Photochemical internalization augments tumor vascular cytotoxicity and specificity of VEGF(121)/rGel fusion toxin

J Control Release. 2014 Apr 28;180:1-9. doi: 10.1016/j.jconrel.2014.02.003. Epub 2014 Feb 13.

Abstract

Vascular targeting for cancer is increasingly recognized as a therapeutic strategy although the lack of objective responses and the development of resistance are major limitations for clinically-available drugs. Endothelial targeted toxins exert increased toxicity compared to antiangiogenic drugs and may therefore overcome these limitations. The specificity and toxicity of targeted toxins may be increased by utilization of a drug delivery system which provides selective release of the targeted toxins in the target cells. Photochemical internalization (PCI) is a non-invasive modality which causes translocation into the cytosol of agents that are trapped in endosomes. This study describes the first use of PCI in combination with a recombinant fusion toxin targeting tumor vasculature. Endothelial cells bearing VEGFR2 treated with VEGF121/rGel showed dramatic enhancement of toxicity after PCI utilizing the photosensitizer TPCS2a (Amphinex®). We compared the PCI of VEGF121/rGel to that of bleomycin which is currently under clinical evaluation. The VEGFR2 specificity of VEGF121/rGel was shown to be preserved by the PCI treatment. PCI of VEGF121/rGel was further shown to induce vascular collapse and edema in the invasive areas of CT26.CL25 colon carcinoma tumors as shown by CD31 IHC. Antitumor effects, as assessed by tumor growth delay were found for PCI of VEGF121/rGel and PCI of bleomycin with cure rates of 40% and 33% respectively. PCI of VEGF121/rGel was, however, better tolerated compared to PCI of bleomycin. Thus, PCI of vascular targeted toxins provides higher specificity and increased tolerability compared to PCI of bleomycin and may represent an interesting clinical future for the PCI technology.

Keywords: Cytosolic delivery; Fusion toxins; Photochemical internalization; Photodynamic; VEGFR; Vascular targeting.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antineoplastic Agents / administration & dosage
  • Antineoplastic Agents / therapeutic use*
  • Cell Line
  • Cell Line, Tumor
  • Colon / drug effects
  • Colon / metabolism
  • Colon / pathology
  • Colonic Neoplasms / blood supply*
  • Colonic Neoplasms / drug therapy*
  • Colonic Neoplasms / metabolism
  • Colonic Neoplasms / pathology
  • Drug Delivery Systems / methods*
  • Female
  • Mice
  • Mice, Inbred BALB C
  • Photosensitizing Agents / administration & dosage
  • Photosensitizing Agents / therapeutic use
  • Porphyrins / administration & dosage
  • Porphyrins / therapeutic use
  • Recombinant Fusion Proteins / administration & dosage
  • Recombinant Fusion Proteins / genetics
  • Recombinant Fusion Proteins / therapeutic use*
  • Swine
  • Vascular Endothelial Growth Factor A / administration & dosage
  • Vascular Endothelial Growth Factor A / genetics
  • Vascular Endothelial Growth Factor A / therapeutic use*
  • Vascular Endothelial Growth Factor Receptor-2 / metabolism*

Substances

  • Antineoplastic Agents
  • Photosensitizing Agents
  • Porphyrins
  • Recombinant Fusion Proteins
  • Vascular Endothelial Growth Factor A
  • meso-tetraphenyl chlorin disulphonate
  • Vascular Endothelial Growth Factor Receptor-2