title: Paclitaxel is incorporated by mesenchymal stromal cells and released in exosomes that inhibit in vitro tumor growth: a new approach for drug delivery.
abstract: Mesenchymal stromal cells (MSCs) have been proposed for delivering anticancer agents because of their ability to home in on tumor microenvironment. We found that MSCs can acquire strong anti-tumor activity after priming with Paclitaxel (PTX) through their capacity to uptake and then release the drug. Because MSCs secrete a high amount of membrane microvesicles (MVs), we here investigated the role of MVs in the releasing mechanism of PTX. The murine SR4987 line was used as MSC model. The release of PTX from SR4987 in the conditioned medium (CM) was checked by HPLC and the anti-tumor activity of both CM and MVs was tested on the human pancreatic cell line CFPAC-1. MVs were isolated by ultracentrifugation, analyzed by transmission (TEM) and scanning electron microscopy (SEM), and the presence of PTX by the Fourier transformed infrared (FTIR) microspectroscopy. SR4987 loaded with PTX (SR4987PTX) secreted a significant amount of PTX and their CM possessed strong anti-proliferative activity on CFPAC-1. At TEM and SEM, SR4987PTX showed an increased number of "vacuole-like" structures and shed a relevant number of MVs, but did not differ from untreated SR4987. However, SR4987PTX-derived-MVs (SR4987PTX-MVs) demonstrated a strong anti proliferative activity on CFPAC-1. FTIR analysis of SR4987PTX-MVs showed the presence of an absorption spectrum in the corresponding regions of the PTX marker, absent in MVs from SR4987. Our work is the first demonstration that MSCs are able to package and deliver active drugs through their MVs, suggesting the possibility of using MSCs as a factory to develop drugs with a higher cell-target specificity.
authors.affiliation: Department of Veterinary Medicine, University of Perugia, Italy.
authors.forename: Luisa
authors.initials: L
authors.lastname: Pascucci
authors.affiliation: Department of Biomedical, Surgical and Dental Sciences, University of Milan, Milan, Italy.
authors.forename: Valentina
authors.initials: V
authors.lastname: Coccè
authors.affiliation: Department of Biomedical, Surgical and Dental Sciences, University of Milan, Milan, Italy.
authors.forename: Arianna
authors.initials: A
authors.lastname: Bonomi
authors.affiliation: Department of Biotechnology and Biosciences, University of Milan Bicocca, Milan, Italy.
authors.forename: Diletta
authors.initials: D
authors.lastname: Ami
authors.affiliation: Department of Veterinary Medicine, University of Perugia, Italy.
authors.forename: Piero
authors.initials: P
authors.lastname: Ceccarelli
authors.affiliation: Laboratory of Clinical Pathology and Neurogenetic Medicine, Fondazione IRCCS Neurological Institute Carlo Besta, Milan, Italy.
authors.forename: Emilio
authors.initials: E
authors.lastname: Ciusani
authors.affiliation: Department of Medical Oncology, Ospedale S. Raffaele Scientific Institute, Milan ,Italy.
authors.forename: Lucia
authors.initials: L
authors.lastname: Viganò
authors.affiliation: Department of Medical Oncology, Ospedale S. Raffaele Scientific Institute, Milan ,Italy.
authors.forename: Alberta
authors.initials: A
authors.lastname: Locatelli
authors.affiliation: Department of Biomedical, Surgical and Dental Sciences, University of Milan, Milan, Italy.
authors.forename: Francesca
authors.initials: F
authors.lastname: Sisto
authors.affiliation: Department of Physics, University of Milan Bicocca, Milan, Italy.
authors.forename: Silvia Maria
authors.initials: SM
authors.lastname: Doglia
authors.affiliation: Cellular Neurobiology Laboratory, Department of Cerebrovascular Diseases, IRCCS Neurological Institute C. Besta, Milan, Italy.
authors.forename: Eugenio
authors.initials: E
authors.lastname: Parati
authors.affiliation: Department of Onco-Hematology, Children's Hospital Bambino Gesù, Roma, Italy.
authors.forename: Maria Ester
authors.initials: ME
authors.lastname: Bernardo
authors.affiliation: Laboratory Medicine, Children's Hospital Bambino Gesù, Roma, Italy.
authors.forename: Maurizio
authors.initials: M
authors.lastname: Muraca
authors.affiliation: Cellular Neurobiology Laboratory, Department of Cerebrovascular Diseases, IRCCS Neurological Institute C. Besta, Milan, Italy.
authors.forename: Giulio
authors.initials: G
authors.lastname: Alessandri
authors.affiliation: Department of Medical Biotechnology and Translational Medicine, University of Milan, Milan, Italy.
authors.forename: Gianpietro
authors.initials: G
authors.lastname: Bondiolotti
authors.affiliation: Department of Biomedical, Surgical and Dental Sciences, University of Milan, Milan, Italy. Electronic address: augusto.pessina@unimi.it.
authors.forename: Augusto
authors.initials: A
authors.lastname: Pessina
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000494:pharmacology; D002460:Cell Line; D045744:Cell Line, Tumor; D016503:Drug Delivery Systems / Q000379:methods*; D055354:Exosomes / Q000378:metabolism*; D006801:Humans; D059630:Mesenchymal Stem Cells / Q000166:cytology* / Q000378:metabolism; D051379:Mice; D009369:Neoplasms / Q000188:drug therapy* / Q000473:pathology; D017239:Paclitaxel / Q000008:administration & dosage* / Q000494:pharmacology
chemical_list: D000970:Antineoplastic Agents; D017239:Paclitaxel
keywords: Drug delivery; Exosome; Mesenchymal stromal cells; Microvesicles; Paclitaxel