A cyclic-RGD-BioShuttle functionalized with TMZ by DARinv ※Click Chemistry§ targeted to 汐v汕3 integrin for therapy

作者：Klaus Braun; Manfred Wiessler; Rudiger Pipkorn; Volker Ehemann; Tobias Buerle; Heinz Fleischhacker; Gabriele Muller; Peter Lorenz; Waldemar Waldeck

来源：International Journal of Medical Sciences, 2010.

Clinical experiences often document, that a successful tumor control requires high doses of drug applications. It is widely believed that unavoidable adverse reactions could be minimized by using gene-therapeutic strategies protecting the tumor-surrounding healthy tissue as well as the bone-marrow. One new approach in this direction is the use of ※Targeted Therapies§ realizing a selective drug targeting to gain effectual amounts at the target site, even with drastically reduced application doses. MCF-7 breast cancer cells expressing the 汐v汕3 [alpha(v)beta(3)] integrin receptor are considered as appropriate candidates for such a targeted therapy. The modularly composed BioShuttle carrier consisting of different units designed to facilitate the passage across the cell membranes and for subcellular addressing of diagnostic and/or therapeutic molecules could be considered as an eligible delivery platform. Here we used the cyclic RGD-BioShuttle as a carrier for temozolomide (TMZ) at the 汐v汕3 integrin receptor realizing local TMZ concentrations sufficient for cell killing. The IC50 values are 12 米Mol/L in the case of cRGD-BioShuttle-TMZ and 100 米Mol/L for underivatized TMZ, which confirms the advantage of TMZ reformulation to realize local concentrations sufficient for cell killing. Our paper focuses on the design, synthesis and application of the cRGD-BioShuttle conjugate composed of the cyclic RGD, a 汐v汕3 integrin-ligand, ligated to the cytotoxic drug TMZ. The ligation was carried out by the Diels Alder Reaction with inverse electron demand (DARinv).