Synthesis and in vivo anticancer evaluation of poly(organo)phosphazene-based metallodrug conjugates

Dalton Trans. 2017 Sep 28;46(36):12114-12124. doi: 10.1039/c7dt01767g. Epub 2017 Sep 1.

Abstract

Within this work we aimed to improve the pharmacodynamics and toxicity profile of organoruthenium and -rhodium complexes which had previously been found to be highly potent in vitro but showed unselective activity in vivo. Different organometallic complexes were attached to a degradable poly(organo)phosphazene macromolecule, prepared via controlled polymerization techniques. The conjugation to hydrophilic polymers was designed to increase the aqueous solubility of the typically poorly soluble metal-based half-sandwich compounds with the aim of a controlled, pH-triggered release of the active metallodrug. The synthesized conjugates and their characteristics have been thoroughly studied by means of 31P NMR and UV-Vis spectroscopy, ICP-MS analyses and SEC coupled to ICP-MS. In order to assess their potential as possible anticancer drug candidates, the complexes, as well as their respective macromolecular prodrug formulations were tested against three different cancer cell lines in cell culture. Subsequently, the anticancer activity and organ distribution of the poly(organo)phosphazene drug conjugates were explored in vivo in mice bearing CT-26 colon carcinoma. Our investigations revealed a beneficial influence of this macromolecular prodrug by a significant reduction of adverse effects compared to the free metallodrugs.

MeSH terms

  • Animals
  • Antineoplastic Agents / chemical synthesis*
  • Antineoplastic Agents / pharmacokinetics
  • Antineoplastic Agents / therapeutic use
  • Cell Line, Tumor
  • Cell Survival / drug effects
  • Colonic Neoplasms / drug therapy
  • Colonic Neoplasms / pathology
  • Coordination Complexes / chemical synthesis
  • Coordination Complexes / pharmacokinetics
  • Coordination Complexes / therapeutic use
  • Drug Carriers / chemistry
  • Drug Liberation
  • Female
  • Humans
  • Mice
  • Mice, Inbred BALB C
  • Mice, Inbred C57BL
  • Organophosphorus Compounds / chemistry*
  • Polymers / chemistry*
  • Prodrugs / chemical synthesis
  • Prodrugs / pharmacology
  • Prodrugs / therapeutic use
  • Rhodium / chemistry*
  • Tissue Distribution
  • Transplantation, Heterologous

Substances

  • Antineoplastic Agents
  • Coordination Complexes
  • Drug Carriers
  • Organophosphorus Compounds
  • Polymers
  • Prodrugs
  • poly(phosphazene)
  • Rhodium