A pH-responsive conjugate based 10-hydroxycamptothecin-thiosemicarbazide-polyethene glycol 2000 (10-HCPT-hydro-PEG) nano-micelles were prepared in our previous study. In the present study, ultra-performance liquid chr...A pH-responsive conjugate based 10-hydroxycamptothecin-thiosemicarbazide-polyethene glycol 2000 (10-HCPT-hydro-PEG) nano-micelles were prepared in our previous study. In the present study, ultra-performance liquid chromatography (UPLC-MS) method is developed to investigate its pharmacokinetics and biodistribution in tumor bearing mice. The results demonstrated that the conjugate circulated for a much longer time in the blood circulation system than commercial 10-HCPT injection, and bioavailability was significantly improved compared with 10-HCPT. In vivo biodistribution study showed that the conjugate could enhance the targeting and residence time in tumor site.展开更多
A novel camptothecin analogue, 9-methyl-10-hydroxycamptothecin （4）, was unexpectedly synthesized from 10-hydroxycamptothecin in two steps. The key step included an efficient Mannich-type reaction. The overall yield ...A novel camptothecin analogue, 9-methyl-10-hydroxycamptothecin （4）, was unexpectedly synthesized from 10-hydroxycamptothecin in two steps. The key step included an efficient Mannich-type reaction. The overall yield was 47.2%. An ether analogue of 4, 9-methyl-10-benzylaminomethoxycamptothecin （5）, was also prepared. These new camptothecin analogues were evaluated for in vitro cytotoxicity against four human cancer cell lines, and exhibited more potent antitumor activities than contrals camptothecin and topotecan against several cancer cells.展开更多
Tumor progression is usually characterized by proliferation,migration,and angiogenesis,which is essential for supplying both nutrients and oxygen to the tumor cells.Therefore,targeting angiogenesis has been considered...Tumor progression is usually characterized by proliferation,migration,and angiogenesis,which is essential for supplying both nutrients and oxygen to the tumor cells.Therefore,targeting angiogenesis has been considered a promising therapeutic strategy for cancer prevention and treatment.In the present study,we demonstrated that in addition to suppressing lung cancer cell proliferation and migration in vitro,10-hydroxycamptothecin(10-HCPT)is also capable of inhibiting angiogenesis in vivo with a miR-181a-dependent manner.Mechanistically,by upregulating miR-181a,which in turn downregulating FOXP1,10-HCPT can inhibit the PI3K/Akt/ERK signaling pathwaymediated angiogenesis.Furthermore,reduced levels of miR-181a have been found in both lung cancer cell lines and xenograft with concurrently elevated levels of FOXP1,VEGF,bFGF,and HDGF.Consistent with the findings from the in vitro experiments,miR-181a impairs neovascularization in our xenograft model.In summary,our findings have not only established the anti-oncogenic role of miR-181a in lung cancer angiogenesis but also suggest that 10-HCPT could be a potential therapeutic reagent for lung cancer treatment.展开更多
The present method gives a detailed description for the development and validation of a simple stability indicating reverse phase liquid chromatographic method for 10-hydroxycamptothecin(10-HCTN) in the presence of it...The present method gives a detailed description for the development and validation of a simple stability indicating reverse phase liquid chromatographic method for 10-hydroxycamptothecin(10-HCTN) in the presence of its impurities namely Imp A and Imp B along with degradation products generated from forced degradation studies. The drug was subjected to stress conditions of hydrolysis (acid, base and neutral), oxidative, photolytic and thermal stress degradation. Degradation was observed when subjected to treatment with peroxides or under conditions normally used for typical acid and base hydrolysis. The drug was found to be stable under other stress conditions attempted such as photolytic and thermal. Successful separation and isolation of the drug from related impurities and degradation products formed under stress conditions was achieved on an Inertsil ODS-3V (250 mm × 4.6 mm, 5 μm) column using a phosphate buffer, acetonitrile, methanol and Nanopure water. The developed HPLC method was validated with respect to specificity, linearity, accuracy, precision, sensitivity, robustness and solution stability. The assay method was found to be linear in the range of 0.16 mg/mL to 0.24 mg/mL with a correlation coefficient of 0.999 and the linearity of the impurities was established from 0.02% (LOQ) to 0.3%. Recoveries of assay and impurities were found between 99.4% and 100.3%. The developed HPLC method can be used to determine the related substances and assay determinations of 10-HCTN and also to evaluate the quality and long term stability of production samples.展开更多
基金supported by the Major National Scientific Research Projects (2015CB932103)
文摘A pH-responsive conjugate based 10-hydroxycamptothecin-thiosemicarbazide-polyethene glycol 2000 (10-HCPT-hydro-PEG) nano-micelles were prepared in our previous study. In the present study, ultra-performance liquid chromatography (UPLC-MS) method is developed to investigate its pharmacokinetics and biodistribution in tumor bearing mice. The results demonstrated that the conjugate circulated for a much longer time in the blood circulation system than commercial 10-HCPT injection, and bioavailability was significantly improved compared with 10-HCPT. In vivo biodistribution study showed that the conjugate could enhance the targeting and residence time in tumor site.
基金the Natural Science Foundation of Jiangsu Province,China(No.BK2007168)
文摘A novel camptothecin analogue, 9-methyl-10-hydroxycamptothecin （4）, was unexpectedly synthesized from 10-hydroxycamptothecin in two steps. The key step included an efficient Mannich-type reaction. The overall yield was 47.2%. An ether analogue of 4, 9-methyl-10-benzylaminomethoxycamptothecin （5）, was also prepared. These new camptothecin analogues were evaluated for in vitro cytotoxicity against four human cancer cell lines, and exhibited more potent antitumor activities than contrals camptothecin and topotecan against several cancer cells.
基金supported by the National Natural Science Foundation of China(Nos.81702296,81772281)the Shandong Science and Technology Committee(Nos.2017GSF18124,ZR2019PC019,ZR2019MH022)+1 种基金the Health Commission of Shandong Province(Nos.2017WS737,2019KJK014)the Shandong Province Taishan Scholar Project(No.ts201712067).
文摘Tumor progression is usually characterized by proliferation,migration,and angiogenesis,which is essential for supplying both nutrients and oxygen to the tumor cells.Therefore,targeting angiogenesis has been considered a promising therapeutic strategy for cancer prevention and treatment.In the present study,we demonstrated that in addition to suppressing lung cancer cell proliferation and migration in vitro,10-hydroxycamptothecin(10-HCPT)is also capable of inhibiting angiogenesis in vivo with a miR-181a-dependent manner.Mechanistically,by upregulating miR-181a,which in turn downregulating FOXP1,10-HCPT can inhibit the PI3K/Akt/ERK signaling pathwaymediated angiogenesis.Furthermore,reduced levels of miR-181a have been found in both lung cancer cell lines and xenograft with concurrently elevated levels of FOXP1,VEGF,bFGF,and HDGF.Consistent with the findings from the in vitro experiments,miR-181a impairs neovascularization in our xenograft model.In summary,our findings have not only established the anti-oncogenic role of miR-181a in lung cancer angiogenesis but also suggest that 10-HCPT could be a potential therapeutic reagent for lung cancer treatment.
文摘The present method gives a detailed description for the development and validation of a simple stability indicating reverse phase liquid chromatographic method for 10-hydroxycamptothecin(10-HCTN) in the presence of its impurities namely Imp A and Imp B along with degradation products generated from forced degradation studies. The drug was subjected to stress conditions of hydrolysis (acid, base and neutral), oxidative, photolytic and thermal stress degradation. Degradation was observed when subjected to treatment with peroxides or under conditions normally used for typical acid and base hydrolysis. The drug was found to be stable under other stress conditions attempted such as photolytic and thermal. Successful separation and isolation of the drug from related impurities and degradation products formed under stress conditions was achieved on an Inertsil ODS-3V (250 mm × 4.6 mm, 5 μm) column using a phosphate buffer, acetonitrile, methanol and Nanopure water. The developed HPLC method was validated with respect to specificity, linearity, accuracy, precision, sensitivity, robustness and solution stability. The assay method was found to be linear in the range of 0.16 mg/mL to 0.24 mg/mL with a correlation coefficient of 0.999 and the linearity of the impurities was established from 0.02% (LOQ) to 0.3%. Recoveries of assay and impurities were found between 99.4% and 100.3%. The developed HPLC method can be used to determine the related substances and assay determinations of 10-HCTN and also to evaluate the quality and long term stability of production samples.
基金Supported by Sino-French Advanced Research Project(PRA B02-07)Scientific and technological achievements promotion project of Guangzhou city(2006C13G0011)
