Glutathione and Reactive Oxygen Species Dual-Responsive Block Copolymer Prodrugs for Boosting Tumor Site-Specific Drug Release and Enhanced Antitumor Efficacy

Biomacromolecules. 2020 Feb 10;21(2):921-929. doi: 10.1021/acs.biomac.9b01578. Epub 2020 Jan 30.

Abstract

A remarkable hallmark of cancer cells is the heterogeneous coexistence of overproduced intracellular glutathione (GSH) and a high level of reactive oxygen species (ROS) compared with those in normal cells, which have been frequently used as the stimuli to trigger drug release from the nanocarriers. Most of the stimuli-responsive delivery vehicles have been designed to respond to only one redox stimulus (e.g., GSH or ROS). Herein, we develop a GSH and ROS dual-responsive amphiphilic diblock copolymer prodrug (BCP) (GR-BCP) consisting of poly(ethylene glycol) (PEG)- and camptothecin (CPT)-conjugated poly(methacrylate) in the side chains via thioether bonds. In comparison, GSH or ROS single-responsive BCPs (G-BCPs or R-BCPs) were prepared, where CPT drugs were linked by disulfide or thioketal bonds, respectively. The three BCPs can form well-defined spherical micellar nanoparticles in an aqueous solution with a diameter of ∼50 nm. Compared with G-BCP and R-BCP, GR-BCP realized the highest cytotoxicity against HeLa cells with the half-inhibitory concentration (IC50) of 6.3 μM, which is much lower than 17.8 μM for G-BCP and 28.9 μM for R-BCP. Moreover, for in vivo antitumor performance, G-BCP, R-BCP, and GR-BCP showed similar efficiencies in blood circulation and tumor accumulation after intravenous injection. However, GR-BCP realized the most efficient tumor suppression with few side effects. Our findings demonstrate that intracellular GSH and ROS dual-responsive BCPs show a more efficient responsive drug release inside tumor cells for boosting the antitumor efficacy as compared with GSH or ROS single-responsive BCPs, which provides novel strategies for designing redox-responsive BCPs.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antineoplastic Agents / administration & dosage
  • Antineoplastic Agents / chemistry
  • Antineoplastic Agents / metabolism*
  • Drug Liberation / physiology*
  • Glutathione / metabolism*
  • HeLa Cells
  • Humans
  • Mice
  • Mice, Inbred BALB C
  • Polyethylene Glycols / administration & dosage
  • Polyethylene Glycols / chemistry
  • Polyethylene Glycols / metabolism
  • Polymers / administration & dosage
  • Polymers / chemistry
  • Polymers / metabolism*
  • Polymethyl Methacrylate / administration & dosage
  • Polymethyl Methacrylate / chemistry
  • Polymethyl Methacrylate / metabolism
  • Prodrugs / administration & dosage
  • Prodrugs / chemistry
  • Prodrugs / metabolism*
  • Reactive Oxygen Species / metabolism*
  • Treatment Outcome

Substances

  • Antineoplastic Agents
  • Polymers
  • Prodrugs
  • Reactive Oxygen Species
  • Polyethylene Glycols
  • Polymethyl Methacrylate
  • Glutathione