A Novel Camptothecin Derivative Incorporated in Nano-Carrier Induced Distinguished Improvement in Solubility, Stability and Anti-tumor Activity Both In Vitro and In Vivo

Abstract

Purpose. An oil/water nanoemulsion was developed in the present study to enhance the solubility, stability and anti-tumor activity of a novel 10-methoxy-9-nitrocamptothecin (MONCPT). Materials and Methods. MONCPT nanoemulsion was prepared using Lipoid E80 and cremophor EL as main emulsifiers by microfluidization. The droplet size of the nanoemulsion was measured by dynamic light scattering. In vitro drug release was monitored by membrane dialysis. Kinetics of MONCPT transformed into carboxylic salt was performed in phosphate buffer at different pH. Hemolysis of MONCPT nanoemulsion was conducted in rabbit erythrocytes. Solubilization character of MONCPT in nanoemulsion was experimented using Nile red as a solvatochromic probe. In vitro cytotoxicity of the nanoemulsion was measured in A549 and S180 cells using Sulforhodamine B protein stain method, and suppression rate of tumor growth was investigated in S180-bearing mice. The cell cycle effects of MONCPT nanoemulsion on S180 cells were analyzed by flow cytometry. Distribution of the nanoemulsion in A549 cells and S180-bearing mice were also investigated by fluorescence image. Results. MONCPT is incorporated in the nanoemulsion in form of lactone with concentration of 489 µg/ml, more than 200 folds higher than that in water. Experiments using Nile red as a solvatochromic probe indicated that more MONCPT might be located in the interfacial surfactant layer of the nanoemulsion than that in discrete oil droplet or continuous aqueous phase. Nanoemulsion could release MONCPT in a sustained way, and it was further shown to notably postpone the hydrolysis of MONCPT with longer hydrolysis half-life time (11.38 h) in nanoemulsion at pH 7.4 than that of MONCPT solution (4.03 h). No obvious hemolysis was caused by MOCPT nanoemulsion in rabbit erythrocytes. MONCPT nanoemulsion showed a marked increase in cytotoxic activity, 23.6 folds and 28.6 folds in S180 cells and A549 cells respectively via arresting the cell at G2 phase, compared to that induced by MONCPT injection. It correlated well to the in vivo anti-tumor activity of MONCPT nanoemulsion with suppression rate of 93.6%, while that of MONCPT injection was only 24.2% at the same dosage. Moreover, nanoemulsion exhibited enhanced capability of delivering drug into malignant cell's nucleus in vitro and induced drug accumulation in tumor in S180-bearing mice using in vivo imaging. Conclusion. The nanoemulsion prepared exhibited an improved MONCPT solubility, stability and antitumor activity, providing a promising carrier for cancer chemotherapy using MONCPT.

The effect of siRNA-Egr-1 and camptothecin on growth and chemosensitivity of breast cancer cell lines

“…Egr-1 is highly induced under these conditions and its activities stimulated angiogenesis and improved survival ONCOLOGY REPORTS 23: 1159-1165, 2010 of tumor cells (4,5,8,14). Camptothecin is a cytotoxic plant alkaloid that exhibits a broad spectrum of anti-neoplastic activity against solid tumors (15)(16)(17)(18). The synthesis of camptothecin analogues exhibiting high antitumor activity of the drug, increasing the chemotherapeutic potential of the drug (18)(19)(20).…”

“…DNA topoisomerase I is ubiquitous in eukaryotes and plays an important role in a number of cellular processes involving DNA, including transcription, recombination and DNA replication (20)(21)(22). There is a variety of camptothecin analogues and in general, there is a strong correlation between the cytotoxic activity of a particular camptothecin analogue in cell culture and animal model systems, and its ability to interfere with the catalytic activity of DNA topoisomerase I (17,18,22).…”

In vitro Anti-Cancer Activity of Rosuvastatin and Ketorolac Nanoformulations against DDX3

“…Nanoemulsion drug delivery have been reported to improve the bioavailability of hydrophobic drugs very effectively 53,54 , increased in vivo performance of anticancer drugs, e.g., dacarbazine 55 and camptothecin. 56 In our present study, we have formulated RST and KT nanoemulsions as a carrier for new DDX3 helicase inhibitor. Stability of nanoemulsions at various pH were performed for the optimized formulation, permeation across porcine -buccal membrane, further evaluated the significance of nanoemulsions of RST and KT in anticancer activity in K-562 cell lines.…”

Targeted Nanoparticulate drug-delivery Systems for Treatment of Solid Tumors: a Review

“…Polyplexes formed by the interaction of plasmid DNA and cationic dendrimers have also been extensively explored. Hyperbranched polyether polyols have been partially functionalized with quaternary or tertiary ammonium groups by Tziveleka and co-workers resulting in dendritic polymers that interact with pDNA affording polyplexes for gene delivery [94].…”