Design, synthesis and evaluation of doxorubicin based anti-cancer drug conjugates

The efficacy of chemotherapy is limited by the lack of selectivity and multi-drug resistance (MDR); many patients eventually succumb to their tumors or recurring metastatic disease. Improved anticancer drugs that can selectively destroy cancer cells and overcome MDR are needed. A series of doxorubicin drug conjugates were designed and synthesized. The widely used tumor chemotherapy agent doxorubicin was covalently conjugated to a synthetic ?-v?-3 integrin binding ligand and a polyarginine at the 14-carbon position. The -v?-3 integrin is over expressed on a number of tumor cells and is necessary for metastatic development. By targeting the drug conjugates to this integrin, the selectivity of the drug to caner cells can be improved. Polyarginie is capable to delivering molecules into mammalian cells. Rapid uptake of the drug by neoplastic cells was expected by incorporating a polyarginine in the conjugate structure. Cytotoxicity of these drug conjugates was evaluated using the invasive human breast cancer cell lime MDA-MD-231 and breast cancer cell line MCF-7. The modified drug conjugates showed decreased cytotoxic activity compared with the free drug. Some of the drug conjugates had selective cytotoxicity toward different cell lines. The cellular internalization and distribution to the drug conjugates was investigative using confocal fluorescence microscope. The drug conjugates with a polyarginine moiety were found to enter cell much faster than free drug. The drug conjugates concentrated first in the cytoplasm and then in the nucleus of living cells. By testing the drug conjugates in a MDR cell line, some of the conjugates were demonstrated to be promising drug candidates to overcome multi-drug resistance.