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PubMed1999

The use of aqueous PEG/dextran phase separation for the preparation of dextran microspheres.

A novel procedure to prepare dextran microspheres, without the use of organic solvents was developed. The method is based on phase separation which occurs in aqueous solutions of PEG and methacrylated dextran (dexMA). After stirring this two phase system a water-in-water emulsion is formed. When dexMA forms the discontinuous phase, dextran microspheres can be obtained by polymerization of the methacryloyl groups attached to dextran. The aim of this study was to gain insight into the formulation parameters that affect the particle characteristics. Therefore, it was necessary to establish dexMA/PEG/water phase diagrams. Lower polymer molecular weights and higher degrees of MA substitution resulted in less pronounced phase separation (binodal shifts to higher concentrations). The volume weight mean microsphere diameter varied between 2.5 and 20 microm, depending on the viscosities of both phases and the PEG/dexMA volume ratio. A more viscous continuous phase and/or a less viscous discontinuous phase resulted in smaller microspheres. Furthermore, the particle size increased with decreasing PEG/dexMA volume ratios. The particle characteristics, like cross-link density, initial water content and size can be tailored by adjusting the formulation parameters.

Dextrans↗
PubMed2003

Solubilization of cyclosporin A in dextran-g-polyethyleneglycolalkyl ether polymeric micelles.

Solubilization of the poorly water-soluble drug, Cyclosporin A (CsA), in aqueous dispersions of dextran-grafted-polyethyleneglycolalkyl ether (DEX-g-PEG-Cn) polymeric micelles was examined as a function of copolymer structure. In aqueous solution, DEX-g-PEG-Cn form polymeric micelles of low critical association concentrations (CAC) and small micelle sizes as determined by fluorescence spectroscopy and dynamic light scattering (DLS). Copolymers with longer polysaccharide chain showed larger CAC and mean diameter. The percentage of CsA loading into micelles was determined by high performance liquid chromatography. It was significantly larger in polymeric micelles compared to unmodified dextrans. It increased with increasing number of PEG-Cn units grafted per dextran chain and decreasing dextran molecular weight. The cytotoxicity of DEX-g-PEG-C(16) polymeric micelles towards Caco-2 cells, tested by MTT cytotoxicity assay, was significantly lower than that of free PEG-C(16) molecules. It can be concluded that the length of the hydrophilic part as well as the content and chemical nature of the hydrophobic substituents have an important effect on the ability of polymeric micelles to solubilize poorly-water soluble drugs.

Caco-2 Cells↗
PubMed1999

Dextran cross-linked gelatin microspheres as a drug delivery system.

This paper describes the use of oxidized dextran as a cross-linker for the preparation of gelatin microspheres. Microspheres were obtained by a thermal gelation method and their dissolution kinetic was examined. In order to find evidence of sugar mediated cross-linking, swelling tests and gelatin microspheres dissolution experiments were performed. The obtained results indicated that oxidized dextran can form a cross-linked gelatin network which can reduce the dissolution of gelatin. More interestingly, gelatin microspheres treated by both native and oxidized dextran slow down, even if to a different extent, the release of the antitumor drug TAPP-Br used as a model compound. Taken together, our results suggest that oxidized dextran could be an interesting means to cross-link gelatin microspheres allowing the use of this delivery formulation for controlled release of drugs.

Dextrans↗
PubMed2003

Preclinical studies of [(99m)Tc]DTPA-mannosyl-dextran .

We report the preclinical testing of a synthetic receptor-binding macromolecule, [(99m)Tc]DTPA-mannosyl-dextran (36 kDa, 8 DTPA and 55 mannosyl units per dextran, K(D) = 0.12 nM), for sentinel node detection. Nonclinical safety studies included cardiac pharmacology safety studies, acute toxicology and pathology studies at 50 and 500 times the scaled human dose in both rats and rabbits after foot pad administration, and perivascular irritation studies in rabbits following intra-muscular administration at 100 and 1000 times the scaled human dose. Biodistribution studies in rabbits at 15 m, 1 h, and 3 h indicated that [(99m)Tc]DTPA-mannosyl-dextran cleared the hind foot pad with a biological half-life of 2.21 +/- 0.27 h. Other than mild hepatocyte hypertrophy in rabbits, no abnormalities in toxicology or pathology were found. Intravenous administration had no effect on survival, any clinical observations, electrocardiograms, or blood pressures. Intramuscular injection had no effect on survival, clinical observations, injection site observations, or injection site histopathology. The estimated absorbed radiation dose to the affected breast was 0.15 mGy/MBq and the effective dose was 1.06 x 10(-2) mSv/MBq. This preclinical study demonstrates that [(99m)Tc]DTPA-mannosyl-dextran has no toxicities and has an acceptable biodistribution and radiation dose.

Animals↗
PubMed2002

Characterization of fluorescein isothiocyanate-dextrans used in vesicle permeability studies.

Fluorescein Isothiocyanate-dextrans of various weight average molecular masses (4,400-487,000) were analyzed in buffer solution for pH, osmolarity, fluorescence intensity as a function of the polymer concentration, average molecular masses, and radii of gyration. Labeling of polymers and conformation of the polymers were characterized by high-performance gel exclusion chromatography (HPLC-GEC) and small-angle X-ray scattering. The fluorescence measurements evidence the absence of fluorescence quenching of the FITC chromophores but the existence of an inner filter effect at high polymer concentration. The conformation of the polymers in buffer is very likely of random coil type, as shown by the relationship between the radii of gyration and the weight-average molecular masses of the dextrans (Mw). The medium used to analyze the FITC-dextrans by HPLC-GEC strongly influences their elution behavior. In buffer medium, they are sieved over the TSK G4000 PW column through a single population according to their Mw. whereas in pure water, they are separated into several species by an exclusion mechanism that depends on the number of labeled sites per dextran molecule. A Monte Carlo simulation was used to analyze the distribution of the fluorescent labels. HPLC-GEC in water could interestingly be applied to yield labeled polymers bearing a known number of functionalized groups.

Chromatography, Gel↗
PubMed2000

Pore sizes in hydrated dextran microspheres.

The average pore size of hydrated dextran microspheres is derived from rheological and protein release data. The microspheres were prepared by cross-linking an aqueous solution of methacrylated dextran emulsified in a continuous poly(ethylene glycol) phase. The rheological data were obtained using a novel micromanipulation technique, which enables the compression of a single microsphere. The so obtained pseudoelasticity moduli of the microspheres were derived from these compression data and corresponded well with the elasticity moduli of macroscopic hydrogels of the same composition, as determined with dynamic mechanical analysis. The modulus increased with decreasing water contents of the microspheres and with increasing degrees of methacrylate substitution of the dextran used. Furthermore, the average pore sizes calculated from the pseudoelasticity moduli were in good agreement with the pore sizes derived from protein release data. In conclusion, this study shows that micromanipulation provides insight into the average pore sizes of dextran microspheres, which is an important characteristic that will modulate the release of encapsulated proteins.

Dextrans↗
PubMed2001

Design of macromolecular prodrug of cisplatin using dextran with branched galactose units as targeting moieties to hepatoma cells.

We previously reported that a macromolecular prodrug synthesized by immobilizing cisplatin (CDDP) to dextran (Dex) through six-membered chelate-type coordination bond (DCM-Dex/CDDP conjugate) showed a significantly longer half-life in bloodstream and excellent in vivo tumor growth inhibitory effect against mice bearing Colon 26 cancer cells. In this report, to provide DCM-Dex/CDDP conjugate having targetability to hepatoma cells, we designed a new macromolecular prodrug of CDDP using dextran having branched galactose units (Gal4As, four branched galactose residues), DCM-Dex/Gal4A/CDDP conjugate. Galactose was employed as a homing device, because it is well-known that galactose receptors (asialoglycoprotein receptors) were exposed on the surface of liver parenchymal cells. The antennary (branched) structure of Gal4A was designed based on the fact that a saccharide cluster having a branched structure shows highly effective binding with the saccharide receptors, that is a "cluster effect". The apparent affinity constant per galactose residue against RCA120 lectin for dextran carrying Gal4As was higher than that for dextran carrying monomeric galactose residues. Moreover, the DCM-Dex/Gal4A/CDDP conjugate showed cell-specific cytotoxic activity against HepG2 human hepatoma cells in vitro. The cytotoxic activity of the conjugate was inhibited by the addition of galactose and strongly inhibited by the addition of Gal4A. The results suggest that the DCM-Dex/Gal4A/CDDP conjugate having branched galactose units has a higher affinity to hepatoma cells.

Antineoplastic Agents↗
PubMedDate not supplied

Tailoring the swelling pressure of degrading dextran hydroxyethyl methacrylate hydrogels.

Swelling pressure measurements were performed on degrading dextran hydroxyethyl methacrylate (dex-HEMA) hydrogels. In these networks, the cross-links are hydrolyzable carbonate ester bonds formed between methacrylate groups and dextran molecules. It is demonstrated that dex-HEMA gels made in the presence of a known amount of free dextran chains exhibit osmotic properties similar to those of partially degraded dex-HEMA gels. The swelling pressure, Pi(sw), of degrading dex-HEMA gels is controlled primarily by the cross-linked dex-HEMA polymer and the free dextran molecules, while the contribution of short poly-HEMA fragments (produced in the degradation process) is negligible. It is found that Pi(sw) only slightly changes during the first 15 days of degradation. Close to the end of the degradation process, however, a much faster increase in Pi(sw) is observed. The swelling pressure profile of these gels strongly depends on the concentration of the cross-linked dex-HEMA and its chemical composition (amount of HEMA groups per 100 glucose units).

Biodegradation, Environmental↗
PubMedDate not supplied

Improved stability of polycationic vector by dextran-grafted branched polyethylenimine.

In vivo instability of a polycationic vector limits its efficacy after systemic administration. Conjugation of hydrophilic polymers with neutral charge onto polycationic vectors has been used to improve the stability by reducing the interactions between the vectors and the blood components, such as serum albumin. In this study, dextrans of molecular weight 10000 (dex-10000) and 1500 (dex-1500) were used to produce various degrees of grafting on linear and branched polyethylenimines (PEI), and the dextran-grafted polymers were used to prepare DNA-polymer complexes. The changes in size and in zeta-potential and the extent of DNA release after the exposure of the complexes to bovine serum albumin (BSA) were used to evaluate the stability of the complexes prepared at various ratios of DNA to polymer. Only the use of dextran-grafted branched PEI was found to be effective to improve the stability of the complexes in the presence of BSA. Dex-10000 was noted to provide a slightly better shielding than dex-1500 against the aggregation caused by BSA and helped maintain the sizes within 200 nm and the zeta-potentials close to neutral. It is thus concluded that the dextran-grafted branched PEI improved the stability of the DNA-polymer complexes and showed potential to conjugate with ligands for in vivo targeted gene delivery.

DNA↗
PubMed2006

In vitro degradation behavior of microspheres based on cross-linked dextran.

The aim of this study was to investigate the in vitro degradation of hydroxyl ethyl methacrylated dextran (dex-HEMA) microspheres. Dextran microspheres were incubated in phosphate buffer pH 7.4 at 37 degrees C, and the dry mass, mechanical strength, and chemical composition of the microspheres were monitored in time. The amount and nature of the formed degradation products were established for microspheres with different cross-link densities by FT-IR (Fourier transformed infrared spectroscopy), NMR, mass spectrometry, SEC analysis, and XPS (X-ray photoelectron microscopy). The dex-HEMA microspheres DS 12 (degree of HEMA substitution; the number of HEMA groups per 100 glucose units) incubated at pH 7.4 and 37 degrees C showed a continuous mass loss, leaving after 6 months a residue of about 10% (w/w) of water-insoluble products. NMR, mass spectrometry, and SEC showed that the water-soluble degradation products consisted of dextran, low molecular weight pHEMA (M(n) approximately 15 kg/mol), and small amounts of unreacted HEMA and HEMA-DMAP (intermediate reaction product of the Baylis-Hillman reaction of HEMA with DMAP (4-dimethyl aminopyridine)). Microscopy revealed that the water-insoluble residue consisted of particles with shape and size similar to that of nondegraded microspheres. However, these particles had lost their mechanical strength as evidenced from micromanipulation experiments. FT-IR and XPS (X-ray photoelectron microscopy) revealed that these particles consisted of pHEMA, of which a small fraction was soluble in methanol (M(n) ranging between 27 and 82 kg/mol). The insoluble material likely consisted of lightly cross-linked pHEMA. In conclusion, in vitro degradation of dex-HEMA microspheres results in the formation of water-soluble degradation products (mainly dextran), leaving a small water-insoluble residue mainly consisting of pHEMA.

Chromatography, Gel↗
PubMed2006

Nonfouling characteristics of dextran-containing surfaces.

Hydroxyl groups in dextrans have been selectively oxidized to aldehyde groups by sodium periodate in a controlled fashion with a percentage of conversion ranging from 6 to 100%. Dextrans (10, 70, 148, 500, and 2000 kDa) and oxidized 10k dextrans have been successfully grafted to functionalized silicon surfaces. The effect of molecular weight on protein adsorption is not nearly as striking as that of the extent of oxidation. When approximately 25% of the hydroxyl groups have been converted to aldehyde groups, there is negligible protein adsorption on surfaces containing the oxidized polysaccharides. Conformations of grafted polymers depend strongly on their chemical structures, that is, the relative amounts of -OH and -CHO groups. The dependence of the chain conformation as well as the protein resistance on the balance of the hydrogen bond donors (-OH) and the acceptors (-OH and -CHO) implies the importance of chemical structure of surface molecules, specifically the interactions between surface and surrounding water molecules on protein adsorption. Oxidized dextrans are potential poly(ethylene glycol) alternatives for nonfouling applications.

Adsorption↗
PubMedDate not supplied

Dependence of transgene expression and the relative buffering capacity of dextran-grafted polyethylenimine.

Branched polyethylenimine (PEI) is a cationic polymer capable of forming self-assembly complexes with DNA to become a highly efficient agent used in gene delivery. Conjugation through the primary amines of PEI is a most commonly used approach further to enable the targeting delivery or to improve the stability of the DNA-polymer complexes. An understanding of how the conjugation affects the transfection mechanisms can help in the design of efficient polycationic vectors. In order to investigate the effects of conjugation, folate and the dextrans of molecular weight 1500 (dex-1500) and 10 000 (dex-10000) were used to prepare three different types of PEI conjugates: dextran-PEI, folate-PEI, and folate-dextran-PEI, which were subsequently employed to form complexes with DNA. These conjugates were found to cause less cytotoxicity than the unmodified PEI as revealed by the MTT method, and to be able to deliver an approximate amount of ethidium monoazide labeled plasmid into the cells. The efficiencies of green fluorescent protein (GFP) expression mediated by these conjugates, however, were less efficient than those mediated by the unmodified PEI. A titration experiment suggested that conjugation through the primary amines of PEI resulted in the loss of relative buffering capacity, a major factor aiding the release of plasmid from the endosomes, presumably because the conjugated molecules hindered the protonation of the PEI conjugates. When a quantitative relationship between relative buffering capacity and transfection efficiency was examined, a threshold of relative buffering capacity, around 50% of the unmodified PEI, was noted to be required for minimal detection of GFP positive cells. In addition, the cytotoxicity could be also related to the relative buffering capacity in an approximately linear trend. It is thus concluded that the severe loss of relative buffering capacity by conjugation might be attributed to the inefficiency of transgene expression mediated by the dextran-PEI conjugates.

Buffers↗
PubMed2000

Binding of hydrogen sulfide by bismuth does not prevent dextran sulfate-induced colitis in rats.

Several lines of evidence suggest that ulcerative colitis could be caused by excessive bacterial production of H2S in the colon. A rodent model of colitis involves the feeding of nonabsorbable, carbohydrate-bound sulfate in the form of dextran sulfate or carrageenan. The observation that metronidazole blocks the development of this colitis suggested that the injurious agent could be a sulfur-containing compound (such as H2S) that is released during the bacterial metabolism of the nonabsorbed sulfate. We tested this possibility by feeding rats dextran sulfate, with or without bismuth subsalicylate, a compound that avidly binds H2S. Bismuth subsalicylate reduced the fecal release of H2S in dextran sulfate-treated rats to values well below that of controls. Nevertheless, all the animals developed colitis. We conclude that excessive H2S production does not play a role in the dextran sulfate model of colitis.

Animals↗
PubMed2001

Resistance of dextran-modified hyaluronidase to inhibition by heparin.

Properties of native and aldehyde dextran-modified hyaluronidase (with surface amino group modification about 98%) were investigated. Optimal endoglycosidase activity of the native enzyme was observed at 0.15 M NaCl and pH 5.5 and electrostatic interactions influenced the enzyme activity. The inhibitory effect of heparin on hyaluronidase activity slightly differed at pH 5.5 (1.5-fold inhibition) and 7.5 (1.2-fold inhibition). Ionic strength of the reaction medium only slightly influenced the effect of heparin. Modification of hyaluronidase with dextran increased hydrophobic interactions and steric hindrance. Conjugation with dextran increased the resistance of hyaluronidase activity to denaturing agents (urea, guanidinium hydrobromide) and extended the optimal conditions for maximal endoglycosidase activity (pH 4.5-6.5, the range of NaCl concentration from 0.1 to 0.3 M). The conjugation also reduced electrostatic effects on the active site of hyaluronidase and efficacy of heparin inhibition. At pH 7.5 the enzyme was almost insensitive to heparin. The resistance of dextran-modified hyaluronidase to heparin points to approaches for subsequent studies of the heparin-binding site of this enzyme and biomedical trial of the stabilized enzyme for the treatment of acute cardiovascular lesions.

Animals↗
PubMed1989

Macromolecular prodrugs. XV. Colon-targeted delivery--bioavailability of naproxen from orally administered dextran-naproxen ester prodrugs varying in molecular size in the pig.

The bioavailability of naproxen after oral administration of aqueous solutions of various dextran-naproxen ester prodrugs in pigs was determined. The dextran prodrugs employed ranged in molecular weight from 10,000 to 500,000. As calculated relative to an equivalent oral dose of parent naproxen, the absorption fractions of all the derivatives were close to 100%. Only small interindividual variation of naproxen bioavailability was observed. The naproxen plasma profiles for all the administered prodrugs exhibited a characteristic lag time of naproxen appearance in the blood (2-3 hr). Compared to administration of the prodrugs alone, coadministration of excess of the parent dextran further delayed the absorption of naproxen from the GI tract. The results of the present study demonstrate the potential of dextran prodrugs for colon site-specific delivery of drugs containing a carboxylic acid functional group.

Administration, Oral↗
PubMed1975

Chalone-like effect abrogated by dextran sulphate and heparin polyanion pretreatment of target cells.

Chalone prepared from primary BALB/c mouse embryo fibroblasts caused a 33% reduction in incorporation of tritiated thymidine in the cultures of the second in vitro passage of BALB/c embryo fibroblasts, whereas chalone prepared from thymus, skin and spleen was without effect. Pretreatment of BALB/c secondary fibroblasts with the polyanions dextran sulphate and heparin abrogated the chalone effect. The polycations DEAE-dextran and polybrene were without effect. The effect of incubation with the dextran sulphate polyanion was reversed when followed by incubation with DEAE-dextran polycation.

Animals↗
PubMed1993

Blood flow in single surface arterioles and venules on the mouse somatosensory cortex measured with videomicroscopy, fluorescent dextrans, nonoccluding fluorescent beads, and computer-assisted image analysis.

Cortical surface vessels were monitored through closed cranial windows with an epifluorescence microscope and SIT or ICCD cameras. Fluorescent dextrans or 1.3 microns latex beads were injected into the contralateral jugular vein for plasma labeling and for vascular transits. For close arterial transits, these tracers or physiological saline were injected into the ipsilateral external carotid artery. AVTTs were calculated from intensity differences of tracers between a branch of the MCA and a vein draining the same cortical region over time. AVTTs for saline dilutions of RBCs were significantly shorter (0.73 times) than for dextrans. Both dextrans and beads distributed with plasma. With FITC-dextran, inner diameters of arterioles and venules averaged 6 microns larger than hemoglobin under green light. This difference was likely due to the segregation of red blood cells and plasma during flow. Velocities of individual fluorescent beads were measured in pial vessels by strobe epi-illumination. Plots of bead velocities against radial position in arterioles were blunted parabolas. Peak shear rates in the marginal layer next to the vessel walls were determined directly from bead tracks in arterioles (D = 21-71 microns) and were 1.32 times the Poiseuille estimate. The calculated peak wall shear stress was 39 +/- 14 dyn/cm2 (mean +/- SD) for these arterioles but was probably severalfold greater in the smallest terminal pial arterioles. Vmax near the axes of arterioles increased with D+0.5. The calculated peak wall shear rate was highest in small arterioles and decreased with D-0.5. The calculated flow Q increased with D+2.5. These methods permit direct, simultaneous, dynamic measurements on multiple identified cerebral microvessels.

Animals↗
PubMed1977

Structural investigation of loose connective tissue by using a series of dextran fractions as non-interacting macromolecular probes.

The ability of the uncharged open-coil dextran molecules to penetrate tissue space, without coil-shape change, was utilized to probe (by partitioning experiments) the structural arrangement of the collagen-fibre network and the proteoglycan system. Hyaluronidase digests most of the proteoglycans away and enables the respective contributions to the exclusion volume to be evaluated by using a series of different-molecular-weight dextrans. It appears that the major part of the exclusion volume is due to the collagen-fibril as a rod and the dextran coil as an impenetrable sphere. The additional exclusion due to the proteoglycans could be accounted for by a set of points (regions of high proteoglycan-segment density) over which the dextran coild cannot pass. These points are an average of 50 nm apart and are indicative of local extensive entanglement of high-molecular-weight proteoglycans with each other. Reasons are given why these entanglements could not act as cross-links in long-term elastic loading of the tissue.

Connective Tissue↗