title: Microvesicle- and exosome-mediated drug delivery enhances the cytotoxicity of Paclitaxel in autologous prostate cancer cells.
abstract: BACKGROUND
  Extracellular vesicles (EVs) are naturally occurring membrane particles that mediate intercellular communication by delivering molecular information between cells. In this study, we investigated the effectiveness of two different populations of EVs (microvesicle- and exosome-enriched) as carriers of Paclitaxel to autologous prostate cancer cells.
  
  
  METHODS
  EVs were isolated from LNCaP- and PC-3 prostate cancer cell cultures using differential centrifugation and characterized by electron microscopy, nanoparticle tracking analysis, and Western blot. The uptake of microvesicles and exosomes by the autologous prostate cancer cells was assessed by flow cytometry and confocal microscopy. The EVs were loaded with Paclitaxel and the effectiveness of EV-mediated drug delivery was assessed with viability assays. The distribution of EVs and EV-delivered Paclitaxel in cells was inspected by confocal microscopy.
  
  
  RESULTS
  Our main finding was that the loading of Paclitaxel to autologous prostate cancer cell-derived EVs increased its cytotoxic effect. This capacity was independent of the EV population and the cell line tested. Although the EVs without the drug increased cancer cell viability, the net effect of enhanced cytotoxicity remained. Both EV populations delivered Paclitaxel to the recipient cells through endocytosis, leading to the release of the drug from within the cells. The removal of EV surface proteins did not affect exosomes, while the drug delivery mediated by microvesicles was partially inhibited.
  
  
  CONCLUSIONS
  Cancer cell-derived EVs can be used as effective carriers of Paclitaxel to their parental cells, bringing the drug into the cells through an endocytic pathway and increasing its cytotoxicity. However, due to the increased cell viability, the use of cancer cell-derived EVs must be further investigated before any clinical applications can be designed.
authors.affiliation: Division of Pharmaceutical Biosciences, Centre for Drug Research, Faculty of Pharmacy, University of Helsinki, P.O. Box 56, Viikinkaari 5E, 00014 Helsinki, Finland.
authors.forename: Heikki
authors.initials: H
authors.lastname: Saari
authors.affiliation: Division of Pharmaceutical Biosciences, Centre for Drug Research, Faculty of Pharmacy, University of Helsinki, P.O. Box 56, Viikinkaari 5E, 00014 Helsinki, Finland.
authors.forename: Elisa
authors.initials: E
authors.lastname: Lázaro-Ibáñez
authors.affiliation: Division of Pharmaceutical Biosciences, Centre for Drug Research, Faculty of Pharmacy, University of Helsinki, P.O. Box 56, Viikinkaari 5E, 00014 Helsinki, Finland.
authors.forename: Tapani
authors.initials: T
authors.lastname: Viitala
authors.affiliation: Department of Chemistry and Bioengineering, Tampere University of Technology, P. O. Box 541, Korkeakoulunkatu 8, FI33101 Tampere, Finland.
authors.forename: Elina
authors.initials: E
authors.lastname: Vuorimaa-Laukkanen
authors.affiliation: Division of Pharmaceutical Biosciences, Centre for Drug Research, Faculty of Pharmacy, University of Helsinki, P.O. Box 56, Viikinkaari 5E, 00014 Helsinki, Finland; Division of Biochemistry and Biotechnology, Department of Biosciences, University of Helsinki, P.O. Box 56, Viikinkaari 9, 00014 Helsinki, Finland.
authors.forename: Pia
authors.initials: P
authors.lastname: Siljander
authors.affiliation: Division of Pharmaceutical Biosciences, Centre for Drug Research, Faculty of Pharmacy, University of Helsinki, P.O. Box 56, Viikinkaari 5E, 00014 Helsinki, Finland. Electronic address: marjo.yliperttula@helsinki.fi.
authors.forename: Marjo
authors.initials: M
authors.lastname: Yliperttula
mesh_terms: D000972:Antineoplastic Agents, Phytogenic / Q000008:administration & dosage / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D055252:Cell-Derived Microparticles / Q000737:chemistry / Q000378:metabolism*; D002626:Chemistry, Pharmaceutical; D004305:Dose-Response Relationship, Drug; D004337:Drug Carriers; D004705:Endocytosis; D055354:Exosomes / Q000737:chemistry / Q000378:metabolism*; D006801:Humans; D008297:Male; D053758:Nanoparticles; D017239:Paclitaxel / Q000008:administration & dosage / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D010641:Phenotype; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D013997:Time Factors
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D004337:Drug Carriers; D017239:Paclitaxel
keywords: Drug delivery; Exosomes; Extracellular vesicles; Microvesicles; Paclitaxel; Prostate cancer