betadex and rubitecan

The aim of this study was to evaluate the safety and anti-tumor effect of 9-nitro-camptothecin/hydroxypropyl-β-cyclodextrin (9-NC/HP-β-CD) complex on tumor-bearing mice. The in vitro anti-tumor activity was tested by MTT assay. Our study revealed that the 9-NC/HP-β-CD complex showed significant anti-tumor activity towards Skov-3, MCF-7, HeLa and S180 cell lines with IC(50) values of 0.24 ± 0.09, 0.59 ± 0.20, 0.83 ± 0.11, and 6.30 ± 2.42 μg/ml, respectively, significantly superior to the free 9-NC. The in vivo therapeutic efficacy was investigated in ICR mice bearing mouse sarcoma S180. Both the high (3mg/kg) and low (1mg/kg) doses of 9-NC/HP-β-CD complex demonstrated high inhibition ratio of tumor growth (>75%). The subacute toxicity test was performed by measuring the body weight, histopathology, blood cell counts and clinical chemistry parameters (total bilirubin, alanine transferase, aspartate transferase, blood urea nitrogen and creatinine), and the results indicated the good safety profile of the complex. Taken together, the results suggested that the 9-NC complexed in HP-β-CD, instead of dissolved in the organic solvent, presented significant anti-tumor activity and low toxicity for the treatment of cancer.

Topics: 2-Hydroxypropyl-beta-cyclodextrin; Adjuvants, Pharmaceutic; Animals; Antineoplastic Agents; beta-Cyclodextrins; Camptothecin; Cell Line, Tumor; Cell Proliferation; Cell Survival; Drug Compounding; Humans; Inhibitory Concentration 50; Mice; Mice, Inbred ICR; Sarcoma 180; Toxicity Tests, Chronic; Xenograft Model Antitumor Assays

The effect of a series of cyclodextrins (CDs), especially hydroxypropyl-beta-cyclodextrin (HP-beta-CD), on aqueous solubility and chemical stability of 9-nitro-camptothecin (9-NC), was investigated with an aim of preparing a stable and effective parenteral formulation. The 9-NC/HP-beta-CD complex was obtained in solid form by freeze drying. Then, the pharmacokinetic profiles in rats of aqueous complex were compared to those of free 9-NC solution having an equivalent concentration. The aqueous solubility of 9-NC was increased to 0.52 mg/ml (lower than 5 microg/ml in distilled water, 25 degrees C) by the combination of pH and temperature adjustment. In addition, hydrolysis of 9-NC following pseudo-first-order kinetics was decelerated significantly in physiologic condition in the presence of HP-beta-CD. Comparison of in vivo pharmacokinetic parameters of free 9-NC with the complex indicated that the complex had higher AUC(0-infinity) (439.39 ng h/ml vs. 632.79 ng h/ml for i.m. administration and 385.39 ng h/ml vs. 538.05 ng h/ml for i.v. administration, respectively) and ratio of lactone form. These results demonstrated that 9-NC/HP-beta-CD complex is an attractive parenteral formulation for cancer therapy.

Topics: 2-Hydroxypropyl-beta-cyclodextrin; Animals; Antineoplastic Agents; Area Under Curve; beta-Cyclodextrins; Camptothecin; Drug Evaluation, Preclinical; Drug Stability; Freeze Drying; Half-Life; Hydrogen-Ion Concentration; Hydrolysis; Male; Rats; Rats, Sprague-Dawley; Solubility; Temperature