Nanoparticles of a New Small-Molecule P-Selectin Inhibitor Attenuate Thrombosis, Inflammation, and Tumor Growth in Two Animal Models

Abstract

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 1 H 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.

Recent Advances on the Molecular Mechanism and Clinical Trials of Venous Thromboembolism

“…THCMA has been successfully developed as a nanomedicine and is 100-fold more effective in inhibiting arterial and venous thrombosis and 10-fold more effective in suppressing inflammation than PSI-697, a drug in clinical trials. 68 , 69 The doses of THCMA that inhibit thrombosis do not produce clotting disorders and no risk of bleeding, the drug significantly improves oral efficacy, which could be used for oral therapy of arterial and venous thrombosis, cancer-related thrombosis and inflammation. 68 …”

“… 68 , 69 The doses of THCMA that inhibit thrombosis do not produce clotting disorders and no risk of bleeding, the drug significantly improves oral efficacy, which could be used for oral therapy of arterial and venous thrombosis, cancer-related thrombosis and inflammation. 68 …”

“…This study has demonstrated the mechanism by which defibrin can counteract thrombotic inflammation mediated by neutrophils in APS. 66 Selection P-selectin is an adhesion molecule expressed on the surface of activated platelets and endothelial cells, 67,68 leading to platelet-monocyte aggregation and stimulating vascular inflammation and thrombosis. 69 Therefore, inhibiting the expression of p-selectin is a good option for reducing the thrombosis.…”

Novel strategies in antithrombotic therapy: targeting thrombosis while preserving hemostasis

“…Antiplatelet effects of P-selectin inhibition have been recognized by investigations using small molecules or monoclonal antibodies. PSI697, a small molecule P-selectin antagonist, reduced both arterial and venous thrombosis in animals ( 96 ), while THCMA, a nanomolecule, was shown to reduce venous thrombosis without inducing bleeding in animal models ( 97 ). Crizanlizumab, a humanized IgG2 monoclonal antibody, was approved in 2019 for patients with sickle cell disease with vaso-occlusive symptoms ( 98 ).…”