Podesta Jennifer E, Al-Jamal Khuloud T, Herrero M Antonia, Tian Bowen, Ali-Boucetta Hanene, Hegde Vikas, Bianco Alberto, Prato Maurizio, Kostarelos Kostas
Centre for Drug Delivery Research The School of Pharmacy, University of London, UK.
Small. 2009 May;5(10):1176-85. doi: 10.1002/smll.200801572.
Carbon nanotubes are novel nanomaterials that are thought to offer potential benefits to a variety of biomedical and clinical applications. In this study, the treatment of a human lung carcinoma model in vivo using siRNA sequences leading to cytotoxicity and cell death is carried out using either cationic liposomes (DOTAP:cholesterol) or amino-functionalized multi-walled carbon nanotubes (MWNT - NH(+)(3)). Validation for the most cytotoxic siRNA sequence using a panel of human carcinoma and murine cells reveals that the proprietary siTOX sequence is human specific and can lead to significant cytotoxic activities delivered both by liposome or MWNT - NH(+)(3) in vitro. A comparative study using both types of vector indicates that only MWNT - NH(+)(3):siRNA complexes administered intratumorally can elicit delayed tumor growth and increased survival of xenograft-bearing animals. siTOX delivery via the cationic MWNT - NH(+)(3) is biologically active in vivo by triggering an apoptotic cascade, leading to extensive necrosis of the human tumor mass. This suggests that carbon-nanotube-mediated delivery of siRNA by intratumoral administration leads to successful and statistically significant suppression of tumor volume, followed by a concomitant prolongation of survival of human lung tumor-bearing animals. The direct comparison between carbon nanotubes and liposomes demonstrates the potential advantages offered by carbon nanotubes for the intracellular delivery of therapeutic agents in vivo. The present work may act as the impetus for further studies to explore the therapeutic capacity of chemically functionalized carbon nanotubes to deliver siRNA directly into the cytoplasm of target cells and achieve effective therapeutic silencing in various disease indications where local delivery is feasible or desirable.
碳纳米管是新型纳米材料，被认为对多种生物医学和临床应用具有潜在益处。在本研究中，使用导致细胞毒性和细胞死亡的siRNA序列，通过阳离子脂质体（DOTAP：胆固醇）或氨基功能化多壁碳纳米管（MWNT - NH(+)(3)）对人肺癌模型进行体内治疗。使用一组人癌细胞和鼠细胞对最具细胞毒性的siRNA序列进行验证，结果表明专利siTOX序列具有人特异性，并且在体外通过脂质体或MWNT - NH(+)(3)递送时均可导致显著的细胞毒性活性。使用这两种载体的比较研究表明，仅瘤内注射MWNT - NH(+)(3)：siRNA复合物可引发异种移植动物肿瘤生长延迟并提高其存活率。通过阳离子MWNT - NH(+)(3)递送siTOX在体内具有生物活性，可触发凋亡级联反应，导致人肿瘤块广泛坏死。这表明通过瘤内给药碳纳米管介导的siRNA递送可成功且在统计学上显著抑制肿瘤体积，进而延长荷人肺癌动物的存活期。碳纳米管与脂质体之间的直接比较证明了碳纳米管在体内细胞内递送治疗剂方面的潜在优势。本研究可能为进一步探索化学功能化碳纳米管将siRNA直接递送至靶细胞细胞质并在局部递送可行或理想的各种疾病适应症中实现有效治疗性沉默的治疗能力提供动力。
