title: Cytoreductive surgery and intraoperative administration of paclitaxel-loaded expansile nanoparticles delay tumor recurrence in ovarian carcinoma.
abstract: BACKGROUND
  Locoregional recurrence significantly impacts survival and quality of life in patients with ovarian carcinoma. We hypothesize that local administration of paclitaxel-loaded expansile nanoparticles (pax-eNP) at the time of cytoreductive surgery decreases local tumor recurrence.
  
  
  METHODS
  In vitro cytotoxicity of pax-eNP was assessed against both the OVCAR-3 human ovarian cancer cell line and tumor cells isolated from a malignant pleural effusion from a patient with multidrug-resistant ovarian cancer. A murine xenogenic model involving surgical cytoreduction of established OVCAR-3 intra-abdominal tumor was used to evaluate in vivo efficacy of intraoperative intraperitoneal (IP) injection of 10 mg/kg of paclitaxel either as pax-eNP or paclitaxel in Cremophor EL/ethanol solution (pax-C/E) versus empty eNP controls. Cytoreductive surgery and intraoperative treatment were performed 4 weeks after established tumor. All animals were sacrificed when empty eNP controls displayed extensive evidence of disease progression.
  
  
  RESULTS
  Labeled-eNP entered tumor cells in vitro within 4 h and specifically accumulated at sites of tumor in vivo. Pax-eNP exhibited dose-dependent cytotoxicity in both OVCAR-3 and patient tumor cells isolated from a malignant pleural effusion and effectively prevented tumor recurrence following debulking (p = 0.003 vs. empty eNP). Furthermore, pax-eNP-treated animals did not develop severe recurrent carcinomatosis compared with 43 % of the pax-C/E-treated cohort, suggesting that single-dose intracavitary pax-eNP is more effective than an equivalent dose of pax-C/E.
  
  
  CONCLUSIONS
  Expansile nanoparticles readily enter human ovarian tumor cells and localize to sites of tumor in vivo with pax-eNP cytotoxicity resulting in superior inhibition of locoregional tumor recurrence following cytoreductive surgery.
authors.affiliation: Division of Thoracic Surgery, Department of Surgery, Brigham and Women's Hospital, Boston, MA, USA. dgilmor1@bidmc.harvard.edu
authors.forename: Denis
authors.initials: D
authors.lastname: Gilmore
authors.forename: Morgan
authors.initials: M
authors.lastname: Schulz
authors.forename: Rong
authors.initials: R
authors.lastname: Liu
authors.forename: Kimberly Ann V
authors.initials: KA
authors.lastname: Zubris
authors.forename: Robert F
authors.initials: RF
authors.lastname: Padera
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Catalano
authors.forename: Mark W
authors.initials: MW
authors.lastname: Grinstaff
authors.forename: Yolonda L
authors.initials: YL
authors.lastname: Colson
mesh_terms: D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000008:administration & dosage* / Q000494:pharmacology; D002277:Carcinoma / Q000188:drug therapy* / Q000601:surgery; D045744:Cell Line, Tumor; D002463:Cell Membrane Permeability; D002470:Cell Survival / Q000187:drug effects; D004337:Drug Carriers; D000431:Ethanol; D005260:Female; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D053758:Nanoparticles; D009364:Neoplasm Recurrence, Local / Q000517:prevention & control*; D009368:Neoplasm Transplantation; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000601:surgery; D017239:Paclitaxel / Q000008:administration & dosage* / Q000494:pharmacology; D014677:Pharmaceutical Vehicles; D011092:Polyethylene Glycols
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D004337:Drug Carriers; D014677:Pharmaceutical Vehicles; C022131:cremophor; D000431:Ethanol; D011092:Polyethylene Glycols; D017239:Paclitaxel