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Issue 12, 2017
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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

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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)-graft-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−1, 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.

Graphical abstract: 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

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Publication details

The article was received on 10 Aug 2017, accepted on 18 Oct 2017 and first published on 20 Oct 2017


Article type: Edge Article
DOI: 10.1039/C7SC03501B
Citation: Chem. Sci., 2017,8, 8443-8450
  • Open access: Creative Commons BY license
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    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

    I. Ekladious, R. Liu, H. Zhang, D. H. Foil, D. A. Todd, T. N. Graf, R. F. Padera, N. H. Oberlies, Y. L. Colson and M. W. Grinstaff, Chem. Sci., 2017, 8, 8443
    DOI: 10.1039/C7SC03501B

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