title: Nanoparticle based systemic gene therapy for lung cancer: molecular mechanisms and strategies to suppress nanoparticle-mediated inflammatory response.
abstract: 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.
authors.affiliation: Department of Thoracic and Cardiovascular Surgery, The University of Texas, M. D. Anderson Cancer Center, 1515 Holcombe Blvd., Box 445, Houston, TX 77030, USA.
authors.forename: Began
authors.initials: B
authors.lastname: Gopalan
authors.forename: Isao
authors.initials: I
authors.lastname: Ito
authors.forename: Cynthia D
authors.initials: CD
authors.lastname: Branch
authors.forename: Clifton
authors.initials: C
authors.lastname: Stephens
authors.forename: Jack A
authors.initials: JA
authors.lastname: Roth
authors.forename: Rajagopal
authors.initials: R
authors.lastname: Ramesh
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology / Q000627:therapeutic use; D002460:Cell Line; D015232:Dinoprostone / Q000378:metabolism; D005260:Female; D015870:Gene Expression; D015316:Genetic Therapy / Q000009:adverse effects*; D006801:Humans; D007249:Inflammation / Q000139:chemically induced* / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D008175:Lung Neoplasms / Q000235:genetics* / Q000276:immunology / Q000378:metabolism / Q000628:therapy*; D051379:Mice; D049329:Nanostructures / Q000009:adverse effects*; D009288:Naproxen / Q000494:pharmacology / Q000627:therapeutic use; D034702:RNA-Binding Protein FUS; D015398:Signal Transduction / Q000187:drug effects; D018808:Transcription Factor AP-1 / Q000378:metabolism; D019076:Transgenes / Q000235:genetics
chemical_list: D000893:Anti-Inflammatory Agents; D034702:RNA-Binding Protein FUS; D018808:Transcription Factor AP-1; D009288:Naproxen; D015232:Dinoprostone