Prostate-specific membrane antigen-targeted liposomes specifically deliver the Zn(2+) chelator TPEN inducing oxidative stress in prostate cancer cells

Nanomedicine (Lond). 2016 May;11(10):1207-22. doi: 10.2217/nnm-2015-0017. Epub 2016 Apr 14.

Abstract

Aim: To evaluate the potential use of zinc chelation for prostate cancer therapy using a new liposomal formulation of the zinc chelator, N,N,N',N'-tetrakis(2-pyridylmethyl)-ethylenediamine (TPEN).

Materials & methods: TPEN was encapsulated in nontargeted liposomes or liposomes displaying an aptamer to target prostate cancer cells overexpression prostate-specific membrane antigen. The prostate cancer selectivity and therapeutic efficacy of liposomal (targeted and nontargeted) and free TPEN were evaluated in vitro and in tumor-bearing mice.

Results & conclusion: TPEN chelates zinc and results in reactive oxygen species imbalance leading to cell death. Delivery of TPEN using aptamer-targeted liposomes results in specific delivery to targeted cells. In vivo experiments show that TPEN-loaded, aptamer-targeted liposomes reduce tumor growth in a human prostate cancer xenograft model.

Keywords: aptamer; liposome; prostate cancer; targeted drug delivery; zinc.

MeSH terms

  • Animals
  • Antigens, Surface / metabolism
  • Aptamers, Nucleotide / metabolism
  • Cell Death / drug effects
  • Chelating Agents / administration & dosage*
  • Chelating Agents / pharmacokinetics
  • Chelating Agents / pharmacology
  • Chelating Agents / therapeutic use*
  • Drug Delivery Systems*
  • Ethylenediamines / administration & dosage*
  • Ethylenediamines / pharmacokinetics
  • Ethylenediamines / pharmacology
  • Ethylenediamines / therapeutic use*
  • Glutamate Carboxypeptidase II / metabolism
  • Humans
  • Liposomes / metabolism
  • Male
  • Mice
  • Oxidative Stress / drug effects
  • Prostate / drug effects
  • Prostate / metabolism
  • Prostate / pathology
  • Prostatic Neoplasms / drug therapy*
  • Prostatic Neoplasms / metabolism
  • Prostatic Neoplasms / pathology
  • Zinc / metabolism*

Substances

  • Antigens, Surface
  • Aptamers, Nucleotide
  • Chelating Agents
  • Ethylenediamines
  • Liposomes
  • FOLH1 protein, human
  • Glutamate Carboxypeptidase II
  • Zinc
  • N,N,N',N'-tetrakis(2-pyridylmethyl)ethylenediamine