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Chemotherapy outcomes for the treatment of glioma remains unsatisfactory due to the inefficient drug transport across the blood-brain barrier (BBB) and insufficient drug accumulation in the tumor region. Although many approaches, including various nanosystems, have been developed to promote the distribution of chemotherapeutics in the brain tumor, the delivery efficiency and the possible damage to the normal brain function still greatly restrict the clinical application of the nanocarriers. Therefore, it is urgent and necessary to discover more safe and effective BBB penetration and glioma-targeting strategies. In the present study, menthol, one of the strongest BBB penetration enhancers screened from traditional Chinese medicine, was conjugated to casein, a natural food protein with brain targeting capability. Then the conjugate self-assembled into the nanoparticles to load anti-cancer drugs. The nanoparticles were characterized to have appropriate size, spheroid shape and high loading drug capacity. Tumor spheroid penetration experiments demonstrated that penetration ability of menthol-modified casein nanoparticles (M-CA-NP) into the tumor were much deeper than that of unmodified nanoparticles. imaging further verified that M-CA-NPs exhibited higher brain tumor distribution than unmodified nanoparticles. The median survival time of glioma-bearing mice treated with HCPT-M-CA-NPs was significantly prolonged than those treated with free HCPT or HCPT-CA-NPs. HE staining of the organs indicated the safety of the nanoparticles. Therefore, the study combined the advantages of traditional Chinese medicine strategy with modern delivery technology for brain targeting, and provide a safe and effective approach for glioma therapy.
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Objective:To establish an LC–MS/MS method for the determination of the active metabolite(SN-38) and secondary metabolite(SN-38G) of irinotecan in rat liver microsomes incubation system, and optimize the incubation conditions. Methods:Meth-anol was selected to precipitate protein in the samples, and then the concentrations were analyzed by LC–MS/MS. All the separation was carried out on a ZORBAX Eclipse XDB-C18 column(2. 1 mm × 50 mm, 3. 5 μm) with the mobile phase of acetonitrile – water (containing 0. 1% formic acid) (23 :77) at a flow rate of 0. 3 ml·min-1. The mass spectrometer was operated with multiple reac-tions monitoring ( MRM) using electrospray ionization ( ESI) . The incubation conditions were optimized by single factor design. Re-sults:SN-38 and SN-38G showed a good linearity ( r≥0. 9972) respectively within the range of 2. 3-920 ng·ml-1 and 2. 5-1000 ng ·ml-1. The intra-and inter-day RSD was below 14. 6%(n=6). The average recovery was within the range of 74. 1%-123. 4% with RSD below 13. 5% (n=6). The optimal incubation conditions were as follows:the concentration of liver microsomal protein was 0. 3 mg·ml-1 and the incubation time was 30 min. Conclusion:The method is rapid, sensitive and accurate in the quantification of SN-38 and SN-38G in the incubation system,which provides methodological basis for the activity determination of UGT1A1 enzyme in vitro.
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OBJECTIVE:To develop a method for simultaneous determination of irinotecan(CPT-11)and its active metabo-lite 7-ethyl-10-hydroxycamptothecin(SN-38)in human plasma.METHODS:After precipitated by acetonitrile and acidified with hy-drochloric acid,using camptothecin as internal standard,the plasma sample was determined by HPLC-FLD. The determination was performed on Waters Luna C18column with mobile phase consisted of 0.05 mol/L sodium dihydrogen phosphate-acetonitrile(70:30, V/V,adjusted pH to 4.0 by phosphoric acid)at flow rate of 1 mL/min. The excitation wavelength was set at 380 nm;the emis-sion wavelengths of CPT-11 and SN-38 were set at 480 nm and 535 nm,respectively. The column temperature was 25 ℃ and the sample size was 20 μL. RESULTS:The linear ranges were 200-1 000 ng/mL for CPT-11(r=0.999 4,n=5)and 5-45 ng/mL for SN-38(r=0.999 2,n=5). RSDs of inter-day and intra-day were 1.68%-5.57%. The relative recoveries of CPT-11 and SN-38 were 90.12%-106.93%(RSD<8%,n=5)and 92.07%-102.56%(RSD<6%,n=5);the extraction recoveries of CPT-11 and SN-38 were 72.23%-86.56%(RSD<6%,n=5)and 71.98%-83.44%(RSD<7%,n=5),respectively. The plasma concentra-tions of CPT-11 and SN-38 in 5 patients with colon cancer were 431.13-617.19,13.97-31.89 ng/mL(1 h after intravenous drip-ping)and 398.14-584.43,11.61-29.94 ng/mL(2 h after intravenous dripping). CONCLUSIONS:The method is simple,rapid, sensitive,reproducible and suitable for the determination of plasma concentration and pharmacokinetic study of CPT-11 and its metabolite SN-38.
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OBJECTIVE:To develop a method for simultaneous determination of irinotecan(CPT-11)and its active metabo-lite 7-ethyl-10-hydroxycamptothecin(SN-38)in human plasma.METHODS:After precipitated by acetonitrile and acidified with hy-drochloric acid,using camptothecin as internal standard,the plasma sample was determined by HPLC-FLD. The determination was performed on Waters Luna C18column with mobile phase consisted of 0.05 mol/L sodium dihydrogen phosphate-acetonitrile(70:30, V/V,adjusted pH to 4.0 by phosphoric acid)at flow rate of 1 mL/min. The excitation wavelength was set at 380 nm;the emis-sion wavelengths of CPT-11 and SN-38 were set at 480 nm and 535 nm,respectively. The column temperature was 25 ℃ and the sample size was 20 μL. RESULTS:The linear ranges were 200-1 000 ng/mL for CPT-11(r=0.999 4,n=5)and 5-45 ng/mL for SN-38(r=0.999 2,n=5). RSDs of inter-day and intra-day were 1.68%-5.57%. The relative recoveries of CPT-11 and SN-38 were 90.12%-106.93%(RSD<8%,n=5)and 92.07%-102.56%(RSD<6%,n=5);the extraction recoveries of CPT-11 and SN-38 were 72.23%-86.56%(RSD<6%,n=5)and 71.98%-83.44%(RSD<7%,n=5),respectively. The plasma concentra-tions of CPT-11 and SN-38 in 5 patients with colon cancer were 431.13-617.19,13.97-31.89 ng/mL(1 h after intravenous drip-ping)and 398.14-584.43,11.61-29.94 ng/mL(2 h after intravenous dripping). CONCLUSIONS:The method is simple,rapid, sensitive,reproducible and suitable for the determination of plasma concentration and pharmacokinetic study of CPT-11 and its metabolite SN-38.
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Objective To prepare a 10-hydroxycamptothecin (10-HCPT) loaded folate-receptor targeted phase-change contrast agent (FR-HCPT-PNPCA),and to study the general characteristics including drug loading,phase changing and targeting capability in vitro.Methods Using a method of two-step emulsification,the phase-change nanoparticles loading anticancer drug (10-HCPT) with lipids shell and liquid pefluorocarbon core were prepared.The entrapment efficiency and the drug-loading amounts were studied by high performance liquid chromatography,and the phase transition of the nanoparticles after heating was observed.The targeting ability was evaluated on liver cancer cell line 7721 in vitro.Results The FR-HCPT-PNPCA,with a drug encapsulation rate of about 70.42 ％ and drug loading amounts of about 20.05 ％,was prepared successfully.When being heated to 70℃,obvious phase changing and microbubbles generating could be observed under microscope.In addition,a large amount of FR-HCPT-PNPCA particles could adhere specifically around the 7721 cells.Conclusion The prepared FR-HCPT-PNPCA,which has a stable characteristic and high performance of drug loading and tumor targeting,is expected to become a promising multifunctional molecular ultrasound probe for diagnosis and treatment of tumor.
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To improve the bioavailability of 10-hydroxycamptothecin, 10-hydroxycamptothecin solid dispersion(HCPT-SD) and 10-hydroxycamptothecin-phospholipid complex-solid dispersion(HCPT-PC-SD) were prepared, and their solubility and dissolution rate were evaluated in this study. SD rates were administered intragastrically with HCPT-SD or HCPT-PC-SD respectively, then their blood samples were collected at different time intervals. The concentration of HCPT in blood was detected by HPLC method with camptothecin as internal standard, and then its pharmacokinetic parameters were calculated and obtained. The results showed that the Cmax, AUC0-t and AUC0-∞ of both kinds of solid dispersion of HCPT were significantly increased than those of crude drug. The AUC0-t of HCPT-SD was increased by 176.87%, and AUC0-t of HCPT-PC-SD was increased by 254.31% as compared with crude drug. Therefore, the two kinds of solid dispersion of HCPT could significantly enhance the bioavailability of HCPT in SD rates, and the effect of HCPT-PC-SD was more obvious.
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7-Ethyl-10-hydroxycamptothecin (SN-38) is a prominent anticancer agent, but it is insoluble in water and the most pharmaceutically acceptable solvents, the lactone ring of SN-38 shows reversible pH-dependent hydrolysis and forms to the open lactone in alkaline condition. All of these factors limit its application in clinic, and a variety of chemical modification studies have been reported to improve the efficient use of SN-38 by improving its solubility in water and pharmaceutical solvents, stabilizing the lactone form, and altering the pharmacological properties. This paper reviews the pharmacological properties of commercial SN-38 derivatives in clinical trials or preclinical studies and their research progress.
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Objective To ch aracterize and evaluate in vitro and in vivo of the 10-hydroxycamptothecin (HCPT) loaded human serum albumin nanoparticle (HSA-NP) prepared by drug-liquid compound method. Methods The HCPT-HSA-NP was prepared with low weight polyethylene glycol drug-liquid compound and blank albumin nanoparticle. Then the in vitro evaluations were conducted with tests of entrapment efficiency, solution stability, accumulative release, morphous investigation and X-ray powder diffraction. At the same time, the primary pharmacodynamics comparison between HCPT injection and the nano preparation (8 mg/kg) was carried out on animal tumor model. Results The obtained HCPT-HSA-NP fitted to the basal features of nano preparation. The entrapment efficiency was averagely higher than 99% for each sample and the solution was stable. In vitro accumulative release study showed that the preparation had long-term release pattern over 100 hours. In vivo pharmacodynamics study showed that the HCPT-HSA-NP was significantly more effective than HCPT injection (P<0.01). Conclusion The drug-liquid compound method can be used to prepare HCPT-HSA-NP.
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7-Ethyl-10-hydroxycamptothecin (SN-38) is a prominent anticancer agent, but it is insoluble in water and the most pharmaceutically acceptable solvents, the lactone ring of SN-38 shows reversible pH-dependent hydrolysis and forms to the open lactone in alkaline condition. All of these factors limit its application in clinic, and a variety of chemical modification studies have been reported to improve the efficient use of SN-38 by improving its solubility in water and pharmaceutical solvents, stabilizing the lactone form, and altering the pharmacological properties. This paper reviews the pharmacological properties of commercial SN-38 derivatives in clinical trials or preclinical studies and their research progress.
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Objective To characterize and evaluate in vitro and in vivo of the 10-hydroxycamptothecin (HCPT) loaded human serum albumin nanoparticle (HSA-NP) prepared by drug-liquid compound method. Methods The HCPT-HSA-NP was prepared with low weight polyethylene glycol drug-liquid compound and blank albumin nanoparticle. Then the in vitro evaluations were conducted with tests of entrapment efficiency, solution stability, accumulative release, morphous investigation and X-ray powder diffraction. At the same time, the primary pharmacodynamics comparison between HCPT injection and the nano preparation-8 mg/kg) was carried out on animal tumor model. Results The obtained HCPT-HSA-NP fitted to the basal features of nano preparation. The entrapment efficiency was averagely higher than 99% for each sample and the solution was stable. In vitro accumulative release study showed that the preparation had long-term release pattern over 100 hours. In vivo pharmacodynamics study showed that the HCPT-HSA-NP was significantly more effective than HCPT injection (P<0.01). Conclusion The drug-liquid compound method can be used to prepare HCPT-HSA-NP.
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Objective: To prepare microcapsules for controlled release of 10-hydroxycamptothecin (HCPT), and determine its encapsulation efficiency and drug release profile in vitro. Methods: The microcapsules loaded with HCPT were prepared using a novel coating technology based on the layer-by-layer (LBL) deposition of oppositely charged polylysine (PLL) and alginate (ALG) polyelectrolytes with good biocompatibility onto microcrystal templates. Results: The microcapsules fabricated by this method had visible core-shell structure observed by scanning electron microscopy (SEM) and confocal laser scanning microscopy (CLSM); The entrapment efficiency of the microcapsules was as high as (68.41 ± 0.72)%; The release rate of HCPT decreased as the bilayers increased in vitro. Conclusion: The microcapsules of HCPT prepared by LBL have higher entrapment efficiency and are characterized with controlled drug release, which has potential for future application.
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Objective To prepare HCC-targeted lipid ultrasound microbubble containing 10-hydroxycamptothecin (10-HCPT), and to assess its targeting function in vitro. Methods After the biotinylated monoclonal antibody Hab18 was prepared, the biotinylated degree was determined. Microbubbles containing 10-HCPT were prepared by mechanical vibration. Then the biotinylated antibody was attached to the surface of the microbubbles by avidin-biotin interaction. The physical property, entrapment efficiency and the drug-loading amounts of 10-HCPT lipid microbubbles were determined. The combination of biotinylated Hab18 with microbubbles containing 10-HCPT was proved by immunofluorescent assay, and the targeting function of the targeted microbubbles containing 10-HCPT was observed with light microscope, served non-targeted microbubbles as control group. Results About 13 biotin molecules were coupled to each antibody in average. The disposition of the prepared microbubbles was steady and the mean diameter was 1.52 μm. The drug entrapment efficiency was 76.32% and the drug-loading amounts was 21.81%. Red fluorescence was observed at the edge of the microbubbles in immunofluorescent assay, and the conjugation of the targeted microbubbles containing 10-HCPT with 7721 cells was tight while control group was negative. Conclusion HCC-targeted lipid ultrasound microbubbles containing 10-HPTC can be prepared successfully, with higher entrapment efficiency and drug-loading amounts and strong targeting function in vitro.