MESENCHYMAL STROMAL CELLS LOADED WITH PACLITAXEL HOME TO BRAIN TUMOR AND INDUCE CYTOTOXIC DAMAGE.

The key goal in cancer chemotherapy still remains to localize the drug effect specifically in the tumor microenvironment minimizing collateral toxicity. Mesenchymal stromal cells (MSCs) have recently gained great interest as therapeutic tool, because of their unique biological features. MSCs exert their therapeutic effects by several mechanisms, including the ability to home to pathological tissues. In previous studies, we demonstrated that MSC without any genetic manipulation, uptake and release the chemotherapeutic drug Paclitaxel (PTX) in an amount enough to impair tumor growth in subcutaneous mice models (1). Here we wanted to assess if PTX-loaded MSCs have a tropism in orthotopic glioblastoma multiforme (GBM) brain xenografts. Moreover, we characterized cytotoxic effect of PTX-loaded MSCs on tumor cells. Materials and Methods We stereotactically implanted the red fluorescent GBM cell line, U87MG Cherry, and the murine GFP-labeled SR4987 BM-MSCs loaded with PTX (SR4987-GFP-PTX) in the brain of immunosuppressed rats. The two cell lines were engrafted in adjacent but different brain sites. Serial brain sections were analyzed by confocal microscopy to, a) address tumor homing of MSC-PTX cells and b) to characterize the cytotoxic damage induced by PTX released in the tumor microenvironment by loaded PTX-MSCs. Results and Discussion SR4987-GFP-PTX migrated from the injection site showing tropism toward the tumor. Notably, a significant number of cells either penetrated into or located around the tumor. Immunohistochemical detection of mitotic spindles and centrosomes revealed a remarkable increase of abnormal spindles as well as of centrosomes in the tumor exposed to SR4987-GFP-PTX. PTX released in the tumor microenvironment significantly increased the percentage of abnormal mitoses predominantly because of multispindles divisions, resulting in a dramatic increase of multinucleated tumor cells. These data demonstrate that dividing tumor cells proceeded through mitosis with abnormal spindles, resulting in chromosome mis-segregation, eventually leading cells to die. Conclusions The use of MSCs for local drug delivery has a therapeutic potentiality since a PTX-specific cytotoxic damage of brain tumors can be achieved avoiding the side effects of systemic delivery.