Microvesicle-Mediated Delivery of Minicircle DNA Results in Effective Gene-Directed Enzyme Prodrug Cancer Therapy
| Autor: | Victoria Toomajian, Christopher H. Contag, Gloria I. Perez, Matthew P. Bernard, Bryan D. Kim, Jonathan Hardy, John A. Ronald, Alicia Withrow, Masamitsu Kanada, Sherif Abd El-Fattah Ibrahim, T. Jessie Ge, Ramasamy Paulmurugan, Sanjiv S. Gambhir, Ahmed A. Zarea, Michael Bachmann |
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| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
Cancer Research Transgene Minicircle Transfection Article 03 medical and health sciences Mice 0302 clinical medicine Animals Humans Prodrugs Chemistry Microvesicle DNA Genetic Therapy Prodrug Fusion protein Microvesicles 030104 developmental biology Oncology Thymidine kinase 030220 oncology & carcinogenesis Cancer research Female |
| Zdroj: | Mol Cancer Ther |
| ISSN: | 1538-8514 |
| Popis: | An emerging approach for cancer treatment employs the use of extracellular vesicles, specifically exosomes and microvesicles, as delivery vehicles. We previously demonstrated that microvesicles can functionally deliver plasmid DNA to cells and showed that plasmid size and sequence, in part, determine the delivery efficiency. In this study, delivery vehicles comprised of microvesicles loaded with engineered minicircle (MC) DNA that encodes prodrug converting enzymes developed as a cancer therapy in mammary carcinoma models. We demonstrated that MCs can be loaded into shed microvesicles with greater efficiency than their parental plasmid counterparts and that microvesicle-mediated MC delivery led to significantly higher and more prolonged transgene expression in recipient cells than microvesicles loaded with the parental plasmid. Microvesicles loaded with MCs encoding a thymidine kinase (TK)/nitroreductase (NTR) fusion protein produced prolonged TK-NTR expression in mammary carcinoma cells. In vivo delivery of TK-NTR and administration of prodrugs led to the effective killing of both targeted cells and surrounding tumor cells via TK-NTR–mediated conversion of codelivered prodrugs into active cytotoxic agents. In vivo evaluation of the bystander effect in mouse models demonstrated that for effective therapy, at least 1% of tumor cells need to be delivered with TK-NTR–encoding MCs. These results suggest that MC delivery via microvesicles can mediate gene transfer to an extent that enables effective prodrug conversion and tumor cell death such that it comprises a promising approach to cancer therapy. |
| Databáze: | OpenAIRE |
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