Pilot Research And Development On A Novel Anticancer Platinum Compound (SM54111) With Modern Analytical Technology

Cisplatin and its analogues belong to one kind of the most valuable chemotherapeutic drugs, with conclusive structure-function relationship.It is a wise way to design, synthesize, or discovery alternative cisplatin analogues following its basic chemical structure, to promote the solubility, stability, toxicity, and drug-resistance.Thereafter, this dissertation aimed at a pilot study on a novel platinum compound of its basic drug-like properties, pharmacokinetics and pharmaceutics. It involves establishing an HPLC-ESI-MS method to investigate the purity and the related substances of this novel anticancer platinum drug candidate, whose chemical name is 1R,2R-cyclohexano-diamoni-3,5-diisopropylsalisilic-Pt(II),SM54111 for short; an HPCE method hyphened with ESI-MS offline to probe its stability in solution with different pH values from 3.7-9.0;and an HPLC method to determine its oil-water partition coefficient in n-octanol by shaking-flask mode.The results proved that the purity of SM54111 was 96% appropriately, and SM54111 remained stability either in daylight or at high temperature.At range of pH 5.0-9.0 SM54111 remained stability in solution also, and its logP value was calculated as 2.72, all of which were meaningfulness to its further development.And the studies on SM54111's pharmacokinetics of plasma in rabbits, tissue distribution, and excretion in urine and feces of rats were carried out respectively. With ICP-MS method and 3P97 software, after intravenous administration in rabbits at concentrations of 2.5,5.0, and 9.0 mg/kg, the initial concentrations of 3 doses (Co) were 8.68±0.80,20.04±1.92, and 28.88±2.32 mg/L correspondingly, the area under concentration-time profile from time 0 to 144 h (AUC0-t)were 94.0±12.9,251.3±40.1,and 396.9±61.1 mg/L/h; the terminal elimination half-life time (t1/2β)29.1±4.8,35.2±7.5,and 29.4±2.8 h; the distribution volume (Vd)0.285±0.047,0.307±0.081 and 0.294±0.017;and the clearance rate(CL)0.026±0.004,0.019±0.002, and 0.022±0.004 L/h, respevtively. It is reasonable to surmise that SM54111 follows first order rate pharmacokinetics, and no saturation was detected at concentrations from 2.5 to 9.0 mg/kg.With 3.0 mg/kg dose, the pharmacokinetic parameters after intravenous administration were as following:the area under concentration-time profile from time 0 to 72 h (AUC0-t) were 20.6 ±10.3 mg/L/h;the terminal elimination half-life time (t1/2β) 11.6±9.9 h;the distribution volume (Vd)0.36±0.03 L; and the clearance rate (CL) 0.156±0.080 L/h, respevtively. Compared with heart, brain, adipose, testicle and ovaries, SM54111 showed much higher concentration in spleen, kidney and liver in rats (p<0.001),higher concentration in lung (p<0.005).The accumulative excretion rates by urine and feces in rats till 96 h were appropriate 25% and 5%,respectively, showing slow elimination by experimental animals. Compared with commercial platinum anticancer drugs available, pharmacokinetic fate of SM54111 in vivo was similar with oxaliplatin, which offered insight of its toxicity and possible anticancer spectrum.Initial research on dosage form was carried out with the preparation of SM54111 liposomes. By rotation-evaporation film method (lipid film hydration method), the entrapment efficiency of SM54111 liposomes was 65% determined with HPLC assay. Under optimum microfludizing condition, its grain size was at the range of 100～300 nm with polydisperity index 0.1-0.4, with the shape of spherical balls under TEM.In summary, it was proved that SM54111 showed amiable drug-like properties, pharmacokinetical characterization in pre-clinic, and suitable to liposomes as its dosage form. SM54111 can be recognized as an encouraging anticancer drug candidate, and it is valuble for further research and development.