Novel tumor-targeting small molecule drug conjugates (TTSMDCs), consisting of biotin as the tumor-targeting molecule, a fluorotaxoid, SB-T-12822-5 (1) as the warhead, and a variety of mechanism-based self-immolative disulfide linkers, were designed and synthesized as 19F NMR probes, e.g. BLT-S-F6 (2). A polyethylene glycol oligomer was inserted into the TTSMDCs to improve solubility. SB-T-12822-5 was designed to bear two CF3 groups in the taxoid moiety as ‘‘3-FAB’’ reporters for enhanced sensitivity. This allows for the investigation of the metabolic stability by real-time monitoring with 19F NMR. Due to the inherent high level of complexity of biological systems, a clear analysis of the linker stability in blood plasma or cell culture media by 1H NMR and many other methods is problematic. Consequently, the use of 19F NMR would provide a practical solution to this problem. In fact, the ‘‘3-FAB’’ method has proven to be highly useful in investigating the stability of the self-immolative disulfide linker system in human blood plasma by 19F NMR. It has also been shown that when polysorbate 80 is employed as an excipient in the formulation, the stability of the disulfide linker system is dramatically increased. Additionally, with a formulation of polysorbate 80/EtOH/saline for in vivo studies, there is evidence to support a high disulfide linker stability in blood plasma, of the TTSMDCs described herein, while the drug release in cancer cells proceeds placidly.

Metabolic stability assessment of tumor-targeted drug delivery systems with fluorine-labeled taxoid probes by 19F NMR

249th National Meeting (2015)

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