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


中文翻译：

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一种新型小分子 P-选择素抑制剂的纳米颗粒可减轻两种动物模型中的血栓形成、炎症和肿瘤生长

目的：评估新设计的小分子口服 P-选择素抑制剂 3 S -1,2,3,4-四氢-β-咔啉-3-甲基天冬氨酰酯 (THCMA) 作为纳米药物是否能增强抗血栓、抗炎，且抗肿瘤活性超过临床试验药物PSI-697。
方法： THCMA 被设计为含有 PSI-697 药效团的两亲物。使用 TEM、SEM、Tyndall 效应、ζ 电位、FT-ICR-MS 和 NOESY 2D ^{1探索其纳米特征}核磁共振氢谱。THCMA 的 P-选择素抑制作用通过分子对接、紫外 (UV) 光谱和竞争性 ELISA 得到证实。体内和体外测定——抗动脉血栓形成、抗静脉血栓形成、抗炎、抗肿瘤生长、抗血小板聚集、鼠尾出血时间、抗凝指数、可溶性 P-选择素 (sP-选择素) 表达和血清 TNFα 表达——用于探索生物活性和潜在机制。使用紫外吸收光谱测量 THCMA 的水溶性。
结果：THCMA 自组装成直径约 100 nm 的纳米环。其水溶性约为 PSI-697 的 1,030 倍。THCMA 表现出比 PSI-697 更有效的 P-选择素抑制作用。THCMA 的口服疗效是 PSI-697 抑制动脉和静脉血栓形成的 100 倍，抑制炎症的 10 倍。THCMA 抑制血栓形成的剂量不会产生凝血障碍和出血风险。THCMA 表现出比 PSI-697 更强的抗肿瘤活性，而没有全身化疗毒性。THCMA 在体外显着抑制血小板聚集，在体内下调血清 sP-选择素和 TNFα 的表达水平。
结论：一种新型小分子 P-选择素抑制剂 THCMA 已成功设计为纳米药物，与临床试验药物 PSI-697 相比，其口服疗效显着增强，因此可能被开发用于口服治疗动脉血栓形成、静脉血栓形成、炎症和癌症相关的血栓形成。

关键词： P-选择素，血栓形成，炎症，癌症，拮抗剂，自组装