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)).
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Authors | Klaus Braun, Manfred Wiessler, Rüdiger Pipkorn, Volker Ehemann, Tobias Bäuerle, Heinz Fleischhacker, Gabriele Müller, Peter Lorenz, Waldemar Waldeck |
Journal | International journal of medical sciences
(Int J Med Sci)
Vol. 7
Issue 6
Pg. 326-39
(Sep 21 2010)
ISSN: 1449-1907 [Electronic] Australia |
PMID | 20922134
(Publication Type: Journal Article)
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Chemical References |
- Antineoplastic Agents, Alkylating
- Integrin alphaVbeta3
- Peptides, Cyclic
- cyclic arginine-glycine-aspartic acid peptide
- Dacarbazine
- Temozolomide
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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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