Editors' ChoiceMolecular Engineering

Healing Achilles’ Heel

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Science Translational Medicine  17 Aug 2011:
Vol. 3, Issue 96, pp. 96ec133
DOI: 10.1126/scitranslmed.3003035

The Greek myth of Achilles tells the story of a warrior who was invincible. However, in battle he was shot in the heel with an arrow, leading to an untimely death. Physiologically, he probably died from complications of blood flow to the foot. Diabetic patients also suffer and can die from complications of poor blood flow to the foot (albeit not caused by arrow wounds). For instance, a seemingly innocuous sore can quickly infect the leg of a person with diabetes; the root of this problem is ischemia, or poor blood flow. Webber and colleagues address the ischemia problem with a molecular engineering strategy for therapeutic angiogenesis—the generation of new blood vessels—aimed at healing the diabetic’s “Achilles’ heel.”

Recent work has demonstrated the therapeutic potential of self-assembling filamentous nanofibers that are formed from customizable peptide amphiphile (PA) molecules. These PA molecules are characterized by dual hydrophobicity (the alkyl segments) and hydrophilicity (the peptide). The peptide has two domains: an amino acid sequence to drive self-assembly into nanofibrils through the formation of β-sheets, and a customizable bioactive domain designed to interact with specific proteins, receptors, or ligands. Webber et al. used vascular endothelial growth factor (VEGF) as the customizable protein. VEGF is a powerful proangiogenic factor that has been limited clinically by the inability to maintain therapeutic levels in the body. After verifying the cylindrical structure of the VEGF-PA assembly, the authors confirmed in vitro activity by measuring phosphorylation of the VEGF receptor.

The VEGF-PA molecule was then tested on two standard in vivo models of angiogenesis: the chicken chorioallantoic membrane (CAM) assay and the mouse hind limb ischemia model. In the CAM assay, there was a 229% increase in blood vessel density over a 3-day period as compared with controls. In the mouse hind limb model, the femoral artery was removed, and blood flow and limb motor function were assessed with laser Doppler perfusion imaging and functional scoring, respectively. Both criteria were significantly enhanced in animals who received VEGF-PA injection into the leg. Capillary density in the ischemic hind limb was also significantly increased with VEGF-PA treatment. Moreover, VEGF-PA remained in the tissue for 28 days, as indicated by fluorescently tagged PA molecules. Webber and colleagues successfully rescued ischemic limbs—the modern-day Achilles’ heel—of mice. In doing so, the authors advanced the field of therapeutic angiogenesis through a unique combination of nanotechnology and molecular biology.

M. J. Webber et al., Supramolecular nanostructures that mimic VEGF as a strategy for ischemic tissue repair. Proc. Natl. Acad. Sci. U.S.A. 1 August 2011 (10.1073/pnas.1016546108). [Abstract]

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