The Anit-tumor Activity And Pharmacokinetics Of Bile Acid Coupled With Camptothecin Derivatives A2

Camptothecin, widely act as cancer chemotherapy, targets the Topoisomerase I during DNA replication. However, due to the molecular structure of camptothecin, it leads to unstable chemical structure, poor water solubility, low rate of binding with plasma proteins, poor and variable oral bioavailability, unpredictable toxicity. All of these disadvantages are limited to the use of camptothecin derivatives.Bile acid can transport drugs by enterohepatic circulation. Drugs coupled with bile acid by chemical method. The new derivatives can target the liver and intestinal in contrast to low others distribution, and they play a key role in curing the liver and intestinal disease. Meanwhile, bile acid is the endogenous substance. It possessed favorable biological compatibility compared with other exogenous carrier. Therefore, bile acid as carrier can achieve the target to liver and intestinal, reduce the side-effect, and improve the uptake and bioavailability.The dissertation studied the activity and toxicity of A2in vitro and in vivo, and oral bioavailability, pharmacokinetics, and tissue distribution of A2in vivo. The results were as follows:A2was synthesized by esterification reaction coupled deoxycholic acid with10site of hydroxycamptothecine. The chemical structure of A2was indentified by:the infrared spectroscopy, mass spectra,1H NMR. The99%purity of A2was detective by HPLC equipped with UV detection.The anti-proliferative activity of A2was analyzed by the MTT assay in virto. A2can inhibit the proliferation of human colon cancer cells (HCT-116), and the effect on HCT-116is equal to CPT. In the meantime, A2has no effect on inhibiting the proliferation of human liver cell (HL-7702), in contrast that CPT shows high toxicity on normal cells. The SMMC-7721cell uptake experiment confirms that A2enter into cells by active transport and passive difussion. Organic anion transport protein (OATP) involved in A2active transport across the membrane. Hence, bile acid as drug carrier plays a key role in drugs entering cells.In single dose acute toxicity test which has been carried out by KM mice, it has been shown that the toxicity of A2is lower than CPT. The tumor growth inhibition rate of A2and CPT is82.9%,58.4%,58.2%and74.7%,74.1%,73.8%, respectively. The tumor growth inhibition of high dose group of A2is higher than CPT. Although concentration of dose administration is different between CPT and A2, the inhibited tumor growth of A2can be improved by increase dose concentration resulted by the low toxicity of A2.A rapid and simple liquid chromatography tandem mass spectrometry method was established. This method is used as quantified the concentration of A2in plasma and tissue distribution. The analysis method, included specificity, linearity, precision and accuracy, the matrix effect and the recovery rate of extraction and stability was validated.After oral administration of A2(50mg/kg), the pharmacokinetics parameters were calculated. A2was absorbed in vivo for longer time than CPT. A2abundantly gathered in intestinal tissue. Intestinal and liver act as the main organs to absorb and metabolize. However, A2exist less in organ which is abundant of blood. After oral administration of A212h, it is not detective A2in heart.The dissertation found that A2was appropriate to cure intestinal cancer resulted from the low toxicity and high oral bioavailability. All of results lay a foundation for further research and clinical evaluation of A2.