Chain length impact on the retro Diels-Alder mediated release of gemcitabine from hybrid nanoparticles towards pancreatic cancer therapy

Oluwasanmi, Adeolu and Lindsay, Sarah and Curtis, Anthony and Perrie, Yvonne and Hoskins, Clare (2023) Chain length impact on the retro Diels-Alder mediated release of gemcitabine from hybrid nanoparticles towards pancreatic cancer therapy. International Journal of Pharmaceutics, 644. 123304. ISSN 0378-5173 (https://doi.org/10.1016/j.ijpharm.2023.123304)

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Abstract

Previously reported gold coated iron oxide nanoparticles (Au-IONP’s) have demonstrated their effectiveness as drug delivery vehicles for gemcitabine conjugated to a thermally labile Diels-Alder linker containing a chain of 4 carbon atoms (TTLD4) for the treatment of pancreatic cancer. Heat generated via laser irradiation of Au-IONPs facilitated retro Diels-Alder mediated release in a burst release profile where approximately half of all total release over 180 min occurred within the first 5 min. Two analogues of TTLD4, which differ only in linker chain length (TTLD3 & TTLD6) were synthesised and conjugated to Au-IONP’s. Heat-mediated release of gemcitabine at 45 ˚C over 180 min from these formulations was confirmed to be based on linker length, which was 94%, 76% and 45% for TTLD3, TTLD4 and TTLD6, respectively. Drug loading of the Diels-Alder linkers in a 5:1 Drug/Au-IONP w/w ratio appears to favour those containing an even number of carbons TTLD4 (76%) & TTLD6 (57%) over TTLD3 (25%), possibly due to the linker likely being positioned perpendicular to the Au-IONP surface because of the 120˚ C-C bond.

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