An Integrin-Targeted, Highly Diffusive Construct for Photodynamic Therapy
Klein, Oliver J.
Nowell, Nicholas H.
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CitationKlein, Oliver J., Hushan Yuan, Nicholas H. Nowell, Charalambos Kaittanis, Lee Josephson, and Conor L. Evans. 2017. “An Integrin-Targeted, Highly Diffusive Construct for Photodynamic Therapy.” Scientific Reports 7 (1): 13375. doi:10.1038/s41598-017-13803-4. http://dx.doi.org/10.1038/s41598-017-13803-4.
AbstractTargeted antineoplastic agents show great promise in the treatment of cancer, having the ability to impart cytotoxicity only to specific tumor types. However, these therapies do not experience uniform uptake throughout tumors, leading to sub-lethal cell killing that can impart treatment resistance, and cause problematic off-target effects. Here we demonstrate a photodynamic therapy construct that integrates both a cyclic RGD moiety for integrin-targeting, as well as a 5 kDa PEG chain that passivates the construct and enables its rapid diffusion throughout tumors. PEGylation of the photosensitizer construct was found to prevent photosensitizer aggregation, boost the generation of cytotoxic reactive radical species, and enable the rapid uptake of the construct into cells throughout large (>500 µm diameter) 3D tumor spheroids. Replacing the cyclic RGD with the generic RAD peptide led to the loss of cellular uptake in 3D culture, demonstrating the specificity of the construct. Photodynamic therapy with the construct was successful in inducing cytotoxicity, which could be competitively blocked by a tenfold concentration of free cyclic RGD. This construct is a first-of-its kind theranostic that may serve as a new approach in our growing therapeutic toolbox.
Citable link to this pagehttp://nrs.harvard.edu/urn-3:HUL.InstRepos:34492293
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