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Ex vivo transfer of nuclear factor-kappaB decoy ameliorates hepatic cold ischemia/reperfusion injury.

Transplant Proc. 2009 Jun;41(5):1504-7

Authors: Yoshizumi T, Ikeda Y, Kaneda Y, Sueishi K

Cold ischemia/reperfusion injury of the hepatic graft has been attributed to the release of various inflammatory cytokines. Specific inhibition of these cytokines may improve viability of the hepatic graft upon reperfusion. Herein we have assessed the efficacy of cis element decoy against nuclear factor-kappaB binding site delivery to the hepatic tissue in a rodent liver transplantation model. At 8 hours after reperfusion of the liver, significant reduction was noted in the livers treated with decoy in the release of cytosolic enzymes from the hepatocytes and in serum tumor necrosis factor alpha (P < .05). The neutrophilic infiltration into the hepatic grafts was significantly suppressed in the livers treated with decoy oligodeoxynucleotides (ODNs). Decoy ODNs against nuclear factor-kappaB binding site delivery improved the viability of the hepatic graft against cold ischemia/reperfusion injury in the rodent liver transplantation model.

PMID: 19545666 [PubMed - indexed for MEDLINE]

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Combined strategies for liposome characterization during in vitro digestion.

J Liposome Res. 2009;19(3):207-19

Authors: Hermida LG, Sabés-Xamaní M, Barnadas-Rodríguez R

Three types of pyranine (HPTS)-containing liposomes were prepared by high-pressure homogenization under optimized conditions. At 37 degrees C, they were 1) fluid-state vesicles made from soybean phosphatidylcholine (SPC), 2) gel-state liposomes made from hydrogenated SPC (HSPC), and 3) solid-disordered membranes obtained from HSPC and cholesterol (HSPC-Chol). These liposome formulations were characterized before, during, and after in vitro digestion, which involved the presence of pH gradients, enzymes, and bile salts. Mean sizes and size distributions of the vesicles were determined by DLS; (31)P-NMR (nuclear magnetic resonance) was used to quantify lyso-PC forms; internal pH was monitored throughout digestion with two different fluorescent pH probes; and changes in bilayer permeability and HPTS encapsulation were determined by size-exclusion chromatography and fluorimetry. Differential scanning calorimetry analysis was also performed in order to study the effect of digestion on HSPC vesicles. SPC liposomes were physically stable during digestion; they presented 8% lyso-forms and an HPTS encapsulation around 85% after in vitro digestion. However, they were extremely permeable to ions, so that the internal pH immediately equilibrated with the bulk pH. HSPC liposomes were the most affected by the digestive process. Even though they were chemically stable, as inferred from the low lyso-PC content, very important changes in their size distribution were observed. A final 50% HPTS leakage was quantified after in vitro digestion. Nevertheless, they were the least permeable to protons under pH gradients. HSPC-Chol vesicles presented intermediate permeability to protons, having their internal pH decreased from approximately 6.8 to 4.6 after 1 hour of incubation at pH 2. This was the most chemically stable formulation and showed the highest encapsulation, even after in vitro digestion. Therefore, HSPC-Chol liposomes would be the most adequate choice for the design of lipid products for oral administration.

PMID: 19548842 [PubMed - indexed for MEDLINE]

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Lipid-shelled vehicles: engineering for ultrasound molecular imaging and drug delivery.

Acc Chem Res. 2009 Jul 21;42(7):881-92

Authors: Ferrara KW, Borden MA, Zhang H

Ultrasound pressure waves can map the location of lipid-stabilized gas micro-bubbles after their intravenous administration in the body, facilitating an estimate of vascular density and microvascular flow rate. Microbubbles are currently approved by the Food and Drug Administration as ultrasound contrast agents for visualizing opacification of the left ventricle in echocardiography. However, the interaction of ultrasound waves with intravenously-injected lipid-shelled particles, including both liposomes and microbubbles, is a far richer field. Particles can be designed for molecular imaging and loaded with drugs or genes; the mechanical and thermal properties of ultrasound can then effect localized drug release. In this Account, we provide an overview of the engineering of lipid-shelled microbubbles (typical diameter 1000-10 000 nm) and liposomes (typical diameter 65-120 nm) for ultrasound-based applications in molecular imaging and drug delivery. The chemistries of the shell and core can be optimized to enhance stability, circulation persistence, drug loading and release, targeting to and fusion with the cell membrane, and therapeutic biological effects. To assess the biodistribution and pharmacokinetics of these particles, we incorporated positron emission tomography (PET) radioisotopes on the shell. The radionuclide (18)F (half-life approximately 2 h) was covalently coupled to a dipalmitoyl lipid, followed by integration of the labeled lipid into the shell, facilitating short-term analysis of particle pharmacokinetics and metabolism of the lipid molecule. Alternately, labeling a formed particle with (64)Cu (half-life 12.7 h), after prior covalent incorporation of a copper-chelating moiety onto the lipid shell, permits pharmacokinetic study of particles over several days. Stability and persistence in circulation of both liposomes and microbubbles are enhanced by long acyl chains and a poly(ethylene glycol) coating. Vascular targeting has been demonstrated with both nano- and microdiameter particles. Targeting affinity of the microbubble can be modulated by burying the ligand within a polymer brush layer; the application of ultrasound then reveals the ligand, enabling specific targeting of only the insonified region. Microbubbles and liposomes require different strategies for both drug loading and release. Microbubble loading is inhibited by the gas core and enhanced by layer-by-layer construction or conjugation of drug-entrapped particles to the surface. Liposome loading is typically internal and is enhanced by drug-specific loading techniques. Drug release from a microbubble results from the oscillation of the gas core diameter produced by the sound wave, whereas that from a liposome is enhanced by heat produced from the local absorption of acoustic energy within the tissue microenvironment. Biological effects induced by ultrasound, such as changes in cell membrane and vascular permeability, can enhance drug delivery. In particular, as microbubbles oscillate near a vessel wall, shock waves or liquid jets enhance drug transport. Mild heating induced by ultrasound, either before or after injection of the drug, facilitates the transport of liposomes from blood vessels to the tissue interstitium, thus increasing drug accumulation in the target region. Lipid-shelled vehicles offer many opportunities for chemists and engineers; ultrasound-based applications beyond the few currently in common use will undoubtedly soon multiply as molecular construction techniques are further refined.

PMID: 19552457 [PubMed - indexed for MEDLINE]

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Phosphatidyl choline-based colloidal systems for dermal and transdermal drug delivery.

J Liposome Res. 2009 Mar 31;

Authors: Ferderber K, Hook S, Rades T

In this study we have prepared various phosphatidyl choline based colloidal systems, namely liposomes, transfersomes, microemulsions and micelles, using similar excipients and compared their ability to deliver drugs into and through the skin under occlusive and non-occlusive conditions. Hydrophilic propranolol hydrochloride (PHCl) and lipophilic propranolol base (PB) were used as model drugs. All tested parameters, that is formulation composition, drug characteristics and testing conditions, influenced skin permeability and skin retention. A trend was observed showing that the skin permeation as well as skin retention decreases with the amount of phosphatidyl choline in the formulations for both tested model drugs (micelles > transfersomes > liposomes > microemulsion). The lipophilic model drug had higher skin permeability especially when incorporated into the systems containing mainly hydrophilic excipients. Skin retention, however, was not affected by the drug hydrophilicity to the same extent as skin permeability. Occlusion increased both skin retention and skin permeation for both model drugs.

PMID: 19552575 [PubMed - as supplied by publisher]

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An immobilized nanoparticle-based platform for efficient gene knockdown of targeted cells in the circulation.

Gene Ther. 2009 Oct;16(10):1271-82

Authors: Huang Z, King MR

It is well established that specific interaction between adhesion molecules of endothelial cells and receptors on leukocytes can separate and recruit leukocytes from the bloodstream to sites of inflammation and coagulation. Previously, we showed that P-selectin can be absorbed onto the surface of a blood-compatible microrenathane tube, and the P-selectin-coated surface could successfully capture P-selectin receptor-positive stem cells from physiological shear flow in vitro and from the bloodstream in vivo. In this paper, P-selectin was covalently attached to the surface of nanoscale liposomes to create targeting nanoparticles (NPs). Small interfering RNA (siRNA) was encapsulated by these nanoscale liposomes, and the liposomes were stabilized by PEGylation with DSPE-PEG2000. Experiments showed that these P-selectin-, PEGylated-, nanoscale-liposomes (PS-DSPE-PEG NPs) could be absorbed onto the inner surface of microrenathane tubing. The coated surface could specifically capture targeted cells from physiological shear flow, efficiently deliver encapsulated siRNA into adherent cells and dramatically silence the targeted gene neutrophil elastase. With this device, we create a high localized concentration for siRNA delivery in the circulatory system, providing circulating target cells adequate time to interact with therapeutic materials. SiRNA is efficaciously delivered into specific target cells, thereby providing a powerful tool for highly efficient siRNA transfection and other therapeutic materials delivery in circulation. The method should prove especially useful for diseases derived from disorders of blood cells.

PMID: 19554031 [PubMed - in process]

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Stability evaluation of temoporfin-loaded liposomal gels for topical application.

J Liposome Res. 2009 Jun 29;

Authors: Dragicevic-Curic N, Winter S, Krajisnik D, Stupar M, Milic J, Graefe S, Fahr A

Temoporfin (mTHPC) is a potent second-generation synthetic photosensitizer. Topical delivery of mTHPC is of great interest for the photodynamic therapy of psoriasis and superficial skin cancer lesions. The aim of this study was to evaluate the stability of hydrophilic gels containing mTHPC-loaded liposomes. Two different mTHPC-loaded liposome dispersions, composed of 15 % (w/w) nonhydrogenated soybean lecithin of different phosphatidylcholine content, were prepared and incorporated (2:1 w/w) into hydrogels of different carbomer concentrations (1.5, 2.25, and 3%; w/w). Obtained liposomal hydrogels, containing 0.15% (w/w) mTHPC, 10% (w/w) phospholipids, and 0, 0.5, or 1% (w/w) carbomer, were analyzed for flow properties, liposome particle size, and polydispersity index (PDI), pH value, and mTHPC content after their preparation and at predetermined time intervals during 6 months of storage at 4 and 23 degrees C. All hydrogels showed, during the whole period of investigation, adequate characteristics for topical application (i.e., they revealed shear-thinning plastic flow behavior). Rheological parameters, particle size, and PDI of liposomes in hydrogels, mTHPC content, and pH value did not show remarkable changes during the storage of gels, which could make them unacceptable for topical use. The obtained results indicated physical and chemical stability of liposomal gels containing mTHPC during 6 months of storage at both temperatures.

PMID: 19558347 [PubMed - as supplied by publisher]

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Liposome coated with low molecular weight chitosan and its potential use in ocular drug delivery.

Int J Pharm. 2009 Sep 8;379(1):131-8

Authors: Li N, Zhuang C, Wang M, Sun X, Nie S, Pan W

In this study liposome coated with low molecular weight chitosan (LCH) was proposed and investigated its in vitro and in vivo properties, and its potential use in ocular drug delivery was evaluated. LCH with a molecular weight of 8kDa was prepared and coated on liposome loaded with diclofenac sodium. The LCH coating changed the liposome surface charge and slightly increased its particle size, while the drug encapsulation was not affected. After coating, the liposome displayed a prolonged in vitro drug release profile. LCH coated liposome also demonstrated an improved physicochemical stability at 25 degrees C in a 30-day storage period. The ocular bioadhesion property was evaluated by rabbit in vivo precorneal retention, and LCH coated liposome achieved a significantly prolonged retention compared with non-coated liposome or drug solution. The LCH coating also displayed a potential penetration enhancing effect for transcorneal delivery of the drug. In the ocular tolerance study, no irritation or toxicity was caused by continual administration of LCH coated liposome in a total period of 7 days. In conclusion, the LCH coating significantly modified the properties of liposome and brought a series of notable advantages for ocular drug delivery.

PMID: 19559775 [PubMed - indexed for MEDLINE]