Biodistribution analysis of cisplatin in liposomal form in animals with cisplatin-resistant and cisplatin-sensitive carcinoma.

AIM: To analyze the relation between pharmacokinetics of cisplatin in liposomal form and antitumor efficacy toward cisplatin-resistant and cisplatin-sensitive variants of Guerin carcinoma. METHODS: Concentration of platinum was measured by atomic absorption spectrophotometry (C115M1 "Selmi", Ukraine). Elimination constant was calculated based on the dynamics of cisplatin concentration in time period between 1 h to 24 h using nonlinear regression analysis. Area under curve (AUC24) was calculated by the trapezium method. RESULTS: It was shown that for liposomal form of cisplatin (LCp) AUC24 in tumor practically didn't depend on the level of the tumor sensitivity, while in animals with the resistant variant (CpRGC), AUC24 for free cisplatin (FCp) decreased by 70% less (p < 0.001) as compared to the sensitive tumor strain (CpSGC). Significant decrease of elimination constant of LCp compared to FCp in blood serum of rats bearing either CpRGC or CpSGC tumors favors cisplatin accumulation in tumor tissues with low vascularization level. The dynamics of cisplatin concentration in CpRGC variant was characterized by 90% higher level in 24 h after administration of LCp as compared to FCp (p < 0.05). This fact may explain increased antitumor efficacy of LCp compared to FCp toward CpRGC variant. In the study of kidney function, AUC24 index for LCp was by 68.6% (p < 0.01) and 50.7% (p < 0.05) lower than AUC24 index for FCp in rats with CpRGC and CpSGC variants, respectively. No significant differences have been found in biodistribution of cisplatin in both pharmaceutical forms in liver and lung in CpRGC- or CpSGC-bearing rats. CONCLUSION: The results suggest that cisplatin in liposomal form possesses higher specificity of antitumor action than free cisplatin.

The study of possibility to elevate antitumor activity and decrease of systemic toxic effects of cisplatin by its binding with deliganded albumin.

AIM: To evaluate antitumor and toxic action of cisplatin (CP) in non-bound form and in a complex with deliganded albumin. METHODS: To study complex-formation between CP and albumin, differential scanning and isothermic flow microcalorimetry were used. For quantitive evaluation of albumin-bound CP, the method of ultrafiltration was applied. Concentration of platinum in the samples was determined by atomic-absorption spectral analysis. Antitumor and toxic effect of CP and CP-albumin complex was studied in vivo using Guerin carcinoma (GC) model. RESULTS: It has been shown that the second drug-binding site, located in the III domain of albumin molecule is one of the main points of binding of CP. Purification of officinal human serum albumin (HSA) on highly active carbon hemosorbents of HSGD mark allows to obtain deliganded albumin (dHSA) with elevated complex-forming ability toward CP. Administration of CP-dHSA complex provides higher rate of GC growth inhibition, than that of CP, and the content of creatinine in blood plasma of GC-bearing rats increases by 15% versus 40% in the case of CP administration. CONCLUSION: The data obtained allow recommend application of CP-dHSA to complex for enhancement of antitumor action and decrease of toxic effects of cisplatin.