Microtubule-targeted antitumor drugs: chemistry, mechanisms and nanoparticle formulations

The ingenious application of vinca alkaloids (vinblastine, vinorelbine, vincristine, vindesine, vinflunine) destabilizing microtubules and of taxanes (paclitaxel, docetaxel) stabilizing microtubules has been a milestone achievement in oncology. Recent investigations into their molecular mechanism revealed that all compounds possess additional pleiotropic effects that converge on induction of apoptosis in cancer cells via activation of signaling pathways. Their success has prompted vigorous investigations into microtubule-targeting activity from natural products as well as synthetic molecules arising from molecular modeling that led to the identification of Epothilones A, B, D, Ixabepilone, Sagopilone, Discodermolides, Dictyostatin, Peloruside A, and ABT-751; an additional purpose for epothilone drug discovery has been to bypass paclitaxel resistance mainly arising from the efflux function of P-glycoprotein. Nanoparticles provide a new mode of cancer drug delivery functioning as a carrier for entry through fenestrations in tumor vasculature. The 130-nm nanoparticle formulation albumin-bound paclitaxel (Nab-paclitaxel, Abraxane (TM)) utilizes the natural properties of albumin to reversibly bind paclitaxel, transport it across the endothelial cell and concentrate in tumors; Abraxane (TM) received regulatory approval in the USA from a higher response rate and longer time to progression than Taxol in patients with metastatic breast cancer. The success of Abraxane (TM) led to an explosion in research on polymer nanoparticle formulations for taxanes using micellar PEGylated hyperbranched polyesters, polyglycerol-polyethylene glycol copolymers, cyclodextrin nanoparticles, polylactide-co-glycolide PEG and many others. Several such formulations are expected to enter the market. Other tubulin polymerization inhibitors reviewed here include tubulysin A, a highly cytotoxic peptide front myxobacteria, CC-5079, bisbenzylisoquinoline alkaloids, aplidine, nocodazole, GMC-5-193, cyclostreptin, colchicine,,TLK-286 and vinflunine, a novel third generation vinca alkaloid. Structural similarities have been used to further modify the successful microtubule-targeted drugs in order to seek molecules of improved efficacy, of lower toxicity or able to overcome tumor resistance. We review the molecular mechanism of these drugs, whenever feasible, we suggest correlations between their chemical structure and mechanism and point to the importance of drug delivery for success.