Gopalan Began, Ito Isao, Branch Cynthia D, Stephens Clifton, Roth Jack A, Ramesh Rajagopal
Department of Thoracic and Cardiovascular Surgery, The University of Texas, M. D. Anderson Cancer Center, 1515 Holcombe Blvd., Box 445, Houston, TX 77030, USA.
Technol Cancer Res Treat. 2004 Dec;3(6):647-57. doi: 10.1177/153303460400300615.
Cancer gene therapy for the treatment of lung cancer has shown promise in the laboratory and in Phase I/II clinical trials. However, it is currently limited to treating localized tumors due to host-immunity against the gene delivery vector and the transgene. Therefore, there is a tremendous effort to develop and test alternate gene delivery vectors that are efficient, non-immunogenic, and applicable for systemic therapy. One such gene delivery vehicle is the non-viral vector, DOTAP:cholesterol (DOTAP:Chol) nanoparticle. Preclinical studies from our laboratory has shown that DOTAP:Chol. nanoparticles are effective systemic gene delivery vectors that efficiently deliver tumor-suppressor genes to disseminated lung tumors. Based on our findings we have recently initiated a Phase-I trial for systemic treatment of lung cancer using a novel tumor suppressor gene, FUS1. Although DOTAP:Chol. nanoparticles complexed to DNA (DNA-nanoparticles) are efficient vectors for systemic therapy, induction of an inflammatory response in a dose-dependent fashion has also been observed thereby limiting its use. A better understanding of the underlying mechanism for DNA-nanoparticles-mediated inflammatory response will allow us to develop strategies to suppress inflammation and expand the therapeutic window in treating human cancer. In the present study we conducted experiments examining the mechanism of nanoparticle-mediated inflammatory response in vitro and in vivo. We demonstrate that systemic administration of DNA-nanoparticles induced multiple signaling molecules both in vitro and in vivo that are associated with inflammation. Use of small molecule inhibitors against the signaling molecules resulted in their suppression and thereby reduced inflammation without affecting transgene expression. Our results provide a rationale to use small molecule inhibitors to suppress nanoparticle-mediated inflammation when administered systemically. Further development and testing will allow us to incorporate this strategy into future clinical trials that is based on systemic non-viral vector gene therapy.
用于治疗肺癌的癌症基因疗法在实验室研究以及I/II期临床试验中已展现出前景。然而，由于宿主对基因递送载体和转基因的免疫反应，目前它仅限于治疗局部肿瘤。因此，人们付出了巨大努力来开发和测试高效、无免疫原性且适用于全身治疗的替代基因递送载体。一种这样的基因递送载体是非病毒载体DOTAP:胆固醇（DOTAP:Chol）纳米颗粒。我们实验室的临床前研究表明，DOTAP:Chol纳米颗粒是有效的全身基因递送载体，能够将肿瘤抑制基因有效递送至播散性肺肿瘤。基于我们的研究结果，我们最近启动了一项使用新型肿瘤抑制基因FUS1对肺癌进行全身治疗的I期试验。尽管与DNA复合的DOTAP:Chol纳米颗粒（DNA纳米颗粒）是全身治疗的有效载体，但也观察到其以剂量依赖方式诱导炎症反应，从而限制了其应用。更好地理解DNA纳米颗粒介导的炎症反应的潜在机制，将使我们能够制定策略来抑制炎症并扩大治疗人类癌症的治疗窗口。在本研究中，我们进行了实验以研究纳米颗粒介导的炎症反应在体外和体内的机制。我们证明，DNA纳米颗粒的全身给药在体外和体内均诱导了多种与炎症相关的信号分子。使用针对这些信号分子的小分子抑制剂导致它们被抑制，从而减轻了炎症，同时不影响转基因表达。我们的结果为全身给药时使用小分子抑制剂抑制纳米颗粒介导的炎症提供了理论依据。进一步的开发和测试将使我们能够将该策略纳入基于全身非病毒载体基因治疗的未来临床试验中。
