title: Paclitaxel-Loaded Polymersomes for Enhanced Intraperitoneal Chemotherapy.
abstract: Peritoneal carcinomatosis is present in more than 60% of gastric cancer, 40% of ovarian cancer, and 35% of colon cancer patients. It is the second most common cause of cancer-related mortality, with a median survival of 1 to 3 months. Cytoreductive surgery combined with intraperitoneal chemotherapy is the current clinical treatment, but achieving curative drug accumulation and penetration in peritoneal carcinomatosis lesions remains an unresolved challenge. Here, we used flexible and pH-sensitive polymersomes for payload delivery to peritoneal gastric (MKN-45P) and colon (CT26) carcinoma in mice. Polymersomes were loaded with paclitaxel and in vitro drug release was studied as a function of pH and time. Paclitaxel-loaded polymersomes remained stable in aqueous solution at neutral pH for up to 4 months. In cell viability assay on cultured cancer cell lines (MKN-45P, SKOV3, CT26), paclitaxel-loaded polymersomes were more toxic than free drug or albumin-bound paclitaxel (Abraxane). Intraperitoneally administered fluorescent polymersomes accumulated in malignant lesions, and immunofluorescence revealed an intense signal inside tumors with no detectable signal in control organs. A dual targeting of tumors was observed: direct (circulation-independent) penetration, and systemic, blood vessel-associated accumulation. Finally, we evaluated preclinical antitumor efficacy of paclitaxel-polymersomes in the treatment of MKN-45P disseminated gastric carcinoma using a total dose of 7 mg/kg. Experimental therapy with paclitaxel-polymersomes improved the therapeutic index of drug over free paclitaxel and Abraxane, as evaluated by intraperitoneal tumor burden and number of metastatic nodules. Our findings underline the potential utility of the polymersome platform for delivery of drugs and imaging agents to peritoneal carcinomatosis lesions. Mol Cancer Ther; 15(4); 670-9. ©2016 AACR.
authors.affiliation: Laboratory of Cancer Biology, Institute of Biomedicine, Centre of Excellence for Translational Medicine, University of Tartu, Tartu, Estonia.
authors.forename: Lorena
authors.initials: L
authors.lastname: Simón-Gracia
authors.affiliation: Laboratory of Cancer Biology, Institute of Biomedicine, Centre of Excellence for Translational Medicine, University of Tartu, Tartu, Estonia.
authors.forename: Hedi
authors.initials: H
authors.lastname: Hunt
authors.affiliation: Laboratory of Cancer Biology, Institute of Biomedicine, Centre of Excellence for Translational Medicine, University of Tartu, Tartu, Estonia. Cancer Research Center, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, California.
authors.forename: Pablo D
authors.initials: PD
authors.lastname: Scodeller
authors.affiliation: Department of Chemistry, University College London, London, United Kingdom. Department of Chemistry, University of Basel, Basel, Switzerland.
authors.forename: Jens
authors.initials: J
authors.lastname: Gaitzsch
authors.affiliation: Cancer Research Center, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, California.
authors.forename: Gary B
authors.initials: GB
authors.lastname: Braun
authors.affiliation: Laboratory of Cancer Biology, Institute of Biomedicine, Centre of Excellence for Translational Medicine, University of Tartu, Tartu, Estonia.
authors.forename: Anne-Mari A
authors.initials: AM
authors.lastname: Willmore
authors.affiliation: Cancer Research Center, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, California. Center for Nanomedicine and Department of Cell, Molecular and Developmental Biology, University of California, Santa Barbara, Santa Barbara, California.
authors.forename: Erkki
authors.initials: E
authors.lastname: Ruoslahti
authors.affiliation: Department of Chemistry, University College London, London, United Kingdom. tambet.teesalu@ut.ee g.battaglia@ucl.ac.uk.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Battaglia
authors.affiliation: Laboratory of Cancer Biology, Institute of Biomedicine, Centre of Excellence for Translational Medicine, University of Tartu, Tartu, Estonia. Cancer Research Center, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, California. tambet.teesalu@ut.ee g.battaglia@ucl.ac.uk.
authors.forename: Tambet
authors.initials: T
authors.lastname: Teesalu
mesh_terms: D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000008:administration & dosage* / Q000737:chemistry / Q000493:pharmacokinetics; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D004317:Doxorubicin / Q000008:administration & dosage; D004337:Drug Carriers / Q000737:chemistry; D004339:Drug Compounding; D065546:Drug Liberation; D004355:Drug Stability; D006801:Humans; D007274:Injections, Intraperitoneal; D051379:Mice; D017239:Paclitaxel / Q000008:administration & dosage* / Q000737:chemistry / Q000493:pharmacokinetics; D010534:Peritoneal Neoplasms / Q000188:drug therapy / Q000473:pathology; D011108:Polymers / Q000737:chemistry; D014018:Tissue Distribution; D023041:Xenograft Model Antitumor Assays
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D004337:Drug Carriers; D011108:Polymers; D004317:Doxorubicin; D017239:Paclitaxel