A Combinatorial Approach for Targeted Delivery using Small Molecules and Reversible Masking to Bypass Non-Specific Uptake In Vivo
| Autor: | Na Cr, David D. Roberts, Yu Angell, Nguyen At, Kevin Burgess, Shi Q, Nancy Smyth Templeton, Brunicardi Fc, Deng D |
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| Jazyk: | angličtina |
| Rok vydání: | 2010 |
| Předmět: |
CD31
liposomes Vascular Endothelial Growth Factor A anti-cancer therapeutics Genetic enhancement Asialoglycoprotein Receptor Biology Transfection Article 03 medical and health sciences Mice 0302 clinical medicine In vivo reversible masking Cell Line Tumor Neoplasms Genetics tumor vascular microenvironment Animals Humans Molecular Biology Cells Cultured 030304 developmental biology 0303 health sciences Tumor microenvironment targeted delivery Endothelial Cells Genetic Therapy Molecular biology In vitro Coculture Techniques 3. Good health Cell biology Platelet Endothelial Cell Adhesion Molecule-1 Vascular endothelial growth factor A 030220 oncology & carcinogenesis Cancer cell Molecular Medicine non-viral delivery Plasmids |
| Zdroj: | Gene therapy |
| ISSN: | 1476-5462 0969-7128 |
| Popis: | We have developed a multi-disciplinary approach combining molecular biology, delivery technology, combinatorial chemistry and reversible masking to create improved systemic, targeted delivery of plasmid DNA while avoiding nonspecific uptake in vivo. We initially used a well-characterized model targeting the asialolglycoprotein receptor in the liver. Using our bilamellar invaginated vesicle (BIV) liposomal delivery system with reversible masking, we increased expression in the liver by 76-fold, nearly equaling expression in first-pass organs using non-targeted complexes, with no expression in other organs. The same technology was then applied to efficiently target delivery to a human tumor microenvironment model. We achieved efficient, targeted delivery by attachment of specific targeting ligands to the surface of our BIV complexes in conjunction with reversible masking to bypass nonspecific tissues and organs. We identified ligands that target a human tumor microenvironment created in vitro by co-culturing primary human endothelial cells with human lung or pancreatic cancer cells. The model was confirmed by increased expression of tumor endothelial phenotypes including CD31 and vascular endothelial growth factor-A, and prolonged survival of endothelial capillary-like structures. The co-cultures were used for high-throughput screening of a specialized small molecule library to identify ligands specific for human tumor-associated endothelial cells in vitro. We identified small molecules that enhanced the transfection efficiency of tumor-associated endothelial cells, but not normal human endothelial cells or cancer cells. Intravenous (i.v.) injection of our targeted, reversibly masked complexes into mice, bearing human pancreatic tumor and endothelial cells, specifically increased transfection to this tumor microenvironment approximately 200-fold. Efficacy studies using our optimized targeted delivery of a plasmid encoding thrombospondin-1 eliminated tumors completely after five i.v. injections administered once every week. |
| Databáze: | OpenAIRE |
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