Diels Alder-mediated release of gemcitabine from hybrid nanoparticles for enhanced pancreatic cancer therapy

Abstract

Hybrid nanoparticles (HNPs) have shown huge potential as drug delivery vehicles for pancreatic cancer. Currently, the first line treatment, gemcitabine, is only effective in 23.8% of patients. To improve this, a thermally activated system was developed by introducing a linker between HNPs and gemcitabine. Whereby, heat generation resulting from laser irradiation of the HNPs promoted linker breakdown resulting in prodrug liberation. In vitro evaluation in pancreatic adenocarcinoma cells, showed the prodrug was 4.3 times less cytotoxic than gemcitabine, but exhibited 11-fold improvement in cellular uptake. Heat activation of the formulation led to a 56% rise in cytotoxicity causing it to outperform gemcitabine by 26%. In vivo the formulation outperformed free gemcitabine with a 62% reduction in tumor weight in pancreatic xenografts. This HNP formulation is the first of its kind and has displayed superior anti-cancer activity as compared to the current first line drug gemcitabine after heat mediated controlled release.

HIV‐1 Tat Peptide‐Gemcitabine Gold (III)‐PEGylated Complex—Nanoflowers: A Sleek Thermosensitive Hybrid Nanocarrier as Prospective Anticancer

“…Physicochemical properties of GEM do not allow an electrostatic interaction with all nanoparticle surface. For this reason, in previous studies, GEM was grafted onto iron‐oxide nanoparticles by cycloaddition through Diels Alder reaction …”

“…Recently, Oluwasanmi et al have studied the process of loading of GEM onto hybrid iron oxide‐nanoparticles (HNPs) by Diels Alder reaction . This formulation was capable of high drug loading (86%) which appeared stable even upon reduction of pH and provided to a rapid liberation of the prodrug at elevated temperatures, through retro Diels Alder breakdown . Previously Li et al have obtained a drug loading of about 55% after self‐assembled of GEM onto Diphosphate‐PEG based gadolinium nanoparticles (GdNPs) .…”

“…In order to check the release of gemcitabine (GEM), several nanocarriers were carried out under specific conditions of synthesis and surface functionalization . Many authors have used micelles on different metals (Au, Ag, or Cu) to graft GEM as nanocarrier.…”

Combined Effect of Anticancer Agents and Cytochrome C Decorated Hybrid Nanoparticles for Liver Cancer Therapy

“…A relatively new type of nanoparticle that has been reported with potential in this area is hybrid iron oxide-gold nanoparticles (HNPs) [11,12]. HNPs have been reported to be efficient as drug carriers in pancreatic cancer therapy, where they guide the drug of choice into the cell via endocytosis—thus resulting in larger quantities of internalised drugs compared with the unformulated molecules [13,14]. Previously, we have reported that cytochrome C can become irreversibly bound onto the surface of these HNPs via dative covalent linkage between the gold surface of the HNP and a thiol (-SH) residue in the cytochrome C [12].…”

Dual Acting Polymeric Nano-Aggregates for Liver Cancer Therapy

“…HNP synthesis has been well reported previously [23,24,25]. Briefly, iron oxide (Fe 3 O 4 ) nanoparticles were prepared through a precipitation reaction and stabilised with poly(ethylenimine) (MW 200,000).…”