Synthesis of poly(1,2-glycerol carbonate)-paclitaxel conjugates and their utility as a single high-dose replacement for multi-dose treatment regimens in peritoneal cancer.

Journal: Chemical science
Published Date: Oct 20, 2017

Abstract

Current chemotherapeutic dosing strategies are limited by the toxicity of anticancer agents and therefore rely on multiple low-dose administrations. As an alternative, we describe a novel sustained-release, biodegradable polymeric nanocarrier as a single administration replacement of multi-dose paclitaxel (PTX) treatment regimens. The first synthesis of poly(1,2-glycerol carbonate)--succinic acid-paclitaxel (PGC-PTX) is described, and its use enables high, controlled PTX loadings of up to 74 wt%. Moreover, the polymer backbone is composed of biocompatible building blocks-glycerol and carbon dioxide. When formulated as nanoparticles (NPs), PGC-PTX NPs exhibit PTX concentrations >15 mg mL, sub-100 nm diameters, narrow dispersity, storage stability for up to 6 months, and sustained and controlled PTX release kinetics over an extended period of 70 days. A safely administered single dose of PGC-PTX NPs contains more PTX than the median lethal dose of standard PTX. In murine models of peritoneal carcinomatosis, in which the clinical implementation of multi-dose intraperitoneal (IP) treatment regimens is limited by catheter-related complications, PGC-PTX NPs exhibit improved safety at high doses, tumor localization, and efficacy even after a single IP injection, with comparable curative effect to PTX administered as a multi-dose IP treatment regimen.

Authors

  • Iriny Ekladious
    Departments of Biomedical Engineering and Chemistry , Boston University , Boston , MA 02215 , USA . Email: mgrin@bu.edu.
  • Rong Liu
    School of Biomedical Engineering, Dalian University of Technology, Dalian, China.
  • Heng Zhang
    Department of Gastroenterology, The Central Hospital of Wuhan, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
  • Daniel H Foil
    Department of Chemistry and Biochemistry , University of North Carolina at Greensboro , Greensboro , NC 27402 , USA.
  • Daniel A Todd
    Department of Chemistry and Biochemistry , University of North Carolina at Greensboro , Greensboro , NC 27402 , USA.
  • Tyler N Graf
    Department of Chemistry and Biochemistry , University of North Carolina at Greensboro , Greensboro , NC 27402 , USA.
  • Robert F Padera
    Department of Pathology , Brigham and Women's Hospital , Boston , MA 02215 , USA.
  • Nicholas H Oberlies
    Department of Chemistry and Biochemistry , University of North Carolina at Greensboro , Greensboro , NC 27402 , USA.
  • Yolonda L Colson
    Department of Surgery , Brigham and Women's Hospital , Boston , MA 02215 , USA . Email: ycolson@bwh.harvard.edu.
  • Mark W Grinstaff
    Departments of Biomedical Engineering and Chemistry , Boston University , Boston , MA 02215 , USA . Email: mgrin@bu.edu.

Keywords

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