In vitro and in vivo evaluation of sanguinarine liposomes prepared by a remote loading method with three different ammonium salts.
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Sanguinarine liposomes were prepared by a remote loading method using three different ammonium salts. A series of studies, including in vitro release, in vitro and in vivo anti-tumor effects and pharmacokinetics in rats, were conducted. The three liposomes showed pH-sensitive release characteristics in vitro, but there were obvious variations in their release profiles. Among the three liposomes, the liposomes made using ammonium citrate and phosphate possessed better anti-tumor activity in vitro and in vivo, compared with the liposome using ammonium sulfate. Pharmacokinetics test results in rats indicated that sanguinarine liposomes have notably elevated AUC (P<0.05) and markedly lower CL (P<0.05) compared with the solution, but there were no obvious differences between the three liposomes. The present study may be useful for better understanding and better choice of a suitable ammonium salt for the remote loading method.Keywords:
Sanguinarine
Ammonium sulfate
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Interior gelation of liposomes leads to changes in the physicochemical properties of liposomes, such as increased rigidity of the lipid bilayers, modified shape, improved physical stability and sustained release of a model drug cytarabine (ara-C), all of which may affect the performance of liposomes in vivo. In this study, we investigated the pharmacokinetics of liposomes with gelated interior (gel-liposomes) in rats and the biodistribution in mice using conventional liposomes as control. The ara-C gelliposomes (GL-ara-C) and conventional liposomes (CL-ara-C) were prepared by a thin-film dispersion method. Both liposomes were determined to have a mean size of about 1.2 microm with narrow size distributions and similar zeta potentials. Free ara-C (F-ara-C) was rapidly eliminated from the circulation (t1/2 = 1.43 h), whereas both conventional liposomes and gelliposomes showed prolonged elimination after intravenous injection with t1/2 of 5.88 h and 27.54 h, respectively. The AUC of CL-ara-C and GL-ara-C were 1.67 and 2.68 times greater than that of F-ara-C, respectively. Due to phagocytic uptake, the two liposomal formulations were mainly distributed in liver, spleen and kidney. Our data indicated that gelliposomes showed slower elimination and prolonged resident time in the body. Compared with that of conventional liposomes, the distribution of gelliposomes was increased in most of the tissues we investigated. These results indicated that interior gelation caused the changes in the physicochemical properties of liposomes, and these changes improved their performance in vivo.
Biodistribution
Zeta potential
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Liposomes are widely used as drug delivery systems. However, inefficient delivery limits their application in serum containing systems. In this study, two cholesterol derivatives were synthesized and incorporated into liposomes. The charge influence on drug delivery was investigated. The results indicated that the positively charged liposomes showed a higher delivery efficiency for drugs with both small molecular weight (DOX, doxorubicin) and macromolecular weight (polyethylene glycol 6000 conjugated with rhodamine B, PEG-RhB) into cells, compared with neutral liposomes even in the presence of serum. The cytotoxicity of the positive liposomes was lower than that of DOTAP (N-(1-(2,3-dioleoyloxy) propyl-N,N,N-trimethylammonium mesylate) liposomes. Moreover, results from confocal microscopy indicated that the positive DOX-liposomes underwent a quick binding process onto the cell membrane, followed by drug uptake by the cell. In vivo experiments also revealed that the positive DOX-liposomes had a higher drug delivery ability into rat retina than the neutral ones.
Rhodamine B
Targeted drug delivery
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Mitomycin C is an anticancer antibiotic agent that has the potential for broad-spectrum use against several cancers, including mammary cancers. Because its half-life is 17 min after a 30 mg intravenous bolus administration, the suitability of mitomycin C for wide use in the clinical setting is limited. Based on tumor pathophysiology, pH-sensitive liposomes could provide better tumor-targeted effects. The aim of this study was to investigate the possibility of diminishing the side effect of mitomycin C by using pH-sensitive liposomes.pH-sensitive liposomes was employed to deliver mitomycin C and evaluate the characterization, release behaviors, cytotoxicity, in vivo pharmacokinetics and biochemical assay.The results demonstrated that mitomycin C-loaded pH-sensitive liposomes had a particle diameter of 144.5±2.8 nm and an entrapment efficiency of 66.5%. The in vitro release study showed that the pH-sensitive liposome release percentages at pH 7.4 and pH 5.5 were approximately 47% and 93%, respectively. The cell viability of MCF-7 cells showed that both the solution and liposome group exhibited a concentration-dependent effect on cell viability. The MCF-7 cell uptake of pH-sensitive liposomes with a folate modification was higher which was indicated by an increased fluorescence intensity compared to that without a folate modification. The area under the concentration-time curve of mitomycin C-loaded pH-sensitive liposomes (18.82±0.51 µg·h/L) was significantly higher than that of the mitomycin C solution group (10.07±0.31 µg·h/L). The mean residence times of the mitomycin C-loaded and mitomycin C solution groups were 1.53±0.16 and 0.05 h, respectively. In addition, there was no significant difference in terms of Vss (p>0.05). Moreover, the half-life of pH-sensitive liposomes and the mitomycin C solution was 1.35±0.15 and 1.60±0.04 h, respectively. In terms of safety, mitomycin C-loaded pH-sensitive liposomes did not affect the platelet count and the levels of blood urea nitrogen and aspartate aminotransferase.The positive results of pH-sensitive liposomes demonstrated maintained the cytotoxicity and decrease the side effect.
Mitomycin C
Viability assay
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Liposomes containing copper and the copper ionophore neocuproine were prepared and characterized for in vitro and in vivo anticancer activity. Thermosensitive PEGylated liposomes were prepared with different molar ratios of 1,2-dipalmitoyl-sn-glycero-3-phosphatidylcholine (DPPC) and hydrogenated soybean phosphatidylcholine (HSPC) in the presence of copper(II) ions. Optimal, temperature dependent drug release was obtained at 70:30 DPPC to HSPC weight ratio. Neocuproine (applied at 0.2 mol to 1 mol phospholipid) was encapsulated through a pH gradient while using unbuffered solution at pH 4.5 inside the liposomes, and 100 mM HEPES buffer pH 7.8 outside the liposomes. Copper ions were present in excess, yielding 0.5 mM copper-(neocuproine)2 complex and 0.5 mM free copper. Pre-heating to 45 °C increased the toxicity of the heat-sensitive liposomes in short-term in vitro experiments, whereas at 72 h all investigated liposomes exhibited similar in vitro toxicity to the copper(II)-neocuproine complex (1:1 ratio). Thermosensitive liposomes were found to be more effective in reducing tumor growth in BALB/c mice engrafted with C26 cancer cells, regardless of the mild hyperthermic treatment. Copper uptake of the tumor was verified by PET/CT imaging following treatment with [64Cu]Cu-neocuproine liposomes. Taken together, our results demonstrate the feasibility of targeting a copper nanotoxin that was encapsulated in thermosensitive liposomes containing an excess of copper.
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Transcellular
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The aim of the present study was to investigate the effect of various transmembrane ammonium salt gradients and different lipid composition on the loading efficiency of liposomal formulations of irinotecan hydrochloride (CPT-11), their behavior in vivo and cytotoxicity. Among ammonium salts studied, ammonium sulfate was successfully used to load CPT-11 into liposomes with the highest encapsulation efficiency. Subsequently, liposomal CPT-11 with different lipid composition was prepared by ammonium sulfate gradient method. CPT-11 can be loaded to a level over 90% into liposomes composed of soybean phospholipids/cholesterol (SPC-L) or hydrogenated natural soybean phospholipids/cholesterol (HSPC-L). In vitro release profiles were also investigated, indicating that HSPC-L had a lower release than that in SPC-L. In vivo, encapsulation of CPT-11 in both liposomal formulations showed higher area under the curve (AUC), a lower rate of clearance (CL) and smaller volume of distribution for CPT-11 than those of irinotecan hydrochloride solution (CPT-11-S). However, CL and AUC of 7-ethyl-10-hydroxycamptothecin (SN-38) were moderately improved in HSPC-L group. Based on the results of comparative pharmacokinetics of liposomal CPT-11 with different lipid composition, the in vitro cytotoxicity of HSPC-L was evaluated with human tumor cell. The result indicated that liposomal CPT-11 showed a great enhancement in vitro cytotoxicity. The results suggested that entrapment of CPT-11 in liposomes especially in those with high phase-transition temperature lipid by ammonium sulfate gradient would be a promising formulation with a better in vivo behavior.
Ammonium sulfate
Hydrochloride
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To develop liposomes containing doxorubicin with different salts and to investigate their influence on the stability of liposomal doxorubicin in vitro and in vivo.Liposomes were prepared by the film method, treated further by extruded through nuclear membrane. The entrapment efficiency was determined by column chromatography. In vitro drug release experiments were carried out with a dialysis bag (Mw cut-off 12000 - 14000). Reverse-phase HPLC was used to study the pharmacokinetics of liposomal doxorubicin.The particle size of liposomes with glycinate buffer, citrate buffer and ammonium sulfate as the inner water phase were (103 +/- 8), (102 +/- 12) and (97 +/- 8) nm. The zeta potential and the encapsulation ratio were (-21.3 +/- 0.5), (-21.7 +/- 0.4), (-20.9 +/- 0.7) mV and 47.8%, 96.7%, 98.6%, respectively. The leaking rate of doxorubicin from liposomes was related to the pH value of the release medium. The leaking rate increased at lowered pH. Pharmacokinetic study showed that the MRT (mean retention time) of liposomes with glycinate buffer, citrate buffer and ammonium sulfate as the inner water phase were 12.13, 23.31 and 29.79 h, respectively.Doxorubicin showed different stability in liposomes with different inner water phases, the weaker the acid in the inner water phase, the stabler the liposome.
Ammonium sulfate
Zeta potential
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Objective To prepare PEGylated liposomes co-encapsulate combretastatin A-4(CA-4)and doxorubicin(DOX)with the function of drug releasing in sequence and evaluate their in vivo pharmacokinetic behavior.Methods EPC/CHOL/DSPE-PEG was chosed as the vehicle materials,thin film dispersion method and the ammonium sulfate gradient method were applied to prepare the CA-4 liposomes and load DOX.Prescription and preparation process were optimized according to the CA-4 entrapment efficiency.In vitro release of the liposomes was evaluated in phosphate buffered saline(pH7.4).Pharmacokinetic behavior was investigated using normal rats by vein injection.Results As m(EPC)∶m(CHOL)∶m(DSPE-PEG)=85∶10∶5,m(drug)∶m(lipids)=1∶20,total lipids concentration was 50 mmol·L-1 after hydration,CA-4 and DOX could be entrapped over 85%and 95%,separately,particle size was around 80 nm.The in vitro release curve demonstrated that the CA-4 released faster than DOX.The pharmacokinetic experiments showed that liposomes could obviously prolonged CA-4 in vivo circulation time,and CA-4 had no effect on pharmacokinetic condition of DOX liposomes as well.Conclusions Liposomes co-encapsulated CA-4 and DOX together achieve sequential drug releasing and prolonge drugs in vivo circulation time,which might be a new strategy for tumor therapy in future.
Combretastatin
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OBJECTIVE The pH-sensitive procationic liposomes were prepared,with hydroxycamptothecin(HCPT) as model drug.METHODS The cationic liposomes were prepared by film dispersion method.The encapsulation efficiency was determined after removing unentrapped HCPT by Sephadex-G50 chromatographic column.Carboxymethyl chitosan was used to coat the cationic liposomes,then the liposomes were extruded through high pressure homogenizer.Zetasizer was used to determine the zeta potential,average size of the HCPT liposomes.pH sensitivity analysis was made through experiments of red blood cell hemolysis and tumor distribution is analysised.RESULTS The size of liposomes was around 96 nm and drug encapsulation efficiency was 78.5%.The membrane fusion of red blood cells with procationic liposomes was significantly different between pH 6.5 and pH 7.4 and the in vivo experiments in tumor-bearing mice suggested that they had a high tumor distribution.CONCLUSION The pH-sensitive procationic nanoliposomes were easy to prepare and were expected to be a promising anti-tumor drug delivery system.
Zeta potential
Cationic polymerization
Homogenizer
Sephadex
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