title: Intratracheal administration of a nanoparticle-based therapy with the angiotensin II type 2 receptor gene attenuates lung cancer growth.
abstract: Targeted gene delivery, transfection efficiency, and toxicity concerns remain a challenge for effective gene therapy. In this study, we dimerized the HIV-1 TAT peptide and formulated a nanoparticle vector (dTAT NP) to leverage the efficiency of this cell-penetrating strategy for tumor-targeted gene delivery in the setting of intratracheal administration. Expression efficiency for dTAT NP-encapsulated luciferase or angiotensin II type 2 receptor (AT2R) plasmid DNA (pDNA) was evaluated in Lewis lung carcinoma (LLC) cells cultured in vitro or in vivo in orthotopic tumor grafts in syngeneic mice. In cell culture, dTAT NP was an effective pDNA transfection vector with negligible cytotoxicity. Transfection efficiency was further increased by addition of calcium and glucose to dTAT/pDNA NP. In orthotopic tumor grafts, immunohistochemical analysis confirmed that dTAT NP successfully delivered pDNA to the tumor, where it was expressed primarily in tumor cells along with the bronchial epithelium. Notably, gene expression in tumor tissues persisted at least 14 days after intratracheal administration. Moreover, bolus administration of dTAT NP-encapsulated AT2R or TNF-related apoptosis-inducing ligand (TRAIL) pDNA markedly attenuated tumor growth. Taken together, our findings offer a preclinical proof-of-concept for a novel gene delivery system that offers an effective intratracheal strategy for administering lung cancer gene therapy.
authors.affiliation: Department of Anatomy & Physiology, Kansas State University College of Veterinary Medicine, Manhattan, Kansas 66506, USA.
authors.forename: Atsushi
authors.initials: A
authors.lastname: Kawabata
authors.forename: Abdulgader
authors.initials: A
authors.lastname: Baoum
authors.forename: Naomi
authors.initials: N
authors.lastname: Ohta
authors.forename: Stephanie
authors.initials: S
authors.lastname: Jacquez
authors.forename: Gwi-Moon
authors.initials: GM
authors.lastname: Seo
authors.forename: Cory
authors.initials: C
authors.lastname: Berkland
authors.forename: Masaaki
authors.initials: M
authors.lastname: Tamura
mesh_terms: D000818:Animals; D018827:Carcinoma, Lewis Lung / Q000235:genetics / Q000628:therapy*; D005260:Female; D018014:Gene Transfer Techniques; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors; D020287:In Situ Nick-End Labeling; D051379:Mice; D008810:Mice, Inbred C57BL; D053758:Nanoparticles / Q000008:administration & dosage*; D060888:Real-Time Polymerase Chain Reaction; D044139:Receptor, Angiotensin, Type 2 / Q000235:genetics*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D054322:tat Gene Products, Human Immunodeficiency Virus
chemical_list: D044139:Receptor, Angiotensin, Type 2; D054322:tat Gene Products, Human Immunodeficiency Virus; C470431:tat peptide (1-72), Human immunodeficiency virus 1