International Journal of Medical Sciences

Impact factor
2.399

12 December 2017

ISSN 1449-1907 News feeds of published articles

My Manuscript | My Account

Journal of Biomedicinenew

Theranostics

Journal of Cancer

Oncomedicine

International Journal of Biological Sciences

Journal of Genomics

Journal of Bone and Joint Infection (JBJI)

Nanotheranostics

PubMed Central Indexed in Journal Impact Factor

Int J Med Sci 2010; 7(6):326-339. doi:10.7150/ijms.7.326

Research Paper

A cyclic-RGD-BioShuttle functionalized with TMZ by DARinv “Click Chemistry” targeted to αvβ3 integrin for therapy

Klaus Braun1* , Manfred Wiessler1*, Rüdiger Pipkorn2, Volker Ehemann3, Tobias Bäuerle1, Heinz Fleischhacker1, Gabriele Müller4, Peter Lorenz1, Waldemar Waldeck4

1. German Cancer Research Center, Dept. of Imaging and Radiooncology, INF 280, D-69120 Heidelberg, Germany
2. German Cancer Research Center, Central Peptide Synthesis Unit, INF 580, D-69120 Heidelberg, Germany
3. University of Heidelberg, Institute of Pathology, INF 220, D-69120 Heidelberg, Germany
4. German Cancer Research Center, Division of Biophysics of Macromolecules, INF 580, D-69120 Heidelberg, Germany
* The authors contributed equally to this work

Abstract

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 αvβ3 [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 αvβ3 integrin receptor realizing local TMZ concentrations sufficient for cell killing. The IC50 values are 12 µMol/L in the case of cRGD-BioShuttle-TMZ and 100 µMol/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 αvβ3 integrin-ligand, ligated to the cytotoxic drug TMZ. The ligation was carried out by the Diels Alder Reaction with inverse electron demand (DARinv).

Keywords: Click-Chemistry, Cycloaddition, BioShuttle, Ligation chemistry, Linker Systems, Adaptor Systems, inverse Diels Alder Reaction, RGD, Tetrazines, targeted Therapy, Temozolomide

This is an open access article distributed under the terms of the Creative Commons Attribution (CC BY-NC) License. See http://ivyspring.com/terms for full terms and conditions.
How to cite this article:
Braun K, Wiessler M, Pipkorn R, Ehemann V, Bäuerle T, Fleischhacker H, Müller G, Lorenz P, Waldeck W. A cyclic-RGD-BioShuttle functionalized with TMZ by DARinv “Click Chemistry” targeted to αvβ3 integrin for therapy. Int J Med Sci 2010; 7(6):326-339. doi:10.7150/ijms.7.326. Available from http://www.medsci.org/v07p0326.htm