Evaluation of RGD-targeted albumin carriers for specific delivery of auristatin E to tumor blood vessels.

Abstract

Induction of apoptosis in endothelial cells is considered an attractive strategy to therapeutically interfere with a solid tumor's blood supply. In the present paper, we constructed cytotoxic conjugates that specifically target angiogenic endothelial cells, thus preventing typical side effects of apoptosis-inducing drugs. For this purpose, we conjugated the potent antimitotic agent monomethyl-auristatin-E (MMAE) via a lysosomal cleavable linker to human serum albumin (HSA) and further equipped this drug-albumin conjugate with cyclic c(RGDfK) peptides for multivalent interaction with alphavbeta3-integrin. The RGD-peptides were conjugated via either an extended poly(ethylene glycol) linker or a short alkyl linker. The resulting drug-targeting conjugates RGDPEG-MMAE-HSA and RGD-MMAE-HSA demonstrated high binding affinity and specificity for alphavbeta3-integrin expressing human umbilical vein endothelial cells (HUVEC). Both types of conjugates were internalized by endothelial cells and killed the target cells at low nM concentrations. Furthermore, we observed RGD-dependent binding of the conjugates to C26 carcinoma. Upon i.v. administration to C26-tumor bearing mice, both drug-targeting conjugates displayed excellent tumor homing properties. Our results demonstrate that RGD-modified albumins are suitable carriers for cell selective intracellular delivery of cytotoxic compounds, and further studies will be conducted to assess the antivascular and tumor inhibitory potential of RGDPEG-MMAE-HSA and RGD-MMAE-HSA.

• Authors: Kai Temming, Damon L Meyer, Roger Zabinski, Eli C F Dijkers, Klaas Poelstra, Grietje Molema, Robbert J Kok
• Journal: Bioconjugate chemistry (Bioconjug Chem) 2006 Nov-Dec Vol. 17 Issue 6 Pg. 1385-94 ISSN: 1043-1802 [Print] United States
• PMID: 17105215 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Albumins
• Drug Carriers
• Oligopeptides
• arginyl-glycyl-aspartic acid
• monomethyl auristatin E

Topics

• Albumins (chemistry, pharmacology)
• Animals
• Cell Survival (drug effects)
• Cells, Cultured
• Drug Carriers (chemistry)
• Endothelial Cells (cytology, drug effects)
• Humans
• Mice
• Molecular Structure
• Neoplasm Transplantation
• Neoplasms (blood supply, pathology)
• Oligopeptides (chemistry)
• Sensitivity and Specificity
• Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization