Docetaxel delivery using folate-targeted liposomes: in vitro and in vivo studies
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Objective(s): Folate-targeted liposomes have been well considered in folate receptor (FR) overexpressing cells including MCF-7 and 4T1 cells in vitro and in vivo. The objective of this study is to design an optimum folate targeted liposomal formulations which show the best liposome cell uptake to tumor cells.Material and Methods: In this study, we prepared and characterized different targeted formulations and a nontargeted form as a control. Physicochemical analysis showed that the liposomes had homogeneous population and appropriate size to accumulate to tumor sites through the enhanced permeation and retention (EPR) mechanism. Moreover, we compared the cell uptake of folate targeted liposomal docetaxel compared to nontargeted liposomes in vitro. Results: The in vitro drug release profile of the formulations at different time points showed none of the formulations did not has burst release. However, targeted liposomes accumulated in tumor tissue in vivo less than nontargeted formulations which could be attributed to their uptake by RES due to relatively greater size of targeted formulations. It is presumable that analyze the biodistribution process at longer time points and the molecular mechanisms behind the tissue accumulation could clear the issue. Conclusion: We conclude that success in vitro studies holds the promise of folate targeting strategy and in vivo study merits further investigations.Keywords:
Folate receptor
Abstract The objective of this work was to investigate the preparation, characterization and pharmacokinetics of N-palmitoyl chitosan anchored docetaxel liposomes. To decrease toxic effects and improve anti-tumour efficacy of the drug, docetaxel has been incorporated in liposomes; the formulation, stability and pharmacokinetics of plain docetaxel liposomes (PDLs), PEGylated docetaxel liposomes (PEGDLs) and N-palmitoyl chitosan anchored docetaxel liposomes (NDLs) were compared. NDL was more stable than PDL and PEGDL in-vitro, especially in the presence of serum at 37°C. The concentration of docetaxel in the plasma of rats after intravenous administration of docetaxel injection, PDL, PEGDL and NDL was studied by RP-HPLC. The pharmacokinetic behaviour of docetaxel injection, PDL, PEGDL and NDL were significantly different. These findings suggest that anchored liposomes could increase the stability of docetaxel in-vivo, as compared with plain liposomes, but the improvement was not more significant than PEGylated liposomes. N-Palmitoyl chitosan as a new polymeric membrane to anchor liposome was useful to stabilize liposomes containing anti-tumour drug.
Characterization
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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.
Sanguinarine
Ammonium sulfate
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Purpose: To investigate the antitumor properties and toxicity of 7-epi docetaxel (7-epi DTX) as an active pharmaceutical ingredient, and in formulations.Methods: Docetaxel-loaded albumin nanoparticles (DTX NPs) were prepared by freeze-drying, while 7- epi DTX was detected and isolated by high performance liquid chromatography (HPLC). Their antitumor properties were evaluated in vitro in CT26 cells and in vivo in BALB/c sk-ov-3 xenograft nude mice model. The tissues were histological examined.Results: The in vivo antitumor effects of DTX NPs at different doses of 7-epi DTX were similar. Moreover, the in vitro anti-cancer effect of 7-epi DTX was comparable to that of DTX. However, the in vivo antitumor effectiveness of 7-epi DTX was inferior to that of DTX. In toxicity studies, 7-epi DTX did not elicit any acute toxic effects both as active pharmaceutical ingredients, and as a component of formulations.Conclusion: The results indicate that 7-epi DTX does not elicit acute toxic effects both as an active pharmaceutical ingredient and in bulk formulations. The antitumor property of 7-epi DTX is less than that of DTX.Keywords: 7-Epidocetaxel, Impurity, Antitumor properties, Toxicity
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A novel liposomal formulation of docetaxel targeting the folate receptor (FR) was synthesized and characterized. Liposomal formulations are less toxic and can provide longer systemic circulation time than the Tween 80 and ethanol based clinical formulation of docetaxel. Folate receptor-alpha (FR) is frequently over-expressed on epithelial cancer cells. Therefore, FR targeted liposomes can potentially enhance tumor cell uptake and antitumor efficacy of encapsulated drugs. The formulation studied had the compositions of egg phosphatidylcholine/cholesterol/methoxy-polyethylene glycol (PEG)2,000-distearoylphosphatidylethanolamine/folate-PEG3,350-cholesteryl hemisuccinate (ePC/Chol/mPEG-DSPE/folate-PEG-CHEMS) at ratios of (80:15:4.5:0.5, mol/mol) and a drug-to-lipid ratio of 1:20, wt/wt. Sucrose was used as a lyoprotectant. The liposomes were prepared by thin-film hydration, polycarbonate membrane extrusion, followed by lyophilization. They remained stable for more than 5 months when stored as lyophilized powder and for 72 h at 4 degrees C following rehydration. The mean particle size of reconstituted liposomes ranged from 110 to 120 nm. FR-targeted liposomes of the same lipid composition entrapping calcein were shown to be efficiently taken up by FR + KB oral carcinoma cells. FR-targeted liposomes containing docetaxel showed 4.4-fold greater cytotoxicity compared to non-targeted liposomes in KB cells. Plasma clearance profiles of FR-targeted and non-targeted liposomeal docetaxel were evaluated and compared with that of docetaxel in Tween 80/ethanol formulation. The liposomal formulations showed much longer terminal half lives (4.92 h and 6.75 h for FR-targeted and non-targeted, respectively) than docetaxel in Tween 80/ethanol solution (1.09 h). FR-targeted liposomes are promising tumor cell-selective nanocarriers for docetaxel with potential for therapeutic applications.
Folate receptor
Targeted drug delivery
Calcein
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The lipid composition, particle diameter and dose have been reported to affect the liposomal uptake in the tumor. However, effects of encapsulation amount of drugs in liposomes on the uptakes have scarecely been reported either in vitro or in vivo. In this study, we examined the uptake of liposomes containing CPT-11 by Ehrlich ascites carcinoma in vitro changing the encapsulation amount of CPT-11, and also the tissue distribution of liposomal CPT-11 in vivo with mice. After the addition of high concentration as CPT-11, the uptakes in the tumor cell by liposomes was about 1/3 of that by the solution in vitro. However, after the addition of same level as tissue distribution of CPT-11 in vivo, there is no difference on CPT-11 uptakes between liposome and solution. Thus lipid satulation in the tumor cells was observed by increasing liposomes in the medium. For a definite dose, the decrease of CPT-11 amount in the liposomes reduced the uptake in the tumor cell. Therefore, we thought that the uptake of liposomes in the tumor cell depended on lipid amount of liposomes. The increase of CPT-11 amount in the liposomes enhanced CPT-11 concentration in the serum, liver and tumor after administration of liposomal CPT-11 to the mice. An enhanced antitumor activity was expected from the result of SN-38 concentration in the tumor.
Ehrlich ascites carcinoma
L1210 cells
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The objective of this study was to investigate the correlation between in vitro and in vivo liposome-complement interactions. Third component of the complement (C3) fragments associated with hydrogenated egg phosphatidylcholine (HEPC)-based liposomes in vivo and complement-dependent destabilization in vitro were determined as an indication of liposome-complement interaction in vivo and in vitro, respectively. C3 fragments on the liposomes were detected in both rats and guinea pigs. Pretreatment with K76COOH (K76), a complement inactivating agent, reduced the binding of C3 fragments. These findings indicated that the liposomes remarkably activated the complement system in both animals in vivo. Interestingly, significant complement-dependent liposome destabilization was observed in rat serum, but not in guinea pig serum, indicating that the liposomes activated the complement system in rats, but not in guinea pigs in vitro. Taken together, it is apparent that in vitro complement activation by the liposomes is not in agreement with in vivo complement activation in ginea pigs. This discrepancy in the liposome-complement interaction would suggest the need for further investigation to utilize the information obtained from the liposome-complement interaction to predict in vivo behavior of the liposomes.
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In vitro studies were conducted to understand the comparative drug diffusion pattern, across artificial membrane, of the drug and of the prepared liposomes of different liposomal membrane composition. In vivo studies were carried out to determine the extent and time-course of pulmonary tissue uptake of administered liposomes containing terbutaline sulphate(TER) on rat lungs. In vitro studies revealed that the drug released from the prepared liposomes obeys Higuchi's diffusion controlled model. Different loading doses and release patterns of drug from the liposomes can be obtained by altering the PC:CHOL ratio and incorporation of cholesterol was found to reduce permeability of the membrane. Similarly drug absorption in vivo in rat's lung following intratracheal instillation, prolonged over 12 hr by liposomal entrapment of TER. The findings of present investigation indicated that liposomally encapsulated TER can be used for pulmonary delivery for maximizing the therapeutic efficacy and reducing undesirable side effects.
Terbutaline
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The aim of this study was to ascertain the folate receptor (FR) targetability by an in vitro study and to acquire FR-targeted images in vivo models by using synthetic folate conjugates. PEG-folate was synthesized and labeled with (99m)Tc and fluorescein isothiocynate (FITC). Cell uptake studies were carried out in KB cells (FR-positive) and A549 cells (FR-negative) using FITC- and the (99m)Tc-labeled conjugates. The radiolabeled conjugate was intravenously injected to KB tumor xenografted mice. After it was injected, gamma images were recorded at 30 min, 1, 2, 3 and 4 hr. Cell uptake studies showed a difference between the KB cells and the A549 cells by flow cytometry analysis and gamma counting. On in vivo images, the tumor-to-normal muscle ratio was greater than 4. It ascertained that the PEG-folate conjugate specifically binds to the FR expressed on tumor cells in vitro. Moreover, it was possible to acquire the FR-targeted gamma images using PEG-folate conjugates in tumor models.
Folate receptor
Conjugate
Imaging agent
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