Delivery of siRNA targeting tumor metabolism using non-covalent PEGylated chitosan nanoparticles: Identification of an optimal combination of ligand structure, linker and grafting method

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• 作者：Cyril Corbet^a ; ¹ ; Hé ; loï ; se Ragelle^b ; ¹ ; ² ; Vincent Pourcelle^c ; ¹ ; Ké ; vin Vanvarenberg^b ; Jacqueline Marchand-Brynaert^c ; Vé ; ronique Pré ; at^b ; ³ ; Olivier Feron^a ; ³ ; ^{olivier.feron@uclouvain.be" class="auth_mail" title="E-mail the corresponding author}
• 关键词：SiRNA ; Chitosan ; RGD peptidomimetic ; Tumor metabolism ; Lactate ; Glutamine
• 刊名：Journal of Controlled Release
• 出版年：2016
• 出版时间：10 February 2016
• 年：2016
• 卷：223
• 期：Complete
• 页码：53-63
• 全文大小：1503 K

文摘

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.