A novel nitric oxide-based anticancer therapeutics by macrophage-targeted poly(l-arginine)-based nanoparticles

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• 作者：Shinpei Kudo^a ; Yukio Nagasaki^a ; ^b ; ^c ; ^{yukio@nagalabo.jp" class="auth_mail" title="E-mail the corresponding author}
• 关键词：Macrophage ; Anti-cancer immunotherapy ; Inducible nitric oxide synthase (iNOS) ; Nitric oxide (NO) ; Poly (l-arginine) ; Polyion complex (PIC) micelle
• 刊名：Journal of Controlled Release
• 出版年：2015
• 出版时间：10 November 2015
• 年：2015
• 卷：217
• 期：Complete
• 页码：256-262
• 全文大小：635 K

文摘

In the immune system, macrophages in tumor tissue generate nitric oxide (NO), producing versatile effects including apoptosis of tumor cells, because inducible NO synthase (iNOS) in the cytoplasm of a macrophage produces NO using l-arginine as a substrate. Here, we propose novel NO-triggered immune therapeutics based on our newly designed nanoparticle system. We designed a poly(ethylene glycol)-block-poly(l-arginine) (i.e., PEG-b-P(l-Arg)) block copolymer and prepared polyion complex micelles (PEG-b-P(l-Arg)/m) composed of PEG-b-P(l-Arg) and chondroitin sulfate for systemic anticancer immunotherapy. iNOS treatment of PEG-b-P(l-Arg) did not generate NO, but NO molecules were detected after trypsin pretreatment, indicating that hydrolysis of P(l-Arg) to monomeric arginine was taking place in vitro. RAW264.7 macrophages abundantly generated NO from the PEG-b-P(l-Arg)/m in comparison with control micelles; this finding is indicative of robustness of the proposed method. It is interesting to note that systemic administration of PEG-b-P(l-Arg)/m had no noticeable adverse effects and suppressed the tumor growth rate in C26 tumor-bearing mice in a dose-dependent manner. Our newly designed nanoparticle-assisted arginine delivery system seems to hold promise as an NO-mediated anticancer immunotherapy.