Design, synthesis and biological evaluation of novel tumor-targeting taxane-based anticancer agents

Cancer has become the number one cause of death in the U.S. for people under 85 years of age according to new statistics released by the American Cancer Society. Traditional cancer chemotherapy relies on the premise that rapidly proliferating cancer cells are more likely to be killed by a cytotoxic agent. In reality, however, cytotoxic agents have very little or no specificity, which leads to systemic toxicity, causing severe undesirable side effects. Therefore, various drug delivery protocols and systems have been explored in the last three decades. Tumor cells overexpress many receptors and biomarkers, which can be used as targets to deliver cytotoxic agents into tumors. In general, a tumor-targeting drug delivery system consists of a tumor recognition moiety and a cytotoxic warhead connected directly or through a suitable linker to form a conjugate.; A novel series of the second-generation taxoid conjugates with o-3 polyunsaturated fatty acids (PUFA) such as docosahexanoic acid (DHA), linolenic acid (LNA) and linoleic acid (LA) has been successfully developed. The new conjugates, tested in vivo, exhibited strong activity against both resistant and sensitive colon and ovarian cancer xenografts. Two of the new conjugates (DHA-SB-T-1214 and DHA-SB-T-1213) caused the total regression of resistant and sensitive type cancers, respectively, with reduced side toxicity.; A new class of disulfide-containing linkers for tumor-targeting prodrugs has also been designed and synthesized. These linkers could be applied to a variety of tumor-targeting molecules (e.g., PUFA, biotin, folic acid, monoclonal antibody, aptamer) and cytotoxic agents (e.g., second-generation taxoid). Novel fatty acid-second-generation taxoid conjugates (DHA-SB-T-1214 and LNA-SB-T-1214) have been prepared through such linkers. A series of model experiments provided the proof of concept, i.e., disulfide bond cleavage by a thiol, fast intramolecular thiolactonization, and the release of a free cytotoxic agent. The key factors involved in this process were studied. A set of new fluorescence-labeled tumor-targeting drug conjugates was also synthesized based on these linkers. Cellular uptake of the conjugate and a free drug/probe release were investigated in pancreatic cancer cell lines.