Integrin-targeted nanocomplexes for tumour specific delivery and therapy by systemic administration
Integrin-targeted nanocomplexes for tumour specific delivery and therapy by systemic administration
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DOI：
10.1016/j.biomaterials.2010.10.037
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发表时间：
2011-02-01
期刊：
影响因子：
14
通讯作者：
Hart, Stephen L.
中科院分区：
文献类型：
--
作者：
Tagalakis, Aristides D.;Grosse, Stephanie M.;Hart, Stephen L.
纳米颗粒制剂为治疗试剂的肿瘤递送提供了机会。受体靶向纳米复合物（RTN）制剂由PEG化的内体可裂解脂质和RGD整联蛋白靶向的内体可裂解肽组成。纳米复合物在与质粒DNA混合时自组装以产生约100 nm的纳米颗粒。环境敏感的接头促进DNA的细胞内分解和释放。将携带荧光素酶基因的RTN静脉内给予携带皮下神经母细胞瘤肿瘤的小鼠。荧光素酶在肿瘤中的表达比在肝、脾和肺中高得多，而质粒生物分布研究支持表达数据。与非靶向纳米复合物相比，整合素靶向肽使肿瘤中的转染增强两倍。RTNs含有白细胞介素-2（IL-2）和IL-12基因静脉内给予7剂，间隔48小时，并监测肿瘤生长。与含有对照质粒的RTNs相比，第11天来自治疗动物的肿瘤约小75%，其中三分之一的治疗小鼠长期存活。在IL 2/IL 12治疗的动物的肿瘤中观察到广泛的白细胞浸润、血管形成减少和坏死面积增加。在Neuro-2A共培养后，来自再激发小鼠的脾细胞显示出增强的IL-2产生，这与浸润研究相结合，表明了细胞毒性T细胞介导的9肿瘤排斥过程。整合素靶向RTN制剂可能在癌症治疗剂的进一步开发中具有更广泛的应用。(C)2010爱思唯尔有限公司版权所有。
Nanoparticle formulations offer opportunities for tumour delivery of therapeutic reagents. The Receptor-Targeted Nanocomplex (RTN) formulation consists of a PEGylated, endosomally-cleavable lipid and an RGD integrin-targeting, endosomally-cleavable peptide. Nancomplexes self-assemble on mixing with plasmid DNA to produce nanoparticles of about 100 nm. The environmentally-sensitive linkers promote intracellular disassembly and release of the DNA. RTNs carrying luciferase genes were administered intravenously to mice carrying subcutaneous neuroblastoma tumours. Luciferase expression was much higher in tumours than in liver, spleen and lungs while plasmid biodistribution studies supported the expression data. Transfection in tumours was enhanced two-fold by integrin-targeting peptides compared to non-targeted nanocomplexes. RTNs containing the interleukin-2 (IL-2) and IL-12 genes were administered intravenously with seven doses at 48 h intervals and tumour growth monitored. Tumours from treated animals were approximately 75% smaller on day 11 compared with RTNs containing control plasmids with one third of treated mice surviving long-term. Extensive leukocyte infiltration, decreased vascularization and increased necrotic areas were observed in the tumours from IL2/IL12 treated animals. Splenocytes from re-challenged mice displayed enhanced IL-2 production following Neuro-2A co-culture, which, combined with infiltration studies, suggested a cytotoxic T cell-mediated9 tumour-rejection process. The integrin-targeted RTN formulation may have broader applications in the further development of cancer therapeutics. (C) 2010 Elsevier Ltd. All rights reserved.