Toward intracellular targeted delivery of cancer therapeutics: progress and clinical outlook for brain tumor therapy

BioDrugs. 2012 Aug 1;26(4):235-44. doi: 10.2165/11631600-000000000-00000.

Abstract

A number of anti-cancer drugs have their targets localized to particular intracellular compartments. These drugs reach the targets mainly through diffusion, dependent on biophysical and biochemical forces that allow cell penetration. This means that both cancer cells and normal cells will be subjected to such diffusion; hence many of these drugs, like chemotherapeutics, are potentially toxic and the concentration achieved at the site of their action is often suboptimal. The same relates to radiation that indiscriminately affects normal and diseased cells. However, nature-designed systems enable compounds present in the extracellular environment to end up inside the cell and even travel to more specific intracellular compartments. For example, viruses and bacterial toxins can more or less specifically recognize eukaryotic cells, enter these cells, and direct some protein portions to designated intracellular areas. These phenomena have led to creative thinking, such as employing viruses or bacterial toxins for cargo delivery to cells and, more specifically, to cancer cells. Proteins can be genetically engineered in order to not only mimic what viruses and bacterial toxins can do, but also to add new functions, extending or changing the intracellular routes. It is possible to make conjugates or, more preferably, single-chain proteins that recognize cancer cells and deliver cargo inside the cells, even to the desired subcellular compartment. These findings offer new opportunities to deliver drugs/labels only to cancer cells and only to their site of action within the cells. The development of such dual-specificity vectors for targeting cancer cells is an attractive and potentially safer and more efficacious way of delivering drugs. We provide examples of this approach for delivering brain cancer therapeutics, using a specific biomarker on glioblastoma tumor cells.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Antineoplastic Agents / administration & dosage*
  • Antineoplastic Agents / therapeutic use
  • Bacterial Toxins / chemistry
  • Brain Neoplasms / drug therapy*
  • Brain Neoplasms / metabolism
  • Brain Neoplasms / pathology
  • Cell Nucleus / metabolism
  • Cytoplasm / metabolism
  • Drug Carriers / chemistry
  • Drug Delivery Systems / methods*
  • Glioblastoma / drug therapy*
  • Glioblastoma / metabolism
  • Glioblastoma / pathology
  • Humans
  • Intercellular Signaling Peptides and Proteins
  • Interleukin-13 Receptor alpha2 Subunit / genetics
  • Interleukin-13 Receptor alpha2 Subunit / metabolism
  • Ligands
  • Peptides / chemistry
  • Protein Engineering
  • Radioisotopes
  • Recombinant Fusion Proteins / chemistry
  • Recombinant Fusion Proteins / genetics

Substances

  • Antineoplastic Agents
  • Bacterial Toxins
  • Drug Carriers
  • Intercellular Signaling Peptides and Proteins
  • Interleukin-13 Receptor alpha2 Subunit
  • KLA peptide
  • Ligands
  • Peptides
  • Radioisotopes
  • Recombinant Fusion Proteins