In vivo comparative study of distinct polymeric architectures bearing a combination of paclitaxel and doxorubicin at a synergistic ratio

J Control Release. 2017 Jul 10:257:118-131. doi: 10.1016/j.jconrel.2016.06.037. Epub 2016 Jun 30.

Abstract

Nowadays, combination therapy became a standard in oncology. In this study, we compare the activity of two polymeric carriers bearing a combination of the anticancer drugs paclitaxel (PTX) and doxorubicin (DOX), which differ mainly in their architecture and supramolecular assembly. Drugs were covalently bound to a linear polymer, polyglutamic acid (PGA) or to a dendritic scaffold, polyglycerol (PG) decorated with poly(ethylene glycol) (PEG), forming PGA-PTX-DOX and PG-PTX-bz-DOX-PEG, respectively. We explored the relationship between the polymeric architectures and their performance with the aim to augment the pharmacological benefits of releasing both drugs simultaneously at the tumor site at a synergistic ratio. We recently designed and characterized a PGA-PTX-DOX conjugate. Here, we describe the synthesis and characterization of PG dendritic scaffold bearing the combination of PTX and DOX. The performance of both conjugates was evaluated in a murine model of mammary adenocarcinoma in immunocompetent mice, to investigate whether the activity of the treatments is affected by the immune system. Drug conjugation to a nano-sized polymer enabled preferred tumor accumulation by extravasation-dependent targeting, making use of the enhanced permeability and retention (EPR) effect. Both PGA-PTX-DOX and PG-PTX-bz-DOX-PEG nano-sized conjugates exhibited superior anti-tumor efficacy and safety compared to the combination of the free drugs, at equivalent concentrations. However, while PGA-PTX-DOX was more efficient than a mixture of each drug conjugated to a separate PGA chain, as was previously shown, PG-PTX-bz-DOX-PEG had similar activity to the mixture of the PG-PTX-bz-PEG and PG-DOX-PEG conjugates. Our results show that both conjugates are potential candidates as precision combination nanomedicines for the treatment of breast cancer.

Keywords: Combination therapy; Dendritic polymer; Doxorubicin; Paclitaxel; Polyglutamic acid; Polyglycerol; Polymeric nanomedicines.

Publication types

  • Comparative Study

MeSH terms

  • Animals
  • Antineoplastic Agents / chemistry*
  • Antineoplastic Agents / pharmacokinetics
  • Antineoplastic Agents / therapeutic use
  • Breast Neoplasms / drug therapy
  • Cell Line, Tumor
  • Cell Survival / drug effects
  • Doxorubicin / chemistry*
  • Doxorubicin / pharmacokinetics
  • Doxorubicin / therapeutic use
  • Drug Combinations
  • Drug Delivery Systems
  • Drug Synergism
  • Female
  • Glycerol / chemistry*
  • Humans
  • Mice
  • Mice, Inbred BALB C
  • Paclitaxel / chemistry*
  • Paclitaxel / pharmacokinetics
  • Paclitaxel / therapeutic use
  • Polyethylene Glycols / chemistry*
  • Polyglutamic Acid / analogs & derivatives*
  • Polymers / chemistry*

Substances

  • Antineoplastic Agents
  • Drug Combinations
  • Polymers
  • Polyglutamic Acid
  • polyglycerol
  • Polyethylene Glycols
  • Doxorubicin
  • Paclitaxel
  • Glycerol