title: Delivery of siRNA targeting tumor metabolism using non-covalent PEGylated chitosan nanoparticles: Identification of an optimal combination of ligand structure, linker and grafting method.
abstract: PEGylated chitosan-based nanoparticles offer attractive platforms for siRNA cocktail delivery into tumors. Still, therapeutic efficacy requires us to select a rational combination of siRNAs and an efficient tumor delivery after systemic administration. Here, we showed that non-covalent PEGylation of chitosan-based nanoparticles loaded with siRNA targeting two key transporters of energy fuels for cancer cells, namely the lactate transporter MCT1 and the glutamine transporter ASCT2, could lead to significant antitumor effects. As a ligand, we tested variations of the prototypical RGD peptidomimetic (RGDp). A higher siRNA delivery was obtained with naphthyridine-containing RGDp randomly conjugated on the PEG chain by clip photochemistry and the use of a lipophilic linker than when using traditional chain-end grafting and RGDp with a hydrophilic linker. The antiproliferative effects resulting from ASCT2 and MCT1 silencing were validated separately in vitro in conditions mimicking specific metabolic profiles of cancer cells and in vivo upon concomitant delivery. The combination of those siRNA and the selected components of targeted RGDp nanoparticles led to a dramatic tumor growth inhibition upon peri-tumoral but also systemic administration in mice. Altogether these data emphasize the convenience of using non-covalent PEGylated chitosan particles to produce sheddable stealth protection compatible with an efficient siRNA delivery in tumors.
authors.affiliation: Université catholique de Louvain, Pole of Pharmacology and Therapeutics, Institut de Recherche Expérimentale et Clinique (IREC), 53 Avenue Mounier B1.53.09, B-1200 Brussels, Belgium.
authors.forename: Cyril
authors.initials: C
authors.lastname: Corbet
authors.affiliation: Université catholique de Louvain, Advanced Drug Delivery and Biomaterials, Louvain Drug Research Institute (LDRI), 73 Avenue Mounier B1.73.12, B-1200 Brussels, Belgium.
authors.forename: Héloïse
authors.initials: H
authors.lastname: Ragelle
authors.affiliation: Université catholique de Louvain, Molecules, Solids and Reactivity, Institute of Condensed Matter and Nanosciences (IMCN), 1 Place Louis Pasteur, L4.01.03, B-1348 Louvain-la-Neuve, Belgium.
authors.forename: Vincent
authors.initials: V
authors.lastname: Pourcelle
authors.affiliation: Université catholique de Louvain, Advanced Drug Delivery and Biomaterials, Louvain Drug Research Institute (LDRI), 73 Avenue Mounier B1.73.12, B-1200 Brussels, Belgium.
authors.forename: Kévin
authors.initials: K
authors.lastname: Vanvarenberg
authors.affiliation: Université catholique de Louvain, Molecules, Solids and Reactivity, Institute of Condensed Matter and Nanosciences (IMCN), 1 Place Louis Pasteur, L4.01.03, B-1348 Louvain-la-Neuve, Belgium.
authors.forename: Jacqueline
authors.initials: J
authors.lastname: Marchand-Brynaert
authors.affiliation: Université catholique de Louvain, Advanced Drug Delivery and Biomaterials, Louvain Drug Research Institute (LDRI), 73 Avenue Mounier B1.73.12, B-1200 Brussels, Belgium.
authors.forename: Véronique
authors.initials: V
authors.lastname: Préat
authors.affiliation: Université catholique de Louvain, Pole of Pharmacology and Therapeutics, Institut de Recherche Expérimentale et Clinique (IREC), 53 Avenue Mounier B1.53.09, B-1200 Brussels, Belgium. Electronic address: olivier.feron@uclouvain.be.
authors.forename: Olivier
authors.initials: O
authors.lastname: Feron
mesh_terms: D026962:Amino Acid Transport System ASC / Q000235:genetics; D000818:Animals; D018797:Cell Cycle Proteins / Q000235:genetics; D045744:Cell Line, Tumor; D048271:Chitosan / Q000008:administration & dosage* / Q000737:chemistry; D005260:Female; D049452:Green Fluorescent Proteins / Q000235:genetics; D006801:Humans; D008024:Ligands; D008819:Mice, Nude; D015778:Minor Histocompatibility Antigens; D015394:Molecular Structure; D053758:Nanoparticles / Q000008:administration & dosage* / Q000737:chemistry; D009369:Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism; D009842:Oligopeptides / Q000008:administration & dosage* / Q000737:chemistry; D015513:Oncogene Proteins / Q000235:genetics; D011092:Polyethylene Glycols / Q000008:administration & dosage* / Q000737:chemistry; D034741:RNA, Small Interfering / Q000008:administration & dosage* / Q000737:chemistry
chemical_list: D026962:Amino Acid Transport System ASC; D018797:Cell Cycle Proteins; D008024:Ligands; C115081:MCTS1 protein, human; D015778:Minor Histocompatibility Antigens; D009842:Oligopeptides; D015513:Oncogene Proteins; D034741:RNA, Small Interfering; C420506:SLC1A5 protein, human; C485184:enhanced green fluorescent protein; D049452:Green Fluorescent Proteins; D011092:Polyethylene Glycols; C047981:arginyl-glycyl-aspartic acid; D048271:Chitosan
keywords: Chitosan; Glutamine; Lactate; RGD peptidomimetic; SiRNA; Tumor metabolism