| Summary: | 碩士 === 高雄醫學大學 === 藥學系碩士班 === 104 === SN-38(7-ethyl-10-hydroxycamptothecin), the active metabolite of the commercial drug, irinotecan, is approximately 100-1000-fold cytotoxicity than irinotecan. Due to the poor solubility, instability in alkaline and severe side effect, SN-38 has not been used in the clinical. The aim of the study was to employ decorated SN38-loaded liposomes to solve the problems above. We have designed a series of decorations including Pluronic® F-68, DSPE-PEG2000, PEG2000 and DSPE-PEG2000-folate. The decorated liposomes existed ideal particle size (69~104 nm), uniform particle size distribution (PDI<0.2, except for the DSPE-PEG2000 groups)and high drug encapsulation efficiency (66~96%). Moreover, DSPE-PEG2000 groups had more negative zeta-potential (-45~-55 mV)compared to another groups (-3~-10 mV). In the release study, all the decorated liposomes followed Higuchi kinetics (R>0.968) in 24 h. To investigate the targeting effect of decorated liposomes, we selected folate receptor over-expressed MCF-7(human breast adenocarcinoma cell line). IC50 of the targeting liposome (fD20) is better than SN-38 solution and other formulations. The confocal laser scanning microscopy (CLSM)images showed that fD20 rapid enter into MCF-7 cells within 4 h. Hence, we selected fD20 to conduct the in vivo test. In vivo biodistribution showed that fD20 was mainly distributed to liver and spleen compared with SN-38 solutions (p<0.05). Moreover, the pharmacokinetic parameters also showed that the higher CL and Vd in fD20, which caused rapid elimination from the central compartment (p<0.001). In addition, the biochemistry data showed that fD20 caused less platelet decrease, AST and ALT increase and less distributed to heart, which presumably had toxic improvement in these organs (p<0.001). The study successfully improved the solubility of SN-38 and avoided it from alkaline by encapsulating it into liposomes. Furthermore, liposomal formulations of SN-38 have potentials in improving side effects.
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