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Synthesis and Evaluation of Targeted Drugs for Treating Breast Cancer
Author(s) -
Lee HeeKyoung,
Sha Jiang,
Hinshaw Jerald C.
Publication year - 2006
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.20.5.a940-d
Subject(s) - doxorubicin , cytotoxicity , cancer cell , cytotoxic t cell , cancer research , breast cancer , chemistry , cancer , targeted therapy , pharmacology , cell , chemotherapy , in vitro , medicine , biochemistry
One of the major problems in cancer chemotherapy are the severe side effects that limit the dose of the anticancer drugs because of their lack of selectivity for tumor versus normal cells. In addition, while initial response rates during therapy can be favorable, the duration of effect is often brief and many tumors return with a multi‐drug resistant phenotype. In this work, we describe a new approach to the design of anticancer drugs that is directed toward improving cytotoxicity against cancer cells, reducing unwanted side effects, and more effectively targeting and destroying metastatic cells. Our approach is to synthesize new drug conjugates that incorporate a specific cancer cell targeting component and a rapid cell membrane translocating/nuclear localization moiety, and to evaluate their cytotoxic effects against cancer cells in vitro . Series of drug conjugates has been synthesized from doxorubicin. The cytotoxic agent is covalently linked to an Arg‐Gly‐Asp peptide that binds to α V β 3 integrin, which is over‐expressed on the surface of breast cancer metastatic cells. The design also includes the incorporation of Tat peptide analog, NH 2 ‐[Arg] 7 ‐COOH, as a rapid cell membrane translocation moiety. Using MDA‐MB‐231 breast cancer cell line, targeted conjugates have been demonstrated to rapidly enter the cells and exhibit cytotoxicity comparable to doxorubicin itself. Confocal microscopy has been used to analyze the cellular uptake of these new drugs. This work was supported by Department of Army.