Squalenoyl Gemcitabine Monophosphate: Synthesis, Characterisation of Nanoassemblies and Biological Evaluation

Abstract

Trialkylammonium 4-(N)-1,1Ј,2-trisnor-squalenoylgemcitabine monophosphate (SQdFdC-MP) salts were prepared from 1,1Ј,2-trisnor-squalenoylgemcitabine by phosphoramiditetype chemistry. This amphiphilic molecule self-assembled into nanoassemblies of about 100 nm in size in aqueous solutions. Cryo-TEM and small-angle X-ray scattering (SAXS) investigations revealed that SQdFdC-MP molecules selforganized into unilamellar liposomes with a membrane

Gemcitabine-based therapy for pancreatic cancer using the squalenoyl nucleoside monophosphate nanoassemblies

“…The synthesis of 1,1 0 ,2-trisnor-squalenic acid, squalenoyl-gemcitabine (SQdFdC) and squalenoyl-gemcitabine monophosphate (SQdFdC-MP) ( Fig. 1) has been previously reported by us (Caron et al, 2011(Caron et al, , 2010Couvreur et al, 2006).…”

“…We have recently described (Caron et al, 2011) the synthesis and the preliminary biological activity of a squalenoyl prodrug of 5 0 -monophosphate gemcitabine (SQdFdC-MP) on the leukaemia cell lines. This conjugate has been obtained from SQdFdC using phosphoramidite type chemistry to implement 5 0 -bis-(9-methylfluorenyl)-phosphate group followed by deprotection upon treatment using either triethylamine or dimethylethanolamine (Fig.…”

“…Indeed, additional in vitro and in vivo studies have attributed the impressive anticancer activity of this nanomedicine to: (i) the significantly higher deposition of SQdFdC nanoassemblies in spleen, liver and lungs, the major metastatic organs, (ii) the better intracellular diffusion of SQdFdC, (iii) the selective activation of the prodrug by cathepsin B, a major enzyme in cancer cells . Furthermore, we extended our strategy using the pronucleotide approach, which consisted in the administration of nanoformulations of protected nucleoside monophosphate derivatives for overcoming cellular resistance induced by the down-regulation of dCK and the poor uptake of the nucleoside monophosphate as a free drug into the cells (Caron et al, 2011(Caron et al, , 2010. The conjugation of a squalenoyl residue at the N-4 position in the cytidine nucleus by phosphoramidite-type chemistry led to squalenoyl prodrug of 5 0 -monophosphate gemcitabine (SQdFdC-MP), which when dispersed in water formed nanoassemblies of 100 nm mean diameter (Caron et al, 2011).…”

“…Furthermore, we extended our strategy using the pronucleotide approach, which consisted in the administration of nanoformulations of protected nucleoside monophosphate derivatives for overcoming cellular resistance induced by the down-regulation of dCK and the poor uptake of the nucleoside monophosphate as a free drug into the cells (Caron et al, 2011(Caron et al, , 2010. The conjugation of a squalenoyl residue at the N-4 position in the cytidine nucleus by phosphoramidite-type chemistry led to squalenoyl prodrug of 5 0 -monophosphate gemcitabine (SQdFdC-MP), which when dispersed in water formed nanoassemblies of 100 nm mean diameter (Caron et al, 2011). Cryo-TEM and small-angle X-ray scattering (SAXS) investigations evidenced that SQdFdC-MP molecules self-organized into unilamellar vesicles with a thickness of about 70 Å for the membrane.…”

Self-assembly drug conjugates for anticancer treatment

“…As a result of the presence of an ester bond between the two drugs, the amphiphilic conjugate was able to release both the compounds after the hydrolysis of this bond in the tumor cells [43]. The same strategy was exploited in a recent study in which the hydrophilic gemcitabine (21) A c c e p t e d M a n u s c r i p t the nanoprecipitation technique [10] and it was demonstrated to form NPs [44].…”