| With the development of society, modern lifestyles and environmental pollution result in dramatic increase in cancer patients. Treatment of cancer is a worldwide problem that humanity has not yet overcome. In order to treat cancer, scientists have spent a lot of energy for the anti-cancer drug research and development. Camptothecin (CPT) is a well-established topoisomerase I inhibitor against a broad spectrum of cancers. Because of its unique anti-tumor mechanism, CPT has been listed as one of the key research of anticancer drugs by the U.S. National Cancer Institute (NCI). However, poor aqueous solubility, instability of the lactone ring in vivo under physiological conditions at pH7.4, and toxic effects to normal tissues have limited CPT clinical development. CZ48(camptothecin-C20-propionate), a C20-propionate ester of camptothecin, was synthesized as a derivative resistant to lactone hydrolysis. CZ48has demonstrated strong anticancer activity with an exceptional lack of toxicity. CZ48acts as a prodrug and exerts its anticancer activity by carboxylesterases mediated hydrolysis to the active metabolite CPT in vivo. CZ48has entered phase I clinical studies in the United States, which of great prospects anticancer drugs development. However, poor aqueous solubility and low degree of bioavailability by oral is still the main problems that hinder the CZ48clinical applications. In this study, two drug carrier systems were fabricated, i.e., a biocompatible and biodegradable polymer material polylactic acid (PLA) as the carrier material, contained CZ48polylactic acid nanoparticles and contained CZ48microbubble ultrasound contrast agent, whose morphology, encapsulation efficiency, drug loading efficiency and release performance in vitro and pharmacokinetic in vivo were studied, The purpose is to extend the residence time of drugs in the body with the aid of good water dispersion and sustained controlled drug release of the drug delivery system. so as to make up for the poor aqueous solubility and low bioavailability of CZ48. The study results are as follows:in the study of CZ48loaded PLA nanoparticles drug carrier systems (1) emulsion solvent evaporation method was used to prepare polylactic acid nanoparticles containing anticancer drugs CZ48nanoparticles, whose encapsulation efficiency and drug loading efficiency were88.7%and11.8%respectively, The average particle size being260.6nm;(2) a determination method of using the fluorescence spectrophotometer determinate concentration of CZ48in phosphate buffered saline (PBS,pH=7.4) was created. Experimental results of drug release in vitro show that CZ48-PLA nanoparticles have a good release effect;(3) using liquid-liquid extraction (LLE) to deal with biological samples, plus HPLC analysis, the methods of simultaneous determination of CZ48content and its major metabolite CPT in biological samples was established, and the comprehensive methodology demonstration were carried out. The advantages of this method lie in the simplicity and practicability, selective specificity, high sensitivity, high accuracy and good reproducibility;(4) pharmacokinetic experiments demonstrated that CZ48-PLA nanoparticles did not show the expected sustained release effect, which may be related to the large number of nanoparticles that were phagocytosed by macrophage in body. In the study of CZ48-loaded microbubbles ultrasound contrast agent drug carrier systems,(1) CZ48-loaded microbubbles ultrasound contrast agent was successfully prepared using double emulsion solvent evaporation and lyophilization methods, a biocompatible, safe and biodegradable high molecular polymer being employed as the shell material. The morphology of the polymeric microbubbles observed with scanning electron microscope appeared regular spherical with hollow structure and a tight size distribution. When preparation of materials contain25mg of PLA,5mL dichloromethane and80mg CZ48, CZ48-loaded microbubbles have the largest encapsulation efficiency and drug loading efficiency of85.73%and26.07%, respectively. The particle size distribution ranges from0.5to6.7urn,98%of which is less than7μm, which meet the requirement of the size for ultrasound contrast agent.(2) The in vitro release studies have found that CZ48-loaded microbubble ultrasound contrast agent had a very good drug release effect. Ultrasound can promote the release of drugs and the longer ultrasound is the promote effects were more obvious.(3) In vitro and in vivo ultrasound contrast effects indicated that CZ48-loaded microbubbles showed high echogenicity and strong stability in vivo.(4) Pharmacokinetics results show that CZ48-loaded microbubbles have delayed time to peak (Tmax), T1/2and MRT, and have increased the AUC0-∞thereby enhancing the CZ48bioavailability and inhibit tumor effect. The significance of this research is:Through fabricating the two drug delivery systems of CZ48contained PLA nanoparticles and carrier the CZ48microbubble ultrasound contrast agent, their drug release behavior in vivo and in vitro was comprehensively studied, which can build the basis for further study of these two systems and even for the research and development CZ48new drug delivery system; the method of simultaneous determination of CZ48and CPT content in biological samples in this study may provide some reference for determinating durg content in other drug delivery system research for CZ48.
|
PDF Full Text Request