Correlation between complicated diverticulitis and visceral fat.

The aim of this study was to examine the relationship of complications related to diverticulitis and visceral obesity. The study was based on a retrospective case note review conducted at the Hanyang University Hospital. Patients were diagnosed with diverticulitis based on clinical symptoms and abdominal computed tomography (CT) findings and divided into two groups: those admitted with complicated diverticulitis and those with a simple diverticulitis episode. We compared the body mass index (BMI) and degree of visceral obesity, measured by abdominal CT. The study included 140 patients, 87 (62.1%) were simple diverticulitis and 53 (37.9%) were complicated diverticulitis. In the complicated diverticulitis group, 9 (6.4%) cases were recurrent, 29 (20.7%) were perforation or abscess patients, and 28 (20%) were patients with systemic inflammatory response syndrome (SIRS). Of the SIRS patients, 13 were involved in other complication groups. When comparing in the two groups, the complicated diverticulitis group had a significantly higher visceral fat area (128.57 cm(2) vs 102.80 cm(2), P = 0.032) and a higher ratio of visceral fat area/subcutaneous fat area (0.997 vs 0.799, P = 0.014). Visceral obesity is significantly associated with complications of diverticulitis.

Topical application of liposomal cobalamin hydrogel for atopic dermatitis therapy.

Topical vitamin B12 was shown to be effective for atopic dermatitis. However, vitamin B12 itself is light sensitive and has low skin permeability, thus reducing its therapeutic effectiveness. In the present study, we prepared a liposomal hydrogel of adenosylcobalamin (AdCbl), a vitamin B12 derivative, and investigated possible beneficial effects of AdCbl on atopic dermatitis using an NC/Nga murine atopic dermatitis model. AdCbl was loaded into liposomes prepared by a thin film hydration method using a pH gradient method that employed citric acid buffer solution. This resulted in AdCbl-loaded liposomes that were 106.4 +/- 2.2 nm in size. The loading efficiency was 40% (of the initial AdCbl amount). Lipo-AdCbl had enhanced skin permeability, being about 17-fold compared with AdCbl-gel. Topical administration of Lipo-AdCbl-gel to 2,4-dinitrochlorobenzene (DNCB)-induced atopic dermatitis-like skin lesions in NC/Nga mice ameliorated lesion intensity scores, dorsal skin thickness, and total serum IgE in a concentration-dependent manner. Other preparations, including AdCbl solution, AdCbl cream, liposomes alone, and a mixture of AdCbl solution and liposomes had little effect. Taken together, our findings indicate that Lipo-AdCbl-gel has protective effects against atopic dermatitis symptoms, and suggest that it may be of benefit in the treatment of human inflammatory skin diseases.

Elastin-like polypeptide modified liposomes for enhancing cellular uptake into tumor cells.

Polyethylene glycol-modified (PEGylated) liposomes have been widely used because of their long circulation time, but they have a major drawback of limited cellular uptake. In this study, liposomes modified with a thermosensitive biopolymer, elastin-like polypeptide (ELP), were prepared to enhance cellular uptake in tumor cells. Synthesized ELP exhibited an inverse transition temperature (T(t)) of 40°C in serum with hyperthermia treatment and contained a lysine residue for conjugation with 1,2-dioleoyl-sn-glycero-3-phosphoethanolamine-N-[poly(ethylene-glycol)]-hydroxy succinamide, PEG MW 2000 (DSPE-PEG2000-NHS). ELP was covalently conjugated with liposomes encapsulating a high concentration of doxorubicin (Dox). Size and drug release properties of liposomes were investigated over a range of temperatures. ELP-modified liposomes tended to aggregate but did not show temperature-triggered release by phase transition of ELP molecules. Cellular uptake efficiency of liposomes was evaluated under normothermic and hyperthermic condition. Dox accumulation from liposomes was determined by flow cytometry and confocal microscopy. Higher internalization occurred in the ELP-modified liposomes than in ELP-unmodified liposomes. The results suggest that dehydration of ELP molecules on the liposomal surface can induce efficient cellular uptake, which can improve existing chemotherapeutic efficacy.

Gd(III)-DOTA-modified sonosensitive liposomes for ultrasound-triggered release and MR imaging.

Ultrasound-sensitive (sonosensitive) liposomes for tumor targeting have been studied in order to increase the antitumor efficacy of drugs and decrease the associated severe side effects. Liposomal contrast agents having Gd(III) are known as a nano-contrast agent system for the efficient and selective delivery of contrast agents into pathological sites. The objective of this study was to prepare Gd(III)-DOTA-modified sonosensitive liposomes (GdSL), which could deliver a model drug, doxorubicin (DOX), to a specific site and, at the same time, be capable of magnetic resonance (MR) imaging. The GdSL was prepared using synthesized Gd(III)-DOTA-1,2-distearoyl-sn-glycero-3-phosphoethanolamine lipid. Sonosensitivity of GdSL to 20-kHz ultrasound induced 33% to 40% of DOX release. The relaxivities (r1) of GdSL were 6.6 to 7.8 mM-1 s-1, which were higher than that of MR-bester®. Intracellular uptake properties of GdSL were evaluated according to the intensity of ultrasound. Intracellular uptake of DOX for ultrasound-triggered GdSL was higher than that for non-ultrasound-triggered GdSL. The results of our study suggest that the paramagnetic and sonosensitive liposomes, GdSL, may provide a versatile platform for molecular imaging and targeted drug delivery.

Gadolinium-based cancer therapeutic liposomes for chemotherapeutics and diagnostics.

Gadolinium (Gd)-based cancer therapeutic liposomes can be used for chemotherapeutics and diagnostics. In this study, dual functional liposomes co-encapsulating doxorubicin (Dox) and Gd were prepared by Dox-transition metal complexation. Preparation conditions were optimized to obtain liposomes containing high concentrations of Dox and Gd. The optimized liposomes Gd250 co-encapsulated 3.6 mM of Dox and 1.9 mM of Gd. The magnetic resonance (MR) properties of Gd250 liposomes were determined using a 4.7 T MR system. Cellular uptake of Dox was determined using a flow cytometer and a confocal microscopy and that of Gd was measured using an inductively coupled plasma-atomic emission spectrometer. Although encapsulated Gd exhibited lower relaxivity than MRbester®, which is widely used for clinical diagnosis, because of limited diffusion across the liposome membrane, Gd250 liposomes showed much higher cellular uptake than that of MRbester®. In Gd250 liposomes, Gd was highly accumulated in B16F10 cells, which could provide improved contrast sensitivity for molecular imaging. Additionally, in Gd250 liposomes, Dox was highly internalized, which could enhance its cancer therapeutic effects. Consequently, we suggest that dual functional liposomes can be used as therapeutic and diagnostic carriers.

Increased stability in plasma and enhanced cellular uptake of thermally denatured albumin-coated liposomes.

Liposomes are nano-scale vesicles that can be used as one of drug carriers. The liposomes are, however, plagued by rapid opsonization of them and hence making their circulation time in bloodstream to be shortened. In this study, cationically charged liposomes of which surface was modified with bovine serum albumin (BSA) were prepared by using electrostatic interaction between cationic liposomes and anionically charged BSA molecules at higher pH than isoelectric point (pI) of BSA. The BSA-coated liposomes (BLs) were denatured by thermal treatment of BL at 100 degrees C. The thermally denatured BSA-coated liposomes (DBLs) have mean particle diameter of 109+/-1 nm. Encapsulation of model drug, doxorubicin (DOX), in the liposomes was carried out by using, so called, remote loading method and loading efficiency of DOX in liposomes was about 90%. DBL800 showed higher stability in plasma compared to Doxil. Results of intracellular uptake evaluated by flow cytometry and confocal microscopy studies showed higher intracellular uptake of DBL800 than that of Doxil. Consequently, the DBL, of which surface was complexed with denatured protein may be applicable as drug delivery carriers for increasing stability in plasma and enhanced cellular uptake efficacy of anticancer drugs.

Disaccharide-modified liposomes and their in vitro intracellular uptake.

Sterically stabilized liposomes (SSL) were known to be accumulated passively in cancer due to the effect of enhanced permeability and retention (EPR). However, drug delivery via SSL to cancer seemed to show an insufficient improvement of chemotherapeutic efficacy. Herein, carbohydrate-binding proteins (lectins) of cell surface, which express on the plasmic membrane of many malignant cells, can be a good model of surface-modified liposomes. In this study, we investigated the in vitro characteristics of liposomes of which the surface was modified with a disaccharide molecule, sucrose or maltose. The disaccharide-modified lipids such as sucrose-modified lipid and maltose-modified lipid, in which the disaccharide was conjugated to the one end of 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-(polyethylene glycol)-2000 (DSPE-PEG2000), was synthesized. The disaccharide-modified liposomes were prepared by thin film-hydration method and then doxorubicin (DOX), an anticancer drug, was loaded to the prepared liposomes by the remote loading method with ammonium ion gradient. Flow cytometry and confocal microscopy analyses showed that the disaccharide-modified liposomes enhanced the intracellular uptake of liposomes into various cancer cell lines via lectin-mediated endocytosis. The disaccharide-modified liposomes in which DOX was loaded inside of liposomes exhibited higher cytotoxicity against various cancer cells than DOX-loaded SSL did. These results suggest that disaccharide-modified liposomes may be promising cancer targeting carriers which can enhance intracellular uptake and cytotoxicity of the drug-loaded liposomes via lectin-mediated endocytosis.

Polyethylene glycol-complexed cationic liposome for enhanced cellular uptake and anticancer activity.

Liposomes as one of the efficient drug carriers have some shortcomings such as their relatively short blood circulation time, fast clearance from human body by reticuloendothelial system (RES) and limited intracellular uptake to target cells. In this study, polyethylene glycol (PEG)-complexed cationic liposomes (PCL) were prepared by ionic complex of cationically charged liposomes with carboxylated polyethylene glycol (mPEG-COOH). The cationic liposomes had approximately 98.6+/-1.0 nm of mean particle diameter and 45.5+/-1.1 mV of zeta potential value. While, the PCL had 110.1+/-1.2 nm of mean particle diameter and 18.4+/-0.8 mV of zeta potential value as a result of the ionic complex of mPEG-COOH with cationic liposomes. Loading efficiency of model drug, doxorubicin, into cationic liposomes or PCL was about 96.0+/-0.7%. Results of intracellular uptake evaluated by flow cytometry and fluorescence microscopy studies showed higher intracellular uptake of PCL than that of Doxil. In addition, in vitro cytotoxicity of PCL was comparable to cationic liposomes. In pharmacokinetic study in rats, PCL showed slightly lower plasma level of DOX than that of Doxil. In vivo antitumor activity of DOX-loaded PCL was comparable to that of Doxil against human SKOV-3 ovarian adenocarcinoma xenograft rat model. Consequently, the PCL, of which surface was complexed with PEG by ionic complex may be applicable as drug delivery carriers for increasing therapeutic efficacy of anticancer drugs.

Amphotericin B-entrapping lipid nanoparticles and their in vitro and in vivo characteristics.

Lipid nanoparticles (LNPs) as nano-scale drug carriers that can entrap poorly water-soluble drugs such as amphotericin B (AmB) in aqueous solution with high drug entrapment efficiency were developed and their in vitro and in vivo characteristics were investigated. The AmB-entrapping plain, anionic and PEG (polyethylene glycol)-LNPs were prepared by using spontaneous emulsification and solvent evaporation (SESE) method. Mean particle size of the AmB-entrapping LNPs ranged from 72.9 to 159.1nm according to a variation of their lipid composition. The surface of AmB-entrapping PEG (0.2)-LNPs having 84.4+/-6nm of particle size was negatively charged showing -50.4+/-5mV of zeta-potential value. Entrapment efficiency of AmB in the PEG-LNPs reached up to 76.5+/-5%. Cytotoxicity of the AmB-entrapping LNPs against human kidney cells, 293 cells, was lower than those of the commercialized AmB-formulations such as Fungizone and AmBisome. Hematotoxicity of the AmB-entrapping LNPs against red blood cells was much lower than that of Fungizone but comparable to AmBisome. Antifungal activity in vitro of AmB-entrapping LNPs against Candida albicans and Aspergillus fumigatus was better than the commercialized AmB formulations showing their low minimum inhibitory concentration (MIC) for 90% of growth inhibition of fungi. The AmB-entrapping LNPs increased circulation half life of AmB in blood stream and it was comparable to AmBisome. Antifungal activity in vivo of the AmB-entrapping PEG-LNPs against Aspergillus fumigatus (ATCC 16424)-infected mice was superior to that of AmBisome. The drug-entrapping LNPs, especially PEG-LNPs, can be applicable to entrapment of poorly water-soluble drugs and enhancement of therapeutic efficacy by modulating pharmacokinetic behaviors and/or drug-related toxicities.