G. Hackett, Ulrich Bierbach
Liposomal formulations have been developed for a highly cytotoxic
platinum–acridine hybrid agent, [PtCl(pn)(C18H21N4)](NO3)2
(PA, pn = propane-1,3-diamine), and fully characterized. PEGylated nanoliposomes consisting of hydrogenated soybean phosphatidylcholine (HSPC), anionic 1,2-dihexadecanoyl-sn-glycero-3-phospho-(1´-rac-glycerol)
(DPPG), and polyethylene glycol-2000-distearoylphosphatidylethanolamine
(DSPE-mPEG2k) were able to stably encapsulate PA at payload-to-lipid
ratios ranging from approximately 2–20%.
The fusogenic properties of the liposomes promote efficient cellular uptake
of PAacross the plasma membrane, which results in vesicular transport of payload
to the nucleus, as confirmed by confocal fluorescence microscopy in cultured lung
cancer cells. Unencapsulated PA
and one of the newly designed liposomal formulations show promising efficacy in
tumor xenografts derived from A549 cells (human lung adenocarcinoma). The findings underscore the utility of
platinum–acridine agents for treating aggressive, chemoresistance cancers and
validate nanoliposomes as a biocompatible, expandable platform for their
intravenous delivery and other potential routes of administration.