Extracellular Vesicles Derived from Human Umbilical Cord Mesenchymal Stromal Cells as an Efficient Nanocarrier to Deliver siRNA or Drug to Pancreatic Cancer Cells

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal cancers worldwide. Treatment of PDAC remains a major challenge. This study aims to evaluate, in vitro, the use of human umbilical cord mesenchymal stromal cell (UC-MSC)-derived EVs to specifically target pancreatic cancer cells. EVs were isolated from the FBS-free supernatants of the cultured UC-MSCs by ultracentrifugation and characterized by several methods. EVs were loaded with scramble or KRASG12D-targeting siRNA by electroporation. The effects of control and loaded EVs on different cell types were evaluated by assessing cell proliferation, viability, apoptosis and migration. Later, the ability of EVs to function as a drug delivery system for doxorubicin (DOXO), a chemotherapeutic drug, was also evaluated. Loaded EVs exhibited different kinetic rates of uptake by three cell lines, namely, BxPC-3 cells (pancreatic cancer cell line expressing KRASwt), LS180 cells (colorectal cell line expressing KRASG12D) and PANC-1 cells (pancreatic cell line expressing KRASG12D). A significant decrease in the relative expression of the KRASG12D gene after incubation with KRAS siRNA EVs was observed by real-time PCR. KRASG12D siRNA EVs significantly reduced the proliferation, viability and migration of the KRASG12D cell lines compared to scramble siRNA EVs. An endogenous EV production method was applied to obtain DOXO-loaded EVs. Briefly, UC-MSCs were treated with DOXO. After 24 h, UC-MSCs released DOXO-loaded EVs. DOXO-loaded EVs were rapidly taken up by PANC-1 cells and induced apoptotic cell death more efficiently than free DOXO. In conclusion, the use of UC-MSC-derived EVs as a drug delivery system for siRNAs or drugs could be a promising approach for the targeted treatment of PDAC.

Treatment of medication-related osteonecrosis of the jaw with cell therapy

“…Several roles have been attributed to EVs, such as signalosomes, biomarkers, and therapeutic agents (El Andaloussi et al, 2023). Furthermore, EVs have emerged as a novel drug delivery vehicle (Draguet et al, 2023b). Dong et al and Zheng et al recently evaluated the potential contribution of EVs in MRONJ (Dong et al, 2021;Zheng et al, 2023) (Dong et al, 2021).…”

Unveiling the Potential of Extracellular Vesicles as Biomarkers and Therapeutic Nanotools for Gastrointestinal Diseases

“…Additionally, HUCMSC-derived exosomes were loaded with KRAS G12D targeting siRNA via electroporation. This combination resulted in the reduced proliferation, migration, and viability of the KRAS G12D -PANC-1 cell line [ 148 ]. In the same study, Draguet et al further investigated the endogenous loading of HUCMSC-EVs with doxorubicin (DOXO).…”

“…They discovered that the rapid uptake of these loaded EVs in PANC-1 cells induced apoptotic cell death more efficiently than free DOXO. Their findings suggest that both methods could serve as effective therapeutic vehicles for delivering DOXO to PC cells [ 148 ]. S. Araujo-Abad et al utilized small EVs derived from the RWP-1 cell line and loaded them with two chemotherapeutic drugs, temozolomide or EPZ015666, aiming to enhance the effectiveness of chemotherapy for treating PDAC, the most common aggressive form of PC.…”

Mesenchymal Stem Cell-Derived Extracellular Vesicles in Cancer Therapy Resistance: from Biology to Clinical Opportunity

“…These findings offer promising prospects for the development of novel therapeutic strategies for osteosarcoma. Furthermore, various RNA species, including mRNAs, siRNAs, and lncRNAs, have been incorporated into the delivery strategies of MSC-EVs for anti-cancer purposes 8 , 119 - 121 . Ongoing research in this area is yielding promising results, and the successful delivery of these RNA molecules via MSC-EVs holds the potential to inform future approaches to cancer therapy.…”