Many cancerous tumors have extracellular pH (pHe) in the range of 6.5-7.0, compared with that of 7.2-7.4 in healthy tissues. This small difference of about half pH unit presents an exciting novel opportunity, as well as a great challenge, for selective drug release to cancer cells. Tumor acidosis can reduce the effectiveness of chemotherapy by decreasing the membrane permeability of amine drugs such as doxorubicin (Dox), topotecan, and vinblastine. Current pH-sensitive cleavable linkers, such as ketal, acetal, cyclic orthoester, imine, acylhydrazone, boronate, and mono-substituted maleamic acid (i.e. cis-aconityl linker), can respond to endosomal acidity of pH 4.5-6.0, but they are not sensitive enough for triggering by tumor acidosis pHe. To address this need, we studied the super-sensitive, di-substituted maleamic acid (DMA) linker and found that it cleaves at pH 6.5 to release ~ 67% Dox (free drug) in 24 hr compared to ~18% Dox release at pH 7.4. The pH 6.5/7.4 release ratio is improved from the previous known best of 2:1 (in terms of drug released, using cyclic orthoester) to ~ 4:1 (using DMA). We also learned that the closed maleimide form (DMI) is a major side-product (15-60%) during drug release at all pH values, as well as a convenient synthetic precursor of DMA for ease of handling and storage. Finally, conjugating Dox to glutathione (used as a membrane-impermeable peptide) via DMA gave a prodrug of Dox that is more cytotoxic under acidic conditions than neutral pH, reversing the pH-profile of free drug cytotoxicity. Such DMA-linked prodrug of Dox may improve chemotherapy by reducing off target side-effects.

Di-substituted maleamic acid as an ultra acid-sensitive, cleavable linker for reversing the cytotoxicity pH-profile of doxorubicin in small molecule prodrugs

253rd National Meeting (2017)

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