title: Nanoparticle tumor localization, disruption of autophagosomal trafficking, and prolonged drug delivery improve survival in peritoneal mesothelioma.
abstract: The treatment outcomes for malignant peritoneal mesothelioma are poor and associated with high co-morbidities due to suboptimal drug delivery. Thus, there is an unmet need for new approaches that concentrate drug at the tumor for a prolonged period of time yielding enhanced antitumor efficacy and improved metrics of treatment success. A paclitaxel-loaded pH-responsive expansile nanoparticle (PTX-eNP) system is described that addresses two unique challenges to improve the outcomes for peritoneal mesothelioma. First, following intraperitoneal administration, eNPs rapidly and specifically localize to tumors. The rate of eNP uptake by tumors is an order of magnitude faster than the rate of uptake in non-malignant cells; and, subsequent accumulation in autophagosomes and disruption of autophagosomal trafficking leads to prolonged intracellular retention of eNPs. The net effect of these combined mechanisms manifests as rapid localization to intraperitoneal tumors within 4 h of injection and persistent intratumoral retention for >14 days. Second, the high tumor-specificity of PTX-eNPs leads to delivery of greater than 100 times higher concentrations of drug in tumors compared to PTX alone and this is maintained for at least seven days following administration. As a result, overall survival of animals with established mesothelioma more than doubled when animals were treated with multiple doses of PTX-eNPs compared to equivalent dosing with PTX or non-responsive PTX-loaded nanoparticles.
authors.affiliation: Department of Surgery, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
authors.forename: Rong
authors.initials: R
authors.lastname: Liu
authors.affiliation: Department of Surgery, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA; Departments of Biomedical Engineering and Chemistry, Boston University, Boston, MA, USA.
authors.forename: Aaron H
authors.initials: AH
authors.lastname: Colby
authors.affiliation: Department of Surgery, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
authors.forename: Denis
authors.initials: D
authors.lastname: Gilmore
authors.affiliation: Department of Surgery, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
authors.forename: Morgan
authors.initials: M
authors.lastname: Schulz
authors.affiliation: Departments of Biomedical Engineering and Chemistry, Boston University, Boston, MA, USA.
authors.forename: Jialiu
authors.initials: J
authors.lastname: Zeng
authors.affiliation: Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
authors.forename: Robert F
authors.initials: RF
authors.lastname: Padera
authors.affiliation: Department of Medicine, Obesity and Nutrition Section, Evans Biomedical Research Center, Boston University School of Medicine, Boston, MA, USA; Department of Clinical Biochemistry, School of Medicine, Ben Gurion University, Beer-Sheva, Israel.
authors.forename: Orian
authors.initials: O
authors.lastname: Shirihai
authors.affiliation: Departments of Biomedical Engineering and Chemistry, Boston University, Boston, MA, USA. Electronic address: mgrin@bu.edu.
authors.forename: Mark W
authors.initials: MW
authors.lastname: Grinstaff
authors.affiliation: Department of Surgery, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA. Electronic address: ycolson@partners.org.
authors.forename: Yolonda L
authors.initials: YL
authors.lastname: Colson
mesh_terms: D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000627:therapeutic use; D000071182:Autophagosomes / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D004337:Drug Carriers / Q000737:chemistry / Q000378:metabolism*; D016503:Drug Delivery Systems; D005260:Female; D006801:Humans; D008654:Mesothelioma / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D008819:Mice, Nude; D053758:Nanoparticles / Q000737:chemistry / Q000378:metabolism*; D017239:Paclitaxel / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000627:therapeutic use; D010534:Peritoneal Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D010537:Peritoneum / Q000187:drug effects / Q000378:metabolism / Q000473:pathology
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D004337:Drug Carriers; D017239:Paclitaxel
keywords: Autophagosome; Drug delivery; Mesothelioma; Nanoparticle; Paclitaxel; Tumor localization