title: Combined Local Pulmonary and Systemic Delivery of AT2R Gene by Modified TAT Peptide Nanoparticles Attenuates Both Murine and Human Lung Carcinoma Xenografts in Mice.
abstract: To evaluate the potential of cell-penetrating peptide-based delivery of apoptosis-inducer gene in cancer therapy, a modified HIV-1 TAT peptide (dimerized TAT peptide, dTAT) was studied. The dTAT and plasmid DNA (pDNA) complexes (dTAT-pDNA) were condensed using calcium chloride (dTAT-pDNA-Ca2+). This simple nonviral formulation approach showed high levels of gene expression in vitro without any cytotoxicity. In mouse studies, a single intratracheal (IT) aerosol spray or 2 intravenous (IV) injections of the dTAT, apoptosis-inducer gene, angiotensin II type 2 receptor (AT2R), and Ca2+complexes (dTAT-pAT2R-Ca2+) significantly attenuated the acutely growing mouse Lewis lung carcinoma allografts in mouse lungs. Furthermore, single IT (p = 0.054) and the combination of IT and IV (p < 0.05) administrations of dTAT-pAT2R-Ca2+markedly attenuated slowly growing and relatively large-sized H358 human bronchioloalveolar carcinoma xenografts in mouse lungs. These results indicate that the dTAT-pDNA-Ca2+effectively delivered the gene to cancer cells by either IT or IV administration although the local pulmonary delivery of the dTAT-pAT2R-Ca2+showed more effective growth inhibition of orthotopic lung cancer grafts. Thus, the present study offers preclinical proof of concept that a dTAT-based nonviral gene delivery method via IT administration may be an effective lung cancer gene therapy.
authors: Department of Anatomy and Physiology, College of Veterinary Medicine, Kansas State University, Manhattan, Kansas 66506.
authors: Susumu
authors: S
authors: Ishiguro
authors: Department of Pharmaceutical Chemistry, University of Kansas, Lawrence, Kansas 66047.
authors: Nabil A
authors: NA
authors: Alhakamy
authors: Department of Anatomy and Physiology, College of Veterinary Medicine, Kansas State University, Manhattan, Kansas 66506.
authors: Deepthi
authors: D
authors: Uppalapati
authors: Department of Anatomy and Physiology, College of Veterinary Medicine, Kansas State University, Manhattan, Kansas 66506.
authors: Jennifer
authors: J
authors: Delzeit
authors: Department of Pharmaceutical Chemistry, University of Kansas, Lawrence, Kansas 66047; Department of Chemical and Petroleum Engineering, University of Kansas, Lawrence, Kansas 66047.
authors: Cory J
authors: CJ
authors: Berkland
authors: Department of Anatomy and Physiology, College of Veterinary Medicine, Kansas State University, Manhattan, Kansas 66506. Electronic address: mtamura@vet.ksu.edu.
authors: Masaaki
authors: M
authors: Tamura
mesh_terms: D000818:Animals; D018827:Carcinoma, Lewis Lung / Q000235:genetics / Q000628:therapy*; D045744:Cell Line, Tumor; D004247:DNA / Q000008:administration & dosage* / Q000235:genetics / Q000627:therapeutic use; D015870:Gene Expression; D018014:Gene Transfer Techniques; D015316:Genetic Therapy; D015497:HIV-1 / Q000737:chemistry; D006801:Humans; D008168:Lung / Q000378:metabolism / Q000473:pathology; D008175:Lung Neoplasms / Q000235:genetics / Q000473:pathology / Q000628:therapy*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D016513:Mice, SCID; D053758:Nanoparticles / Q000737:chemistry*; D010957:Plasmids / Q000008:administration & dosage / Q000235:genetics / Q000627:therapeutic use; D044139:Receptor, Angiotensin, Type 2 / Q000235:genetics*; D054322:tat Gene Products, Human Immunodeficiency Virus / Q000737:chemistry*
chemical_list: D044139:Receptor, Angiotensin, Type 2; D054322:tat Gene Products, Human Immunodeficiency Virus; D004247:DNA
keywords: angiotensin II type 2 receptor; apoptosis; dTAT peptide; lung cancer; nanoparticles; nonviral gene delivery