Optimized synthesis, characterization and in vitro systematic evaluation of adamantane-doxorubicin prodrugs sensitive to pH in breast cancer cells

Doxorubicin(Dox) is a potent anti-cancer drug used in the treatment of triple negative breast cancer (TNBC), however, it causes dose-dependent cardiotoxicity once the treatment is concluded. One of the new strategies to overcome this problem is the design of pH sensitive prodrugs, which can improve its selectivity and reduce the toxic effects of the free drug. For that reason, the synthesis of Dox attached to adamantane (Ad) was firstly optimized by using three different pH sensitive linkers; ester, amide and hydrazone in order to reduce the toxicity of free Dox. To evaluate the stimulus-sensitive behavior of the prodrugs, the kinetics of the in vitro hydrolysis of the three proposed linkers was determined by simulating both, the pH of the tumor microenvironment and the intracellular pH changes that occur in the tumor tissue. The cytotoxic activity of the hydrazone-cleavable prodrug showed a similar behavior to the free drug as well as the best release profile, using a new promising linker in the development of Dox prodrugs. The obtained results demonstrate the importance of choosing the appropriate linker in the design of pH sensitive Dox prodrugs which can improve the drug efficiency and used in the design of controlled drug delivery systems. (C) 2018 Elsevier B.V. All rights reserved.