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

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 α(v)β(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 α(v)β(3) 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 α(v)β(3) integrin-ligand, ligated to the cytotoxic drug TMZ. The ligation was carried out by the Diels Alder Reaction with inverse electron demand (DAR(inv)).
AuthorsKlaus Braun, Manfred Wiessler, Rüdiger Pipkorn, Volker Ehemann, Tobias Bäuerle, Heinz Fleischhacker, Gabriele Müller, Peter Lorenz, Waldemar Waldeck
JournalInternational journal of medical sciences (Int J Med Sci) Vol. 7 Issue 6 Pg. 326-39 (Sep 21 2010) ISSN: 1449-1907 [Electronic] Australia
PMID20922134 (Publication Type: Journal Article)
Chemical References
  • Antineoplastic Agents, Alkylating
  • Integrin alphaVbeta3
  • Peptides, Cyclic
  • cyclic arginine-glycine-aspartic acid peptide
  • Dacarbazine
  • Temozolomide
Topics
  • Antineoplastic Agents, Alkylating (chemistry, pharmacokinetics, therapeutic use)
  • Breast Neoplasms (drug therapy)
  • Cell Line, Tumor
  • Cell Size (drug effects)
  • Dacarbazine (analogs & derivatives, chemistry, pharmacokinetics, therapeutic use)
  • Female
  • Flow Cytometry
  • HeLa Cells
  • Humans
  • Inhibitory Concentration 50
  • Integrin alphaVbeta3 (antagonists & inhibitors, metabolism)
  • Microscopy, Confocal
  • Peptides, Cyclic (chemistry)
  • Temozolomide
  • Uterine Cervical Neoplasms (drug therapy)

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