title: Mesenchymal stromal cells loaded with paclitaxel induce cytotoxic damage in glioblastoma brain xenografts.
abstract: BACKGROUND
  The goal of cancer chemotherapy is targeting tumor cells and/or tumor-associated microvessels with the lowest systemic toxicity. Mesenchymal stromal cells (MSCs) are promising vehicles for selective drug delivery due to their peculiar ability to home to pathological tissues. We previously showed that MSCs are able to uptake and subsequently to release the chemotherapeutic compound Paclitaxel (PTX) and to impair the growth of subcutaneous glioblastoma multiforme (GBM) xenografts. Here we used an orthotopic GBM model 1) to assess whether PTX-loaded MSCs (PTX-MSCs) retain a tropism towards the tumor cells in the brain context, and 2) to characterize the cytotoxic damage induced by MSCs-driven PTX release in the tumor microenvironment.
  
  
  METHODS
  U87MG GBM cells were fluorescently labeled with the mCherry protein and grafted onto the brain of immunosuppressed rats. In adjacent brain regions, we injected green fluorescent protein-expressing murine MSCs, either loaded with PTX or unloaded. After 1 week survival, the xenografted brain was assessed by confocal microscopy for PTX-induced cell damage.
  
  
  RESULTS
  Overall, MSCs showed remarkable tropism towards the tumor. In rats grafted with PTX-MSCs, the nuclei of U87MG cells showed changes that are typically induced by PTX, including multi-spindle mitoses, centrosome number alterations, and nuclear fragmentation. Multi-spindle mitoses resulted in multinucleated cells that were significantly higher in tumors co-grafted with PTX-MSCs than in controls. Nuclear changes did not occur in astrocytes and neurons surrounding the tumor.
  
  
  CONCLUSIONS
  MSCs appear particularly suited for anti-neoplastic drug delivery in the brain since PTX-specific damage of GBM cells can be achieved avoiding side effects to the normal tissue.
authors.affiliation: Institute of Neurosurgery, Università Cattolica del Sacro Cuore, Largo Agostino Gemelli 8, 00168, Rome, Italy. simone.pacioni@ibcn.cnr.it.|CNR-Institute of Cell Biology and Neurobiology (IBCN), via del Fosso di Fiorano 64, 00143, Rome, Italy. simone.pacioni@ibcn.cnr.it.
authors.forename: Simone
authors.initials: S
authors.lastname: Pacioni
authors.affiliation: Institute of Neurosurgery, Università Cattolica del Sacro Cuore, Largo Agostino Gemelli 8, 00168, Rome, Italy. giorgiodal@hotmail.it.
authors.forename: Quintino Giorgio
authors.initials: QG
authors.lastname: D'Alessandris
authors.affiliation: Institute of Anatomy, Università Cattolica del Sacro Cuore, Largo Agostino Gemelli 8, 00168, Rome, Italy. s.giannetti@rm.unicatt.it.
authors.forename: Stefano
authors.initials: S
authors.lastname: Giannetti
authors.affiliation: Institute of Anatomy, Università Cattolica del Sacro Cuore, Largo Agostino Gemelli 8, 00168, Rome, Italy. liliana.morgante@rm.unicatt.it.
authors.forename: Liliana
authors.initials: L
authors.lastname: Morgante
authors.affiliation: Institute of Pathology, Università Cattolica del Sacro Cuore, Largo Agostino Gemelli 8, 00168, Rome, Italy. ivanadepascalis@gmail.com.
authors.forename: Ivana
authors.initials: I
authors.lastname: De Pascalis
authors.affiliation: Department of Biomedical, Surgical and Dental Sciences, University of Milan, via Pascal 36, 20133, Milan, Italy. valentina.cocce@unimi.it.
authors.forename: Valentina
authors.initials: V
authors.lastname: Coccè
authors.affiliation: Department of Biomedical, Surgical and Dental Sciences, University of Milan, via Pascal 36, 20133, Milan, Italy. arianna.bonomi@unimi.it.
authors.forename: Arianna
authors.initials: A
authors.lastname: Bonomi
authors.affiliation: Department of Veterinary Medicine, University of Perugia, via San Costanzo 4, 06126, Perugia, Italy. luisa.pascucci@unipg.it.
authors.forename: Luisa
authors.initials: L
authors.lastname: Pascucci
authors.affiliation: Department of Cerebrovascular Diseases, Fondazione IRCCS Neurological Institute Carlo Besta, via Giovanni Celoria 11, 20133, Milan, Italy. cisiamo2@yahoo.com.
authors.forename: Giulio
authors.initials: G
authors.lastname: Alessandri
authors.affiliation: Department of Biomedical, Surgical and Dental Sciences, University of Milan, via Pascal 36, 20133, Milan, Italy. augusto.pessina@unimi.it.
authors.forename: Augusto
authors.initials: A
authors.lastname: Pessina
authors.affiliation: CNR-Institute of Cell Biology and Neurobiology (IBCN), via del Fosso di Fiorano 64, 00143, Rome, Italy. marialaura.falchetti@cnr.it.
authors.forename: Maria Laura
authors.initials: ML
authors.lastname: Falchetti
authors.affiliation: Institute of Neurosurgery, Università Cattolica del Sacro Cuore, Largo Agostino Gemelli 8, 00168, Rome, Italy. pallini@rm.unicatt.it.
authors.forename: Roberto
authors.initials: R
authors.lastname: Pallini
mesh_terms: D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000008:administration & dosage* / Q000627:therapeutic use / Q000633:toxicity; D001932:Brain Neoplasms / Q000188:drug therapy*; D045744:Cell Line, Tumor; D005909:Glioblastoma / Q000188:drug therapy*; D006801:Humans; D045164:Mesenchymal Stem Cell Transplantation; D059630:Mesenchymal Stem Cells / Q000187:drug effects; D017239:Paclitaxel / Q000008:administration & dosage* / Q000627:therapeutic use / Q000633:toxicity; D051381:Rats; D017208:Rats, Wistar
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D017239:Paclitaxel