title: Two-Step Delivery: Exploiting the Partition Coefficient Concept to Increase Intratumoral Paclitaxel Concentrations In vivo Using Responsive Nanoparticles.
abstract: Drug dose, high local target tissue concentration, and prolonged duration of exposure are essential criteria in achieving optimal drug performance. However, systemically delivered drugs often fail to effectively address these factors with only fractions of the injected dose reaching the target tissue. This is especially evident in the treatment of peritoneal cancers, including mesothelioma, ovarian, and pancreatic cancer, which regularly employ regimens of intravenous and/or intraperitoneal chemotherapy (e.g., gemcitabine, cisplatin, pemetrexed, and paclitaxel) with limited results. Here, we show that a "two-step" nanoparticle (NP) delivery system may address this limitation. This two-step approach involves the separate administration of NP and drug where, first, the NP localizes to tumor. Second, subsequent administration of drug then rapidly concentrates into the NP already stationed within the target tissue. This two-step method results in a greater than 5-fold increase in intratumoral drug concentrations compared to conventional "drug-alone" administration. These results suggest that this unique two-step delivery may provide a novel method for increasing drug concentrations in target tissues.
authors.affiliation: Departments of Biomedical Engineering and Chemistry, Metcalf Center for Science and Engineering, Boston University, Boston, MA 02215.|Division of Thoracic Surgery, Department of Surgery, Brigham and Women's Hospital, Boston, MA 02115.
authors.forename: Aaron H
authors.initials: AH
authors.lastname: Colby
authors.affiliation: Division of Thoracic Surgery, Department of Surgery, Brigham and Women's Hospital, Boston, MA 02115.
authors.forename: Rong
authors.initials: R
authors.lastname: Liu
authors.affiliation: Division of Thoracic Surgery, Department of Surgery, Brigham and Women's Hospital, Boston, MA 02115.
authors.forename: Morgan D
authors.initials: MD
authors.lastname: Schulz
authors.affiliation: Department of Pathology, Brigham and Women's Hospital, Boston, MA 02115.
authors.forename: Robert F
authors.initials: RF
authors.lastname: Padera
authors.affiliation: Division of Thoracic Surgery, Department of Surgery, Brigham and Women's Hospital, Boston, MA 02115.
authors.forename: Yolonda L
authors.initials: YL
authors.lastname: Colson
authors.affiliation: Departments of Biomedical Engineering and Chemistry, Metcalf Center for Science and Engineering, Boston University, Boston, MA 02215.
authors.forename: Mark W
authors.initials: MW
authors.lastname: Grinstaff
mesh_terms: D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D004337:Drug Carriers; D016503:Drug Delivery Systems; D005260:Female; D006801:Humans; D006863:Hydrogen-Ion Concentration; D057927:Hydrophobic and Hydrophilic Interactions; D008654:Mesothelioma / Q000188:drug therapy / Q000473:pathology; D051379:Mice; D053758:Nanoparticles / Q000737:chemistry; D009369:Neoplasms / Q000188:drug therapy / Q000473:pathology; D017239:Paclitaxel / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D023041:Xenograft Model Antitumor Assays
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D004337:Drug Carriers; D017239:Paclitaxel