N-(3-hydroxymethyl-β-carboline-1-yl-ethyl-2-yl)-L-Phe: development toward a nanoscaled antitumor drug capable of treating complicated thrombosis and inflammation

Jianhui Wu,1–4 Ming Zhao,1–5 Yuji Wang,1–4 Yaonan Wang,1–4 Haimei Zhu,1–4 Shurui Zhao,1–4 Lin Gui,1–4 Xiaoyi Zhang,1–4 Shiqi Peng1–4 1Beijing Area Major Laboratory of Peptide and Small Molecular Drugs, 2Engineering Research Center of Endogenous Prophylactic, Ministry of Education of China, 3Beijing Laboratory of Biomedical Materials, 4College of Pharmaceutical Sciences, Capital Medical University, Beijing, People’s Republic of China; 5Department of Biomedical Science and Environmental Biology, Kaohsiung Medical University, Kaohsiung, Taiwan, Republic of China Abstract: It is well documented that the surfaces of cancer cells, activated platelets and inflammatory cells are rich in P-selectin. N-(3-hydroxymethyl-β-carboline-1-yl-ethyl-2-yl)-l-Phe (HMCEF) is a P-selectin inhibitor capable of simultaneously inhibiting thrombosis and inflammation. Based on the knowledge that P-selectin is a common target for antithrombotic, anti-inflammatory and antitumor drugs, the aim of this study article was to estimate the possibility of HMCEF as a nanoscaled antitumor drug. Images of transmission electron micro­scopy, scanning electron microscopy and atomic force microscopy proved that HMCEF forms nanoparticles with a diameter of <120 nm that promote delivery in blood circulation. In vitro HMCEF intercalates into calf thymus DNA, cuts off DNA pBR22 and inhibits the proliferation of cancer cells. In vivo HMCEF dose dependently (0.2, 2 and 200 nmol/kg per day) slows tumor growth in treated S180 mice, and has a minimal effective dose of 2 nmol/kg per day. At 200 nmol/kg per day, HMCEF does not affect the liver and the kidney of the treated S180 mice, and at 20,000 nmol/kg HMCEF does not affect the liver and the kidney of the treated healthy ICR mice. HMCEF is a promising antitumor drug, which is characterized b