AT2R Gene Delivered by Condensed Polylysine Complexes Attenuates Lewis Lung Carcinoma after Intravenous Injection or Intratracheal Spray
Autor: | Masaaki Tamura, Susumu Ishiguro, Cory Berkland, Nabil A. Alhakamy, Deepthi Uppalapati |
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Jazyk: | angličtina |
Rok vydání: | 2015 |
Předmět: |
0301 basic medicine
Male Cancer Research Cell Survival Genetic enhancement Gene Expression Apoptosis Gene delivery Transfection Receptor Angiotensin Type 2 Article 03 medical and health sciences Carcinoma Lewis Lung Mice 0302 clinical medicine Cell Line Tumor medicine Animals Humans Polylysine Lung cancer Cell Proliferation Drug Carriers Chemistry Gene Transfer Techniques Lewis lung carcinoma Cancer Genetic Therapy medicine.disease Allografts Xenograft Model Antitumor Assays Tumor Burden Disease Models Animal 030104 developmental biology Oncology Cell culture 030220 oncology & carcinogenesis Immunology Cancer cell Injections Intravenous Cancer research Calcium Imines Polyethylenes Plasmids |
Popis: | Transfection efficiency and toxicity concerns remain a challenge for gene therapy. Cell-penetrating peptides (CPP) have been broadly investigated to improve the transfection of genetic material (e.g., pDNA and siRNA). Here, a synthetic CPP (polylysine, K9 peptide) was complexed with angiotensin II type 2 receptor (AT2R) plasmid DNA (pAT2R) and complexes were condensed using calcium chloride. The resulting complexes were small (∼150 nm) and showed high levels of gene expression in vitro and in vivo. This simple nonviral formulation approach showed negligible cytotoxicity in four different human cell lines (cervix, breast, kidney, and lung cell lines) and one mouse cell line (a lung cancer cell line). In addition, this K9-pDNA-Ca2+ complex demonstrated cancer-targeted gene delivery when administered via intravenous injection or intratracheal spray. The transfection efficiency was evaluated in Lewis lung carcinoma (LLC) cell lines cultured in vitro and in orthotopic cancer grafts in syngeneic mice. Immunohistochemical analysis confirmed that the complex effectively delivered pAT2R to the cancer cells, where it was expressed mainly in cancer cells along with bronchial epithelial cells. A single administration of these complexes markedly attenuated lung cancer growth, offering preclinical proof-of-concept for a novel nonviral gene delivery method exhibiting effective lung tumor gene therapy via either intravenous or intratracheal administration. Mol Cancer Ther; 15(1); 209–18. ©2015 AACR. |
Databáze: | OpenAIRE |
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