Preparation and the in-vivo evaluation of paclitaxel liposomes for lung targeting delivery in dogs

Objectives The aim of this study was to develop paclitaxel liposomes for a lung targeting delivery system. Methods The liposomes composed of Tween‐80/HSPC/cholesterol (0.03 : 3.84 : 3.84, mol/mol), containing paclitaxel and lipids (1 : 40, mol/mol), were prepared by a combination of solid dispersion and effervescent techniques, and then subjected to ultrasonication. The pharmacokinetics and biodistribution of liposomal and injectable formulation of paclitaxel in dogs were studied after intravenous administration. Key findings The mean diameter, polydispersity index, zeta‐potential and entrapment efficiency of the liposomes were 501.60 ± 15.43 nm, 0.28 ± 0.02, ?20.93 ± 0.06 mV and 95.17 ± 0.32%, respectively. The liposomal formulation kept stable for at least 3 months at 6 ± 2°C and didn't cause haemolysis. The liposome carrier decreased the area under the curve and terminal half‐life of paclitaxel compared with paclitaxel injection ranging from 0.352 ± 0.031 mg/l*h and 0.0671 ± 0.144 h to 0.748 ± 0.062 mg/l*h and 1.978 ± 0.518 h, respectively. The paclitaxel liposomes produced a drug concentration in the lung that was markedly higher than that in other organs or tissues and was about 15‐fold of that of paclitaxel injection at 2 h. Conclusions To sum up, these results demonstrated that the paclitaxel liposomes are an effective lung targeted carrier in the treatment of lung cancer.     

Paclitaxel targeting to lungs by way of liposomes prepared by the effervescent dispersion technique

In order to develop a novel lung targeting drug delivery system (LTDDS) with large-sized liposomes containing paclitaxel (PTX), the liposomes composed of PTX, phosopholipon 90H and tween-80 were prepared by the effervescent dispersion technique with optimal formulation composition. The liposomes were found to be relatively uniform in particle size (8.166 ± 0.459 μm) with a negative zeta-potential (?12.45 ± 1.34 mv), and high entrapment efficiency (92.20 ± 2.56 %). They kept stable for at least 3 months and exhibited a slow release behavior without any hemolysis reaction. Via intravenous administration in rabbits, the PTX liposomes presented a longer mean residence time and elimination half-life, and a much larger area under the plasma drug concentration–time curve compared with its injection; meanwhile, the liposomes altered its biodistribution and exhibited a significant lung targeting characteristic. For example, the relative intake rate (Re) and the ratio of peak concentration (Ce) of lung were 14.87 and 26.44, respectively. Compared with heart, liver, spleen and kidney, the ratios of targeting efficacy (Te)_liposomes to (Te)_injection of lung were increased by a factor of 20.08, 11.10, 6.97 and 14.41, respectively. To sum up, the liposome could be a promising drug carrier for PTX as LTDDS for lung cancer treatment.     

Targeted delivery of doxorubicin via estrone-appended liposomes

Estrone-appended liposomal formulation of doxorubicin was designed to enhance the capability of clinically used liposomal doxorubicin formulation with the added advantage of delivery of doxorubicin to its destination site, i.e. cancerous cells over-expressing estrogen receptors (ERs). Estrone was conjugated with distearoyl phosphatidylethanolamine (DSPE) using succinic anhydride as a linker and the conjugate was characterized by IR and mass spectroscopies. Estrone-coupled liposomes were prepared with the composition of egg phosphatidylcholine/cholesterol/distearoyl phosphatidylethanolamine–estrone (PC/CHOL/DSPE–ES) at the molar and drug–lipid ratios of 7:3:0.5 and 0.1:1 (w/w), respectively. The average vesicle sizes of the conventional and estrone-appended liposomes were found to be 193 ± 24 and 207 ± 28 nm, respectively. The fluorescent microscopy studies were performed with estrone-appended liposomes loaded with 6-carboxyfluorescein (6-CF). Results of in vivo biodistribution studies showed that estrone-appended liposomes were effectively taken up by cells expressing ERs. The drug uptake study showed that accumulation of ligand-appended liposomes in the breast and uterus was 13.9 and 12.7 times higher when compared with plain drug, and 11.05 and 10.3 times higher when compared with conventional liposomes, respectively, after 8 h of tail vein intravenous administration. The findings are seminal for selective targeting of antineoplastic agents to the ER, which are frequently over-expressed on carcinoma of breast and uterine origin, and opens the promising possibilities for non-immunogenic, site-specific delivery of bioactive(s) to these sites.     

Characterization, lung targeting profile and therapeutic efficiency of dipyridamole liposomes

The acute respiratory distress syndrome (ARDS) is a severe form of acute lung injury (ALI). Its pathogenesis is closely linked with reactive oxygen species (ROS). Antioxidation has been considered as an efficient treatment. Besides, liposomes are widely investigated as potential drug carriers due to their ability to protect and carry drug molecules to the target organ such as the lung. The present study was undertaken to investigate whether dipyridamole (DIP), delivered as a liposomal preparation, can ameliorate the lipopolysaccharides (LPS)-induced ALI due to the changes of its biodistribution. First, the liposomes entrapping DIP were prepared by film hydration for treating ARDS. Subsequently, the characterizations including entrapment efficiency, size, span and micrograph of DIP liposomes were measured. The concentration change of DIP in tissues and plasma of mice after intravenous administration of DIP injection and DIP liposomes was determined by RP-HPLC and calculated to lung targeting parameters. To prove the therapeutic efficiency, the effects of DIP liposomes on LPS-induced ALI were studied compared with DIP injection. The results showed DIP liposomes have the relative high entrapment efficiency and satisfying particle size. Compared with DIP injection, the liposomes increased the accumulation of DIP in the lung on a vast scale. Furthermore, DIP liposomes alleviated the ALI induced by LPS significantly. All of the results suggested that DIP liposomes have the potential efficacy in treating ALI/ARDS due to their obvious lung targeting.     

Characterization,lung targeting profile and therapeutic efficiency of dipyridamole liposomes

The acute respiratory distress syndrome (ARDS) is a severe form of acute lung injury (ALI). Its pathogenesis is closely linked with reactive oxygen species (ROS). Antioxidation has been considered as an efficient treatment. Besides, liposomes are widely investigated as potential drug carriers due to their ability to protect and carry drug molecules to the target organ such as the lung. The present study was undertaken to investigate whether dipyridamole (DIP), delivered as a liposomal preparation, can ameliorate the lipopolysaccharides (LPS)-induced ALI due to the changes of its biodistribution. First, the liposomes entrapping DIP were prepared by film hydration for treating ARDS. Subsequently, the characterizations including entrapment efficiency, size, span and micrograph of DIP liposomes were measured. The concentration change of DIP in tissues and plasma of mice after intravenous administration of DIP injection and DIP liposomes was determined by RP-HPLC and calculated to lung targeting parameters. To prove the therapeutic efficiency, the effects of DIP liposomes on LPS-induced ALI were studied compared with DIP injection. The results showed DIP liposomes have the relative high entrapment efficiency and satisfying particle size. Compared with DIP injection, the liposomes increased the accumulation of DIP in the lung on a vast scale. Furthermore, DIP liposomes alleviated the ALI induced by LPS significantly. All of the results suggested that DIP liposomes have the potential efficacy in treating ALI/ARDS due to their obvious lung targeting.     

Improved targeting of antimony to the bone marrow of dogs using liposomes of reduced size

A novel liposomal formulation of meglumine antimoniate (MA), consisting of vesicles of reduced size, has been evaluated in dogs with visceral leishmaniasis to determine its pharmacokinetics as well as the impact of vesicle size on the targeting of antimony to the bone marrow. Encapsulation of MA in liposomes was achieved through freeze-drying of empty liposomes in the presence of sucrose and rehydration with a solution of MA. The resulting formulation, with a mean vesicle diameter of about 400 nm, was given to mongrel dogs with visceral leishmaniasis as an i.v. bolus injection at 4.2 mgSb/kg of body weight. The pharmacokinetics of antimony were assessed in the blood and in organs of the mononuclear phagocyte system and compared to those achieved with the free drug and the drug encapsulated in large sized liposomes (mean diameter of 1200 nm). The targeting of antimony to the bone marrow was improved (approximately three-fold) with the novel liposomal formulation, when compared to the formulation of MA in large sized liposomes. This study provides the first direct experimental evidence that passive targeting of liposomes to the bone marrow of dogs is improved by the reduction of vesicle size from the micron to the nanometer scale.     

Liposomes for systematic delivery of vancomycin hydrochloride to decrease nephrotoxicity: Characterization and evaluation

Vancomycin hydrochloride （VANH）, the first glycopeptide antibiotic, is a water-soluble drug for the treatment of acute osteomyelitis. Liposomal formulations of VANH have already been manipulated and characterized, which was a mean of increasing their therapeutic index, reducing their toxicity and altering drug biodistribution. One of the challenges for preparing VANH-Lips is their low encapsulation efficiency (EE). In the present study, we aim to improve the liposomal formulation of VANH for higher EE, longer systemic circulation, reduced nephrotoxicity and enhanced antimicrobial activities. Vancomycin hydrochloride-loaded liposomes (VANH-Lips) were formulated by the method of modified reverse phase evaporation. Based on the optimization of formulation with orthogonal experimental design, the average drug encapsulation efficiency and the mean particle size of VANH-Lips were found to be 40.78 ± 2.56% and 188.4 ± 2.77 nm. In vitro drug release of VANH-Lips possessed a sustained release characteristic and their release behavior was in accordance with the Weibull equation. After intravenous injection to mice, the mean residence time (MRT) of VANH-Lips group was significantly prolonged in vivo and the AUC value was improved as well compared with the vancomycin hydrochloride solution (VANH-Sol) group. Furthermore, the biodistribution results in mice showed that VANH-Lips decreased the accumulation of VANH in kidney after intravenous injection. In conclusion, VANH-Lips may be a potential delivery system for VANH to decrease nephrotoxicity in the treatment of osteomyelitis.     

Enhanced solubility and stability of PEGylated liposomal paclitaxel: in vitro and in vivo evaluation

An improved PEGylated liposomal formulation of paclitaxel has been developed with the purpose of improving the solubility of paclitaxel as well as the physicochemical stability of liposome in comparison to the current Taxol formulation. The use of 3% (v/v) Tween 80 in the hydration media was able to increase the solubility of drug. The addition of sucrose as a lyoprotectant in the freeze-drying process increased the stability of the liposome particles. There was no significant difference in the entrapment efficiency of paclitaxel between the conventional non-PEGylated liposomes and our PEGylated liposomes. Cytotoxicity in human breast cancer cell lines (MDA-MB-231 and SK-BR-3) of our paclitaxel formulation was less potent compared to Taxol after 24h incubation, but was equipotent after 72 h due to the slower release of drug from the liposome. Our PEGylated liposomes increased the biological half-life of paclitaxel from 5.05 (+/-1.52)h to 17.8 (+/-2.35)h compared to the conventional liposomes in rats. Biodistribution studies in breast cancer xenografted nude mouse model showed that our liposomes significantly decreased the uptake in reticuloendothelial system (RES)-containing organs (liver, spleen and lung) while increasing the uptake in tumor tissues after injection compared to Taxol or the conventional liposomal formulation. Moreover, the PEGylated liposome showed greater tumor growth inhibition effect in in vivo studies. Therefore, our PEGylated liposomal formulation of paclitaxel could serve as a better alternative for the passive targeting of human breast tumors.     

Pharmacokinetics and targeting property of TFu-loaded liposomes with different sizes after intravenous and oral administration

The purpose of the study was to develop the liposomal formulations of TFu for oral and intravenous (i.v.) administration, clarify the biodistribution characteristics and in vivo pharmacokinetic behaviors of TFu-loaded liposomes. Four TFu-loaded liposomes of different sizes were prepared and characterized. The pharmacokinetic characteristics and the biodistribution of TFu-loaded liposomes with different sizes were investigated after i.v. or oral administration to mice. The pharmacokinetic studies indicated that TFu-loaded liposomes with different sizes all resulted in higher bioavailabilities than the TFu suspension after oral administration, and the gastrointestinal absorption increased with the reduction in liposome sizes. Following i.v. administration to mice, larger TFu-loaded liposomes (530 and 400 nm) showed higher hepatic and splenic targeting properties and lower cardiac and renal accumulations, while smaller sized liposomes (180 nm) significantly enhanced drug plasma concentration, bioavailability and prolonged retention time in circulation. Therefore, it can be concluded that both the oral and the injectable TFu-loaded liposomes are promising anticancer formulations for improved bioavailability; larger sized liposomes are potential passive targeting therapeutic agents for hepatoma and splenoma through i.v. administration while smaller liposomes might be preferable for oral administration due to its enhancing oral absorption possibility. Consequently, TFu-loaded liposomes with different sizes might have different clinical applications according to different goals of treatment.     

Preparation of itraconazole-loaded liposomes coated by carboxymethyl chitosan and its pharmacokinetics and tissue distribution

Liposomes are potential carriers for targeting and controlled drug delivery by the intravenous route. Carboxymethyl chitosan (CMC) is a ramification of chitosan with intrinsic water-solubility. The aim of this study is to prepare itraconazole-loaded liposomes coated by carboxymethyl chitosan (CMC-ITZ-Lips), to evaluate its physico-chemical characteristics and the tissue targeting after being injected intravenously (i.v.). This study uses a film dispersion method to prepare itraconazole-loaded liposomes (ITZ-Lips) prior to coating them with CMC. The concentrations of ITZ in selected organs were determined using reversed-phase high-performance liquid chromatography (HPLC) following i.v. administration of ITZ-Sol, ITZ-Lips, and CMC-ITZ-Lips. CMC-ITZ-Lips had an average diameter of 349.3?±?18?nm with a zeta potential of ?35.71?±?0.62 mV and the in vitro antifungal activity was not inhibited by the entrapment. The CMC-ITZ-Lips exhibited a longer elimination half life (t_1/2β) in vivo compared with ITZ-Sol and ITZ-Lips after i.v. injection to mice. The biodistribution in mice was also changed after ITZ was encapsulated in CMC coated liposomes. CMC-ITZ-Lips performed significant lung targeting efficiency with AUC, Te and Re of lung all showed obvious elevation. In this study itraconazole was successfully encapsulated into carboxymethyl chitosan-modified liposomes for application of injection.     

Stavudine-loaded mannosylated liposomes: in-vitro anti-HIV-I activity, tissue distribution and pharmacokinetics

Cells of the mononuclear phagocyte system (MPS) are important hosts for human immunodeficiency virus (HIV). Lectin receptors, which act as molecular targets for sugar molecules, are found on the surface of these cells of the MPS. Stavudine-loaded mannosylated liposomal formulations were developed for targeting to HIV-infected cells. The mannose-binding protein concanavalin A was employed as model system for the determination of in-vitro ligand-binding capacity. Antiretroviral activity was determined using MT-2 cell line. Haematological changes, tissue distribution and pharmacokinetic studies of free, liposomal and mannosylated liposomal drug were performed following a bolus intravenous injection in Sprague-Dawley rats. The entrapment efficiency of mannosylated liposomes was found to be 47.2 +/- 1.57%. Protein-carbohydrate interaction has been utilized for the effective delivery of mannosylated formulations. Cellular drug uptake was maximal when mannosylated liposomes were used. MT2 cells treated continuously with uncoated liposomal formulation had p24 levels 8-12 times lower than the level of free drug solution. Further, the mannosylated liposomes have shown p24 levels that were 14-20 and 1.4-2.3 times lower than the level of free drug and uncoated liposomal formulation treatment, respectively. Similar results were observed when infected MT2 cells were treated overnight. Stavudine, either given plain or incorporated in liposomes, led to development of anaemia and leucocytopenia while mannosylated liposomes overcame these drawbacks. These systems maintained a significant level of stavudine in the liver, spleen and lungs up to 12 h and had greater systemic clearance as compared with free drug or the uncoated liposomal formulation. Mannosylated liposomes have shown potential for the site-specific and ligand-directed delivery systems with desired therapeutics and better pharmacological activity.     

PEGylated elastic liposomal formulation for lymphatic targeting of zidovudine

The present study was aimed at in vitro and in vivo evaluation of PEGylated elastic liposomal formulation for lymphatic targeting of zidovudine (AZT). PEGylated elastic liposomal formulation was prepared and characterized for characteristic in vitro, ex-vivo and in vivo parameters. The plain and PEGylated elastic liposomal formulation showed transdermal flux of 99.8+/-5.8 and 119.5+/-5.2 microg/cm(2)/hr, respectively across the rat skin. Results of biodistribution study indicated 27-fold higher accumulation of AZT in lymphoid tissues after application of PEGylated elastic liposomes as compared to free drug. The efficient localization of elastic liposomal formulation in lymphatic system is of particular interest for HIV therapy, taking in account that replication of HIV mainly takes place in the lymphoid system. The Cellular uptake studies showed significantly higher cellular uptake in lymphoid cells (MT-2 cell line) from PEGylated elastic liposomal formulation (88.9+/-8.7%) in comparison to phosphate buffer saline (PBS, pH 7.4) solution of drug (27.1+/-2.8%). The entrapment of AZT into PEGylated elastic liposomes represents a potential approach for overcoming the toxicity by its selective uptake in lymphoid organs. This represents attractive approach for sustained and targeted delivery of AZT.     

Liposomal topotecan formulation with a low polyethylene glycol grafting density: pharmacokinetics and antitumour activity

Objectives PEGylated liposomes could evade recognition by the reticulo‐endothelial system and prolong the circulation time of vesicles, resulting in enhanced targeting efficiency and antitumour effect. Typically, vesicles are modified with distearoylphosphatidylethanolamine (DSPE)‐polyethylene glycol (PEG) at a high PEG grafting density. However, long circulation time and slow drug release rate might induce severe hand‐foot syndrome in clinical practice. In this study, a liposomal topotecan formulation with a low PEG grafting density was prepared and its pharmacokinetics, acute toxicity and antitumour effect were investigated. Methods Topotecan was loaded into liposomes using an ammonium sulfate gradient. The resulting formulation was injected to healthy Wistar rats at different dose levels to investigate whether its clearance followed linear kinetics. Biodistribution was performed in Lewis lung cancer‐bearing mice. The acute toxicity was evaluated in healthy mice and beagle dogs. To compare the antitumour effects of different formulations and dose schedule, RM‐1 prostate, Lewis lung, H446 and L1210 cancer models were used. Key findings Topotecan could be encapsulated into low DSPE‐PEG liposomes with ～100% loading efficiency. The clearance of the liposomal formulation followed linear kinetics at a dose level ranging from 0.5 to 4 mg/kg despite the fact that the vesicles were coated at a low PEG density. Compared with free topotecan the liposomal formulation preferentially accumulated into tumour zones instead of normal tissues. Both formulations could rapidly accumulate into liver and tumour, but the liposomal formulation was cleared from tissues at a slow rate relative to the conventional formulation. In rats and beagle dogs, liposomal formulations could not induce skin toxicity. In all the tumour models, smaller split doses were more therapeutically active than larger doses when the overall dose intensity was equivalent. Conclusions This has been the first report that plasma kinetics of a liposomal formulation with a low PEG density followed linear kinetics. Moreover, due to its short circulation half‐life, the formulation did not induce skin toxicity. Our data revealed that the dose schedule of liposomal drugs should be adjusted in accordance with the biophysical and biological properties of the formulations to achieve the optimal therapeutic efficacy.     

Optimization, in vitro-in vivo evaluation, and short-term tolerability of novel levofloxacin-loaded PLGA nanoparticle formulation

A novel poly(lactic-co-glycolic acid) (PLGA)-based nanoformulation of levofloxacin was developed for multidrug-resistant tuberculosis with the purpose of achieving sustained release in plasma. After lyophilization of levofloxacin-loaded nanoparticles, the average size, charge, and polydispersity index were 268 ± 18 nm, -10.2 ± 1.5 mV, and 0.15 ± 0.03, respectively. The maximum drug encapsulation efficiency and loading capacity were 36.9 ± 6.1% (w/w) and 7.2 ± 1.2 mg/100 mg nanopowder, respectively. Biphasic extended-release profile was produced in vitro. Scanning electron microscopy and Fourier transform infrared studies showed spherical shape of drug-loaded nanoparticles and no drug-polymer interactions were observed. After single oral administration in mice, levofloxacin-loaded PLGA nanoparticles produced sustained release of levofloxacin for 4 days in plasma against 24 h for free levofloxacin. Levofloxacin was detected in organs (lung, liver, and spleen) for up to 4-6 days in case of levofloxacin-loaded nanoparticles, whereas free levofloxacin was cleared within 24 h. This novel formulation did not show any significant adverse effects on body weight and clinical signs in mice. No treatment-related changes were found in hematological and biochemical parameters and on histopathological evaluation. These results indicate the feasibility of development of an orally efficacious safe formulation of levofloxacin with sustained-release properties.     

Liposomal drug formulations in the treatment of rheumatoid arthritis

Liposomes have been extensively investigated as drug delivery systems in the treatment of rheumatoid arthritis (RA). Low bioavailability, high clearance rates and limited selectivity of several important drugs used for RA treatment require high and frequent dosing to achieve sufficient therapeutic efficacy. However, high doses also increase the risk for systemic side effects. The use of liposomes as drug carriers may increase the therapeutic index of these antirheumatic drugs. Liposomal physicochemical properties can be changed to optimize penetration through biological barriers and retention at the site of administration, and to prevent premature degradation and toxicity to nontarget tissues. Optimal liposomal properties depend on the administration route: large-sized liposomes show good retention upon local injection, small-sized liposomes are better suited to achieve passive targeting. PEGylation reduces the uptake of the liposomes by liver and spleen, and increases the circulation time, resulting in increased localization at the inflamed site due to the enhanced permeability and retention (EPR) effect. Additionally liposomal surfaces can be modified to achieve selective delivery of the encapsulated drug to specific target cells in RA. This review gives an overview of liposomal drug formulations studied in a preclinical setting as well as in clinical practice. It covers the use of liposomes for existing antirheumatic drugs as well as for new possible treatment strategies for RA. Both local administration of liposomal depot formulations and intravenous administration of passively and actively targeted liposomes are reviewed.     

Brain-specific delivery of rifampin from lactyl stearate-coupled liposomes via monocarboxylic acid transporters

Background

The blood-brain barrier (BBB) is an obstacle for pharmacologists wishing to find treatments for patients with brain disorders. The BBB restricts the uptake of many valuable hydrophilic drugs and limits their efficacy because of the presence of tight junctions, a high metabolic capacity, low pinocytic vesicular traffic, and efficient efflux mechanisms.

Aim

The present study aimed to characterize lactyl stearate-coupled liposomes and their potential for the brain targeting of rifampin (rifampicin).

Method

A liposomal delivery system was prepared for achieving the brain-targeted delivery of rifampin in 21 albino rats utilizing the monocarboxylic acid transport system. Liposomes were prepared by the cast-film method using phosphatidylcholine and cholesterol. Similarly, lactyl stearate-coupled liposomal systems were prepared by casting lactyl stearate film with lipids. These liposomal formulations were characterized for entrapment efficiency, vesicle size, in vitro drug release (using dialysis membrane), and in vivo drug accumulation in various tissues.

Results

Coupling of lactyl stearate to liposomes had a profound influence on entrapment efficiency. Entrapment efficiency was reduced from 41.28 ± 2.02% in uncoupled liposomes to 34.23 ± 1.60% in coupled liposomes. The vesicle size was increased after coupling with lactyl stearate. The in vitro drug release for the uncoupled formulation LIPO-3 was 62.9 ± 3.01% after 24 hours, whereas that of the coupled formulation LIPO-3-Ls-III was 44.5 ± 2.09%. The percentage of rifampin dose recovered from the brain following administration of lactyl stearate-coupled liposomes to albino rats at different time intervals was about 6–8 times higher than with uncoupled liposomes and about 10–12 times higher than with the plain drug solution.

Conclusion

Lactyl stearate-coupled liposomes were better localized within the brain compared to uncoupled liposomes. Lactyl stearate-coupled liposomes could be an excellent carrier system for brain targeting of the hydrophilic drug rifampin.     

Preparation and passive target of 5-fluorouracil solid lipid nanoparticles

This work studied the intravenous injection formulation of solid lipid nanoparticles (SLNs) loaded with 5-fluorouracil (5-FU). The goal was to design longer drug residence in vivo and passive targeting nanoparticles which could improve therapeutic efficacy and reduce side-effects. Based on the optimized results of uniform design experiment, 5-FU-SLNs were prepared by multiple emulsion-ultrasonication (w/o/w). The SLNs were found to be relatively uniform in size (182.1?±?25.8?nm) with a negative zeta potential (?27.89?±?5.1 mV). The average drug entrapment efficiency and loading were 74% and 10%, respectively. Compared with the 5-FU solution (t_1/2β, 0.593h; MRT, 0.358h) after intravenous injection to rats, the pharmacokinetic parameters of 5-FU-SLNs exhibited a longer retention time. (t_1/2β, 4.0628h; MRT, 3.5321h). The area under curve of plasma concentration-time (AUC) of 5-FU-SLNs was 1.48 times greater than that of free drugs. The overall targeting efficiency (TE^C) of the 5-FU-SLNs was enhanced from 13.25–20.45% in the lung and from 11.48–23.16% in kidney while the spleen distribution of 5-FU was significantly reduced as compared with that of the 5-FU solution. These results indicated that 5-FU-SLNs were promising passive targeting therapeutic agents for curing primary lung carcinoma.     

Biodistribution and improved anticancer effect of NIK-siRNA in combination with 5-FU for hepatocellular carcinoma

Increase of NF-κB inducing kinase (NIK) is known to promote the proliferation of the hepatitis B virus-derived hepatocellular carcinoma (HCC) cells. Previously, we have reported that NIK-specific siRNA in cationic liposomes was shown to suppress the expression of NIK and the proliferation of HCC cells (Cho et al., 2009). More improved suppression of NIK, followed by the improved antiproliferative effect on Hep3B cells, was achieved when 5-FU was cotreated with siRNA. Furthermore, biodistribution study after intravenous injection of siRNA into Hep3B-bearing Balb/c nude mice revealed that siRNA was highly accumulated in liver, followed by tumor, lung, spleen, kidney and heart. When encapsulated in cationic liposomes, larger amount of siRNA was found in tumor owing to the protection of siRNA from enzymatic degradation and enhanced permeability by liposome, suggesting a possible therapeutic modality of siRNA in liver-targeting cationic liposomal formulation for the treatment of hepatitis B virus-derived HCC.     

Synthesis of diethylenetriaminepentaacetic acid conjugated inulin and utility for cellular uptake of liposomes

The synthesis, binding of radioactive cations, liposomal encapsulation, and biodistribution of the oxidized-inulin reaction product with ethylenediamine and diethylenetriaminepentaacetic acid (4) are described. The four-step synthesis of the inulin derivative proceeded in a good overall yield of 72%. The complex of the inulin derivative with either 67Ga3+ or 111In3+ was stable in vivo and did not readily distribute into tissues, being excreted primarily in urine after intravenous administration to mice. The liposome-entrapped inulin derivative can be loaded with radioactive heavy metal cations by mobile ionophores in high radiochemical yields of 80-91%. Following the intravenous administration of the liposomal encapsulation of the indium-111-labeled inulin derivative, the entrapped compound had a biodistribution characteristic of liposomes and allowed an estimation of the extent of the intracellular uptake of liposomes. The ability of the inulin derivative to chelate many different types of metals will allow the use of this probe for studying subtle differences in tissue distribution resulting from different drug targeting or delivery protocols in the same animal by multiple labeling techniques. Moreover, the chelate-conjugated inulin permits studies of the applications of drug delivery systems in primates or human subjects by noninvasive techniques such as gamma-scintigraphic or nuclear magnetic resonance imaging methods.     

Elastic Liposomal Formulation for Sustained Delivery of Colchicine: In Vitro Characterization and In Vivo Evaluation of Anti-gout Activity

Colchicine, an alkaloid found in extracts of the plants Colchicum autumnale and Gloriosa superb, is effective in the treatment of acute gout and dermatological conditions like leuko-cytoclastic vasculitis, psoriasis, and Sweet’s syndrome. Oral administration of colchicine is associated with gastrointestinal side effects and its accumulation in the body leads to bone marrow suppression. In the present study, an attempt has been made for development and in vitro and in vivo evaluation of elastic liposomal formulation for topical delivery of colchicine. The in vitro skin permeation study across rat skin found transdermal flux for different elastic liposomal formulations to range between 32.8?±?1.2 and 44.4?±?1.9 μg h^?1 cm^?2, which was approximately seven to 11 times higher than obtained using drug solution (4.3?±?0.6 μg h^?1 cm^?2). The results of skin deposition study showed that elastic liposomal formulation provide 12.5-fold higher skin deposition as compared to drug solution of colchicine. Confocal laser scanning microscopy also revealed better accumulation and deeper penetration (up to 200 μm) of elastic liposomes than drug solution (up to 12 μm). The biological evaluation of various vesicular formulations and drug solution was carried out using monosodium urate-induced air pouch model. The results of anti-gout activity in rats showed better and sustained biological effects in 24 h measured in terms of exudate volume (63.1?±?5.7% and 9.6?±?0.5% reduction with elastic liposomes and drug solution, respectively), reduction in leukocyte count (74.2?±?6.0% and 4.1?±?0.3% reduction with elastic liposomes and drug solution, respectively), decrease in inflammatory cells accumulation, and collagen deposition with elastic liposomal formulation than drug solution. Hence, the present study reveals that elastic liposomal formulation of colchicine possesses greater potential to enhance skin accumulation, prolong drug release, and improve the site-specificity of colchicine.