Radiation-tailored xyloglucan-doxorubicin nanoparticles for cancer therapy

Abstract

Polysaccharides are long chains of monosaccharides linked by glycosidic bonds. They are widely utilized in biomedical applications, for tissue engineering and wound management, and as excipients of pharmaceutical formulations. In cancer therapy, the development of nanoscale drug delivery systems aims at addressing issues related to the low efficacy of chemotherapeutics and protein drugs due to poor solubility and stability, and to off-target effects that severely affect patients’ body conditions. Biocompatibility, availability of functional groups, amenability of chemical derivatisation and multifunctional conjugation with drugs and targeting ligands make polysaccharide nanoparticles interesting drug delivery devices for cancer treatment. Targeting and controlling the drug release at the tumour site are promising approaches to maximise the anti-tumour effects and reduce side-effects. Xyloglucan is a highly branched, hydrophilic polysaccharide composed of a -D-glucan main chain and -D-xylose branches, partially substituted by -D-galactoxylose. Xyloglucan extracted from tamarind seeds (TS-XG) is commercially available, non-toxic, biodegradable and FDA-approved as food additive. Due to the high molecular weight and tendency to associate in ribbon-like aggregates, aqueous colloidal dispersions of xyloglucan are characterised by relatively large nanoparticles with a broad size distribution. Gamma irradiation of either the colloidal dispersion of xyloglucan (XG) or the solid powder is a very effective and clean methodology to resize the molecular weight of the polysaccharide and reduce the particle size of its colloidal dispersions. When xyloglucan is irradiated as aqueous dispersion, irradiation causes extensive chain scission, with a dramatic reduction of molecular weight already at low doses (50-500 Gy). In contrast, when it is irradiated in the solid state, higher doses are required to change the molecular weight (20-40 kGy), with moisture playing a protective role. Selected systems have been conjugated to doxorubicin (DOX), a powerful anticancer drug that is extensively applied in the clinical treatment of human malignancies, such as leukemia and cancer of the liver, ovary and breast. This drug causes severe peripheral toxicity that poses limits to the maximum dosage that can be administered, and the emergence of multidrug resistance. DOX has been bound to irradiated XG through a cleavable bond and then further loaded with DOX by self-assembly. Xyloglucan contains galactose, which can be recognised and internalised by asialoglycoprotein receptor (ASGP-R). In order to increase the targeting efficiency, XG has been also conjugated to folic acid. Drug release efficiency and tumour cells selectivity are under investigation.