Mesenchymal Stromal Cells Primed with Paclitaxel Provide a New Approach for Cancer Therapy

Abstract

BackgroundMesenchymal stromal cells may represent an ideal candidate to deliver anti-cancer drugs. In a previous study, we demonstrated that exposure of mouse bone marrow derived stromal cells to Doxorubicin led them to acquire anti-proliferative potential towards co-cultured haematopoietic stem cells (HSCs). We thus hypothesized whether freshly isolated human bone marrow Mesenchymal stem cells (hMSCs) and mature murine stromal cells (SR4987 line) primed in vitro with anti-cancer drugs and then localized near cancer cells, could inhibit proliferation.Methods and Principal FindingsPaclitaxel (PTX) was used to prime culture of hMSCs and SR4987. Incorporation of PTX into hMSCs was studied by using FICT-labelled-PTX and analyzed by FACS and confocal microscopy. Release of PTX in culture medium by PTX primed hMSCs (hMSCsPTX) was investigated by HPLC. Culture of Endothelial cells (ECs) and aorta ring assay were used to test the anti-angiogenic activity of hMSCsPTX and PTX primed SR4987(SR4987PTX), while anti-tumor activity was tested in vitro on the proliferation of different tumor cell lines and in vivo by co-transplanting hMSCsPTX and SR4987PTX with cancer cells in mice. Nevertheless, despite a loss of cells due to chemo-induced apoptosis, both hMSCs and SR4987 were able to rapidly incorporate PTX and could slowly release PTX in the culture medium in a time dependent manner. PTX primed cells acquired a potent anti-tumor and anti-angiogenic activity in vitro that was dose dependent, and demonstrable by using their conditioned medium or by co-culture assay. Finally, hMSCsPTX and SR4987PTX co-injected with human cancer cells (DU145 and U87MG) and mouse melanoma cells (B16) in immunodeficient and in syngenic mice significantly delayed tumor takes and reduced tumor growth.ConclusionsThese data demonstrate, for the first time, that without any genetic manipulation, mesenchymal stromal cells can uptake and subsequently slowly release PTX. This may lead to potential new tools to increase efficacy of cancer therapy.

Paclitaxel is incorporated by mesenchymal stromal cells and released in exosomes that inhibit in vitro tumor growth: A new approach for drug delivery

“…Indeed, we found that MSCs, derived from bone marrow (BM), upon in vitro exposure to very high concentrations of Paclitaxel (PTX), incorporated significant amounts of the drug that have been subsequently released in the culture medium when cells were subcultured [7]. The concentrations of PTX released in conditioned medium (CM) by MSCs were high enough to strongly inhibit cancer cell proliferation not only in vitro but also in vivo either when the PTX loaded MSCs (MSCsPTX) were co-injected with cancer cells or injected into mice bearing tumors [8].…”

Nanoparticle engineered TRAIL-overexpressing adipose-derived stem cells target and eradicate glioblastoma via intracranial delivery

“…By using stem cells as drug delivery vehicles, different biological drugs have been delivered, including chemotherapeutic agents, prodrugs (10)(11)(12)(13), and genetic signals (14). One limitation of delivering chemotherapeutic agents is that they generally could not differentiate cancerous cells from normal cells.…”

Gemcitabine-releasing mesenchymal stromal cells inhibit in vitro proliferation of human pancreatic carcinoma cells

“…The effects of GCB, MSCsGCB-CM and MSCsGCB-LYS were studied on CFPAC-1 in 96-multi-well plates (Greiner Bio-One) with the use of the 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2-H-tetrazolium (MTT) assay as previously described [19]. The inhibitory concentrations (IC 50 and IC 90 ) were determined according to the Reed and Muench formula [26].…”

“…On the basis of these data and the previous procedure developed with paclitaxel [19], we selected to prime MSCs with 2000 ng/mL for 24 h. These conditions were considered suitable for GCB and both types of MSCs because (as confirmed by the cell-cycle analysis and the PDT calculation) cell proliferation was almost completely blocked but cell viability was not substantially affected. Indeed, if primed cells were sub-cultured for 144 h after MSCsGCB-CM collection, the viability values were 75.55% AE 8.11% for BMMSCsGCB and 91.20% AE 4.53% for pMSCsGCB (Supplementary Figure S2).…”