Ligand-targeted delivery of small interfering RNAs to malignant cells and tissues

Ann N Y Acad Sci. 2009 Sep;1175:32-9. doi: 10.1111/j.1749-6632.2009.04977.x.


Potential clinical applications of small interfering RNA (siRNA) are hampered primarily by delivery issues. We have successfully addressed the delivery problems associated with off-site targeting of highly toxic chemotherapeutic agents by attaching the drugs to tumor-specific ligands that will carry the attached cargo into the desired cancer cell. Indeed, several such tumor-targeted drugs are currently undergoing human clinical trials. We now show that efficient targeting of siRNA to malignant cells and tissues can be achieved by covalent conjugation of small-molecular-weight, high-affinity ligands, such as folic acid and DUPA (2-[3-(1, 3-dicarboxy propyl)-ureido] pentanedioic acid), to siRNA. The former ligand binds a folate receptor that is overexpressed on a variety of cancers, whereas the latter ligand binds to prostate-specific membrane antigen that is overexpressed specifically on prostate cancers and the neovasculature of all solid tumors. Using these ligands, we show remarkable receptor-mediated targeting of siRNA to cancer tissues in vitro and in vivo.

MeSH terms

  • Animals
  • Carrier Proteins / metabolism
  • Female
  • Folate Receptors, GPI-Anchored
  • Folic Acid / administration & dosage*
  • Folic Acid / chemistry
  • Folic Acid / metabolism
  • Glutarates / administration & dosage*
  • Glutarates / chemistry
  • Glutarates / metabolism
  • HeLa Cells
  • Humans
  • Ligands
  • Male
  • Mice
  • Mice, Mutant Strains
  • Neoplasms / therapy*
  • RNA, Small Interfering / administration & dosage*
  • RNA, Small Interfering / chemistry
  • Receptors, Cell Surface / metabolism
  • Urea / administration & dosage
  • Urea / analogs & derivatives*
  • Urea / chemistry
  • Urea / metabolism
  • Xenograft Model Antitumor Assays


  • 2-(3-(1,3-dicarboxypropyl)ureido)pentanedioic acid
  • Carrier Proteins
  • Folate Receptors, GPI-Anchored
  • Glutarates
  • Ligands
  • RNA, Small Interfering
  • Receptors, Cell Surface
  • Urea
  • Folic Acid