Bioresponsive albumin-conjugated paclitaxel prodrugs for cancer therapy

Drug Deliv. 2018 Nov;25(1):807-814. doi: 10.1080/10717544.2018.1451935.

Abstract

The efficacy of traditional chemotherapy often suffers from rapid clearance and off-target toxicity. Drug delivery systems and controlled release are applied to improve the therapeutic efficiencies of small-molecule drugs. In this work, two novel oxidative/reductive (Ox/Re) -sensitive and one non-sensitive Paclitaxel (PTX) prodrugs were synthesized with a maleimide group, which rapidly conjugates with albumin in vivo. Albumin serves as a good vehicle to deliver more prodrug to tumors due to the enhanced permeation and retention (EPR) effect. PTX was then released from the prodrugs in glutathione(GSH)/ reactive oxygen species(ROS)-rich tumor microenvironments. This bioresponsive prodrug strategy demonstrates potent chemotherapeutic efficiency in vivo and may be utilized in clinical cancer therapy.

Keywords: EPR effect; Ox/Re-sensitive release; Paclitaxel; albumin-conjugate; maleimide.

Publication types

  • Comparative Study

MeSH terms

  • Absorption, Physiological
  • Animals
  • Antineoplastic Agents, Phytogenic / administration & dosage*
  • Antineoplastic Agents, Phytogenic / metabolism
  • Antineoplastic Agents, Phytogenic / pharmacokinetics
  • Antineoplastic Agents, Phytogenic / therapeutic use
  • Apoptosis / drug effects*
  • Cell Line, Tumor
  • Drug Delivery Systems*
  • Drug Liberation
  • Female
  • Glutathione / chemistry
  • Glutathione / metabolism
  • Humans
  • Injections, Intravenous
  • Male
  • Mice, Inbred BALB C
  • Optical Imaging
  • Oxidation-Reduction
  • Paclitaxel / administration & dosage*
  • Paclitaxel / metabolism
  • Paclitaxel / pharmacokinetics
  • Paclitaxel / therapeutic use
  • Prodrugs / administration & dosage*
  • Prodrugs / metabolism
  • Prodrugs / pharmacokinetics
  • Prodrugs / therapeutic use
  • Prostatic Neoplasms / diagnostic imaging
  • Prostatic Neoplasms / drug therapy*
  • Prostatic Neoplasms / metabolism
  • Prostatic Neoplasms / pathology
  • Reactive Oxygen Species / chemistry
  • Reactive Oxygen Species / metabolism
  • Serum Albumin, Bovine / chemistry
  • Serum Albumin, Human / chemistry*
  • Tissue Distribution
  • Tumor Microenvironment
  • Whole Body Imaging
  • Xenograft Model Antitumor Assays

Substances

  • Antineoplastic Agents, Phytogenic
  • Prodrugs
  • Reactive Oxygen Species
  • Serum Albumin, Bovine
  • Glutathione
  • Paclitaxel
  • Serum Albumin, Human

Grants and funding

Generous support is given from the “Innovative Research Team of the Ministry of Education” and “Innovative Research Team in SYPHU by the Supporting Fund for Universities from the Chinese Central Government [51150039]”; The authors also acknowledge the funding from “the Program for Liaoning Innovative Research Team in University”.