Purpose: To assess whether the newly designed small-molecule oral P-selectin inhibitor 3S-1,2,3,4-tetrahydro-β-carboline-3-methyl aspartyl ester (THCMA) as a nanomedicine enhances antithrombosis, anti-inflammation, and antitumor activity more than the clinical trial drug PSI-697.
Methods: THCMA was designed as an amphiphile containing pharmacophores of PSI-697. Its nanofeatures were explored with TEM, SEM, Tyndall effect, ζ-potential, FT-ICR-MS, and NOESY 2D ¹H NMR. The P-selectin inhibitory effect of THCMA was demonstrated with molecular docking, ultraviolet (UV) spectra, and competitive ELISA. In vivo and in vitro assays — anti-arterial thrombosis, anti–venous thrombosis, anti-inflammation, antitumor growth, anti–platelet aggregation, rat-tail bleeding time, anticoagulation index, soluble P-selectin (sP-selectin) expression, and serum TNFα expression — were performed to explore bioactivity and potential mechanisms. Water solubility of THCMA was measured using UV-absorption spectra.
Results: THCMA self-assembled into nanorings of approximately 100 nm in diameter. Its water solubility was about 1,030-fold that of PSI-697. THCMA exhibited more potent P-selectin inhibitory effect than PSI-697. The oral efficacy of THCMA was 100-fold that of PSI-697 in inhibiting arterial and venous thrombosis and tenfold in inhibiting inflammation. THCMA inhibited thrombosis at a dose that produces no coagulation disorders and no bleeding risk. THCMA exhibited enhanced antitumor activity over PSI-697 without systemic chemotherapy toxicity. THCMA significantly inhibited platelet aggregation in vitro and downregulated the expression levels of serum sP-selectin and TNFα in vivo.
Conclusion: A new small-molecule P-selectin inhibitor, THCMA, has been successfully designed as a nanomedicine with largely enhanced oral efficacy compared to the clinical trial drug PSI-697, and thus might be developed for the oral treatment of arterial thrombosis, venous thrombosis, inflammation, and cancer-associated thrombosis.
Keywords: P-selectin, thrombosis, inflammation, cancer, antagonist, self-assembly