BACKGROUND: Inhibition of tumor-induced angiogenesis may restrict tumor growth and metastasis. Long-term systemic delivery of angiogenic inhibitors is associated with toxicity, as well as other severe side-effects. The utility of cells as vehicles for gene therapy to deliver therapeutic molecules has been suggested to represent an efficient approach. Mesenchymal stem cells (MSCs) exhibit a tropism to cancer tissue, and may serve as a cellular delivery vehicle and a local producer of anti-angiogenic agents. METHODS: In the present study, we attempted to assess production of the transgene, α1-antitrypsin (AAT), in lentivirus-transduced human MSCs and its cytotoxicity against human umbilical cord vein endothelial cells (HUVEC). The secreted protein from these effector cells was determined by an enzyme-linked immunosorbent assay. The cytotoxicity of hMSCs that overexpress the human AAT gene against HUVEC was evaluated with an apoptotic assay. RESULTS: Lentivirus-transduced hMSCs produced functional AAT and displayed much higher cytotoxicity against HUVEC than untransduced hMSCs. Moreover, AAT secreted from transduced hMSCs significantly inhibited HUVEC proliferation compared to untransduced hMSCs. The data obtained demonstrate for the first time that genetically modified hMSCs released abundant and functional AAT that caused obvious cytotoxicity to HUVEC. CONCLUSIONS: hMSC may serve as an effective platform for the targeted delivery of therapeutic proteins to cancer sites.
BACKGROUND: Inhibition of tumor-induced angiogenesis may restrict tumor growth and metastasis. Long-term systemic delivery of angiogenic inhibitors is associated with toxicity, as well as other severe side-effects. The utility of cells as vehicles for gene therapy to deliver therapeutic molecules has been suggested to represent an efficient approach. Mesenchymal stem cells (MSCs) exhibit a tropism to cancer tissue, and may serve as a cellular delivery vehicle and a local producer of anti-angiogenic agents. METHODS: In the present study, we attempted to assess production of the transgene, α1-antitrypsin (AAT), in lentivirus-transduced human MSCs and its cytotoxicity against human umbilical cord vein endothelial cells (HUVEC). The secreted protein from these effector cells was determined by an enzyme-linked immunosorbent assay. The cytotoxicity of hMSCs that overexpress the humanAAT gene against HUVEC was evaluated with an apoptotic assay. RESULTS: Lentivirus-transduced hMSCs produced functional AAT and displayed much higher cytotoxicity against HUVEC than untransduced hMSCs. Moreover, AAT secreted from transduced hMSCs significantly inhibited HUVEC proliferation compared to untransduced hMSCs. The data obtained demonstrate for the first time that genetically modified hMSCs released abundant and functional AAT that caused obvious cytotoxicity to HUVEC. CONCLUSIONS: hMSC may serve as an effective platform for the targeted delivery of therapeutic proteins to cancer sites.
Authors: Paz de la Torre; Juan L Paris; Miguel Fernández-de la Torre; María Vallet-Regí; Ana I Flores Journal: Pharmaceutics Date: 2021-02-10 Impact factor: 6.321