Endostatin Genetically Engineered Placental Mesenchymal Stromal Cells Carrying Doxorubicin-Loaded Mesoporous Silica Nanoparticles for Combined Chemo- and Antiangiogenic Therapy

Abstract

Combination therapies constitute a powerful tool for cancer treatment. By combining drugs with different mechanisms of action, the limitations of each individual agent can be overcome, while increasing therapeutic benefit. Here, we propose employing tumor-migrating decidua-derived mesenchymal stromal cells as therapeutic agents combining antiangiogenic therapy and chemotherapy. First, a plasmid encoding the antiangiogenic protein endostatin was transfected into these cells by nucleofection, confirming its expression by ELISA and its biological effect in an ex ovo chick embryo model. Second, doxorubicin-loaded mesoporous silica nanoparticles were introduced into the cells, which would act as vehicles for the drug being released. The effect of the drug was evaluated in a coculture in vitro model with mammary cancer cells. Third, the combination of endostatin transfection and doxorubicin-nanoparticle loading was carried out with the decidua mesenchymal stromal cells. This final cell platform was shown to retain its tumor-migration capacity in vitro, and the combined in vitro therapeutic efficacy was confirmed through a 3D spheroid coculture model using both cancer and endothelial cells. The results presented here show great potential for the development of combination therapies based on genetically-engineered cells that can simultaneously act as cellular vehicles for drug-loaded nanoparticles.

Amnion-derived hydrogels as a versatile platform for regenerative therapy: from lab to market

“…It can also happen as a result of ECM proteins, including collagen α2 (IV), laminin-1, laminin-5, fibronectin, collagen type VII, integrin 4, and integrin 6, which are known for their inhibition effect on corneal neovascularization ( Fukuda et al, 1999 ). Moreover, the amniotic cells can secrete cytokines with an anti-angiogenesis effect, such as endostatin and thrombospondin-1 ( Hossain et al, 2019 ; Bakhshandeh et al, 2021 ; de la Torre et al, 2021 ). Thrombospondin-1 is a potential anti-angiogenic peptide produced by mesenchymal cells ( Ju et al, 2022 ), whereas endostatin is an anti-angiogenesis factor that prevents the growth of endothelial cells ( Ghazani et al, 2022 ).…”

“…It can also happen as a result of ECM proteins, including collagen α2 (IV), laminin-1, laminin-5, fibronectin, collagen type VII, integrin 4, and integrin 6, which are known for their inhibition effect on corneal neovascularization (Fukuda et al, 1999). Moreover, the amniotic cells can secrete cytokines with an anti-angiogenesis effect, such as endostatin and thrombospondin-1 (Hossain et al, 2019;Bakhshandeh et al, 2021;de la Torre et al, 2021).…”

Mesoporous silicas in materials engineering: Nanodevices for bionanotechnologies

“…Mesenchymal stromal cells (MSC) have been proposed as alternative cancer-targeting agents due to their capacity to selectively and actively migrate to tumors in addition to their safety profile. This approach has been adopted by Flores and collaborators [ 177 ] that chose MSC derived from the decidua (DMSC) of human placenta that show target ability to cancer well as an intrinsic anticancer activity. Specifically, authors engineered DMSC to produce the antiangiogenic protein endostatin and simultaneously carry Dox-loaded MSNs for combined chemo- and antiangiogenic therapy.…”

Nanofunctionalized Microparticles for Glucose Delivery in Three-Dimensional Cell Assemblies

“…In tissue engineering applications, MSNs have been utilized to function as delivery vehicles and as part of matrix-mimicking scaffolding biomaterials, at the same time . However, the use of MSNs in combination with cell spheroids has mostly been limited to cancer nanomedicine, − as they can release anticancer drugs intracellularly .…”