title: 9-nitrocamptothecin polymeric nanoparticles: cytotoxicity and pharmacokinetic studies of lactone and total forms of drug in rats.
abstract: The objective of this study was to evaluate the cytotoxicity and pharmacokinetics of total and lactone forms of 9-nitrocamptothecin (9-NC), an effective antineoplastic drug, after intravenous injection of drug incorporated into poly (DL-lactic-glycolic acid) nanoparticles (NPs). Drug-loaded NPs (9-NC.NP) were prepared by the nanoprecipitation method and examined for particle characteristics and in-vitro release in phosphate buffered saline. The best formulation showed a narrow size with an average diameter of 207+/-26 nm and a drug loading of more than 33.5%. The drug release profile showed a sustained 9-NC release up to 160 h. For a pharmacokinetic study, the concentration of 9-NC as the lactone form (9-NC.lac) and as the total of the lactone and carboxylate forms (9-NC.tot) in plasma was determined by using reverse-phase high performance liquid chromatography after intravenous administration of 9-NC.NP and a control solution to cannulated Wistar rats. In-vitro cytotoxic activity of 9-NC.NP and control solution was evaluated on the human ovarian cancer cell line (A2780sn) by MTT cell cytotoxicity assay. Results of in-vivo studies showed that NP encapsulation markedly increased the plasma concentration of both lactone and total forms of 9-NC compared with free drug. In comparison with free drug, NPs resulted in 3.63-fold and 5.40-fold increases in area under the plasma concentration-versus-time curve (AUC(0-infinity)) for lactone and total forms of 9-NC, respectively. The values of mean residence time and elimination half-life (T(1/2)) were also significantly higher for NPs than for free drug. The in-vitro cytotoxicity study revealed that the IC50 value of NPs decreased 10-fold compared with the drug solution. Prepared NPs described here were considered potentially useful in both stabilizing and delivering 9-NC and enhancing the efficacy of this drug for cancer treatment for which high drug retention in the body, protection from the drug-active lactone form, and gradual drug release appeared to be related.
authors.affiliation: Department of Pharmaceutics, School of Pharmacy, Shaheed Beheshti Medical University, Tehran, Iran. Sdadashzadeh@sbmu.ac.ir
authors.forename: Simin
authors.initials: S
authors.lastname: Dadashzadeh
authors.forename: Katayoun
authors.initials: K
authors.lastname: Derakhshandeh
authors.forename: Farshad Hoseini
authors.initials: FH
authors.lastname: Shirazi
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000494:pharmacology*; D019540:Area Under Curve; D002166:Camptothecin / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000494:pharmacology; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D006801:Humans; D007275:Injections, Intravenous; D007783:Lactones; D008297:Male; D053758:Nanoparticles; D051381:Rats; D017208:Rats, Wistar; D013778:Tetrazolium Salts; D013844:Thiazoles
chemical_list: D000970:Antineoplastic Agents; D007783:Lactones; D013778:Tetrazolium Salts; D013844:Thiazoles; C022616:thiazolyl blue; C079905:rubitecan; D002166:Camptothecin