Small molecule PZL318: forming fluorescent nanoparticles capable of tracing their interactions with cancer cells and activated platelets, slowing tumor growth and inhibiting thrombosis

Abstract

Low selectivity of chemotherapy correlates with poor outcomes of cancer patients. To improve this issue, a novel agent, N-(1-[3-methoxycarbonyl-4-hydroxyphenyl]-β-carboline-3-carbonyl)-Trp-Lys-OBzl (PZL318), was reported here. The transmission electron microscopy, scanning electron microscopy, and atomic force microscopy images demonstrated that PZL318 can form nanoparticles. Fluorescent and confocal images visualized that PZL318 formed fluorescent nanoparticles capable of targeting cancer cells and tracing their interactions with cancer cells. In vitro, 40 μM of PZL318 inhibited the proliferation of tumorigenic cells, but not nontumorigenic cells. In vivo, 10 nmol/kg of PZL318 slowed the tumor growth of S180 mice and alleviated the thrombosis of ferric chloride-treated ICR mice, while 100 μmol/kg of PZL318 did not injure healthy mice and they exhibited no liver toxicity. By analyzing Fourier transform–mass spectrometry and rotating-frame Overhauser spectroscopy (ROESY) two-dimensional nuclear magnetic resonance spectra, the chemical mechanism of PZL318-forming trimers and nanoparticles was explored. By using mesoscale simulation, a nanoparticle of 3.01 nm in diameter was predicted containing 13 trimers. Scavenging free radicals, downregulating sP-selectin expression and intercalating toward DNA were correlated with the antitumor mechanism of PZL318.

Docking of THPDTPI: to explore P-selectin as a common target of anti-tumor, anti-thrombotic and anti-inflammatory agent

“…To support THPDTPI inhibiting P-selectin expression the intensity of nitrobenzoxadiazole (NBD) fluorescence was measured with flow cytometry experiments [ 20 ]. The NBD fluorescence intensity of PE-anti-CD62P unlabeled platelets (background), PE-anti-CD62P labeled platelets (reference), PE-anti-CD62P labeled and AA activated platelets without THPDTPI (positive control), PE-anti-CD62P labeled and AA activated platelets with THPDTPI (0.1 nM) and PE-anti-CD62P labeled resting platelets with THPDTPI (0.1 nM) are shown in Figure 4A–4E , respectively.…”

“…The minimal effective dose is 0.1 µmol/kg. The anti-thrombotic activity of THPDTPI was also assayed on mouse model by soaking the isolated aorta with FeCl 3 solution according to the literature method [ 20 ]. Figure 7D indicates that the arterial thrombus weight of the mice orally receiving THPDTPI (dose, 1 µmol/kg) is equivalent to that of the mice orally receiving aspirin (dose, 167 µmol/kg).…”

<em>N</em>-(3-hydroxymethyl-&beta;-carboline-1-yl-ethyl-2-yl)-L-Phe: development toward a nanoscaled antitumor drug capable of treating complicated thrombosis and inflammation

“…Structural similarity of intercalators N -[2(3-carboxyl-9-benzyl/H-carboline-1-yl)ethyl-1-yl]-amino acids,24–27 benzyl1-(4-hydroxy-3-methoxycarbonyl-phenyl)-9H-pyrido[3,4-b] indole-3-carboxylate (BPIC),28 N -[1-(3-methoxycarbonyl-4-hydroxyphenyl)-β-carboline-3-carbonyl]-Trp-Lys-OBzl (PZL318)29 and benzyl N ω -nitro- N α -(9H-pyrido[3,4-b]indole-3-carbonyl)-L-argininate (NRCB)30 with HMCEF means that HMCEF may be an intercalator (Figure 1). …”