Dextran Derivatives Research Articles

New biodegradable dextran-based hydrogels for protein delivery: Synthesis and characterization

A new derivative of dextran grafted with polyethylene glycol methacrylate through a carbonate bond (DEX–PEG–MA) has been synthesized and characterized. The photo-crosslinking reaction of DEX–PEG–MA allowed the obtainment of biodegradable networks tested for their mechanical and release properties. The new hydrogels were compared with those made of dextran methacrylate (DEX–MA), often employed as drug delivery systems of small molecules. The inclusion of PEG as a spacer created additional interactions among the polymeric chains improving the extreme fragility and lack of hardness typical of gels made of DEX–MA. Moreover, the different behavior in terms of swelling and degradability of the networks was able to affect the release of a model macromolecule over time, making DEX–PEG–MA matrices suitable candidates for the delivery of high molecular weight peptides. Interestingly, the combination of the two dextran derivatives showed intermediate ability to modulate the release of high molecular weight macromolecules.

Water soluble cationic dextran derivatives containing poly(amidoamine) dendrons for efficient gene delivery

To develop new dextran derivatives for efficient gene delivery, the conjugation of poly(amidoamine) dendrons onto biocompatible dextran was carried out by a Cu(I)-catalyzed azide-alkyne cycloaddition, as confirmed by FTIR and 1H NMR analyses. For resultant dextran conjugates with various generations of poly(amidoamine) dendrons, their buffering capacity and in vitro cytotoxicity were evaluated by acid–base titration and MTT tests, respectively. In particular, their physicochemical characteristics for the complexation with plasmid DNA were investigated by the combined analyses from agarose gel electrophoresis, zeta potential, particle size, transmission electron microscopy and fluorescence emission spectra. Moreover, their complexes with plasmid DNA were studied with respect to their transfection efficiency in human embryonic kidney (HEK293) cell lines. In the case of a higher generation of poly(amidoamine) dendrons, such a dextran conjugate was found to have much lower cytotoxicity and better gene delivery capability when compared to branched polyethylenimine (bPEI, 25kDa), a commonly used gene vector.

Dual stimuli polysaccharide nanovesicles for conjugated and physically loaded doxorubicin delivery in breast cancer cells.

The present work reports the development of pH and enzyme dual responsive polysaccharide vesicular nano-scaffolds for the administration of doxorubicin via physical loading and polymer-drug conjugation to breast cancer cells. Dextran was suitably modified with a renewable resource 3-pentadecyl phenol unit through imine and aliphatic ester chemical linkages that acted as pH and esterase enzyme stimuli, respectively. These dual responsive polysaccharide derivatives self-organized into 200 ± 10 nm diameter nano-vesicles in water. The water soluble anticancer drug doxorubicin (DOX·HCl) was encapsulated in the hydrophilic pocket to produce core-loaded polysaccharide vesicles whereas chemical conjugation produced DOX anchored at the hydrophobic layer of the dextran nano-vesicles. In vitro studies revealed that about 70-80% of the drug was retained under circulatory conditions at pH = 7.4 and 37 °C. At a low pH of 6.0 to 5.0 and in the presence of esterase; both imine and ester linkages were cleaved instantaneously to release 100% of the loaded drugs. Cytotoxicity assays on Wild Type Mouse Embryonic Fibroblasts (WTMEFs) confirmed the non-toxicity of the newly developed dextran derivatives at up to 500 μg mL(-1) in PBS. MTT assays on fibroblast cells revealed that DOX·HCl loaded nano-vesicles exhibited better killing abilities than DOX conjugated polymer nano-vesicles. Both DOX loaded and DOX conjugated nano-vesicles were found to show significant killing in breast cancer cells (MCF 7). Confocal microscopy images confirmed the uptake of DOX loaded (or conjugated) nano-vesicles by cells compared to free DOX. Thus, the newly developed pH and enzyme dual responsive polysaccharide vesicular assemblies are potential drug vectors for the administration of DOX in both loaded and chemically conjugated forms for the efficient killing of breast cancer cells.

Correction to Radiolabeled Mannosylated Dextran Derivatives Bearing a NIR-Fluorophore for Sentinel Lymph Node Imaging

Correction to Radiolabeled Mannosylated Dextran Derivatives Bearing a NIR-Fluorophore for Sentinel Lymph Node Imaging

Phosphorylated polysaccharide derivatives as efficient separation agents for zinc and ferric oxides particles from water

The separation efficiency of some anionic polysaccharides, namely phosphorylated derivatives of dextran and cellulose, in model zinc oxide (ZnO) and ferric oxide (hematite, Fe2O3) particle suspensions has been evaluated by turbidity and zeta potential measurements. The investigation was performed with respect to the polyanion dose, the polysaccharide nature and molar mass. The turbidimetric results showed higher separation efficacy in case of polyanions based on dextran than that based on cellulose. Possible reasons for this finding have been discussed. The zeta potential values at optimum polymer dose (either close to zero in the presence of the dextran derivative or negative in the presence of the cellulose one) suggest the contribution from charge neutralization/charge patch mechanisms in the destabilization of both oxide particle suspensions. The viscosity behavior of the polymers was also examined and the experimental data were plotted in terms of the Wolf method.

Kinetics of formation of polysaccharide-covered micrometric oil droplets under mechanical agitation

• Amphiphilic dextrans were used for preparing emulsions under mechanical agitation. • Kinetics of droplet formation was investigated by in situ rheo-optical measurements. • Droplet rupture was controlled by the ratio of shear forces to Laplace pressure. • Oil volume fraction had no effect on the kinetics of droplet formation. Hexadecane-in-water emulsions were prepared by mechanical agitation in vane geometry using amphiphilic derivatives of dextran (nonionic bacterial polysaccharide) as stabilizers. Thanks to a laboratory-made experimental device coupling rheometry and back-scattered light analysis, we investigated the kinetics of droplet formation and the simultaneous variation of global shear stress. Oil volume fraction was varied between 10 and 50% and rotation speed between 40 and 100 rad s −1 . The viscosity of aqueous phase was controlled by addition of sodium alginate and thus exhibited non-Newtonian rheological behavior. After forming a coarse emulsion, droplet rupture led to emulsions with volume-average droplet radius between 5 and 10 μm provided that rotation speed and aqueous phase viscosity were high enough. Monitoring was consistent with droplet rupture occurring under shear forces such that capillary number remained approximately constant and close to its critical value. Although rotational speed and sodium alginate concentration had strong effect on emulsification kinetics, oil volume fraction had no significant effect.

Targeting the C-type lectins-mediated host-pathogen interactions with dextran.

Dextran, the α-1,6-linked glucose polymer widely used in biology and medicine, promises new applications. Linear dextran applied as a blood plasma substitute demonstrates a high rate of biocompatibility. Dextran is present in foods, drugs, and vaccines and in most cases is applied as a biologically inert substance. In this review we analyze dextran's cellular uptake principles, receptor specificity and, therefore, its ability to interfere with pathogen-lectin interactions: a promising basis for new antimicrobial strategies. Dextran-binding receptors in humans include the DC-SIGN (dendritic cell-specific intercellular adhesion molecule 3-grabbing nonintegrin) family receptors: DC-SIGN (CD209) and L-SIGN (the liver and lymphatic endothelium homologue of DC-SIGN), the mannose receptor (CD206), and langerin. These receptors take part in the uptake of pathogens by dendritic cells and macrophages and may also participate in the modulation of immune responses, mostly shown to be beneficial for pathogens per se rather than host(s). It is logical to predict that owing to receptor-specific interactions, dextran or its derivatives can interfere with these immune responses and improve infection outcome. Recent data support this hypothesis. We consider dextran a promising molecule for the development of lectin-glycan interaction-blocking molecules (such as DC-SIGN inhibitors) that could be applied in the treatment of diseases including tuberculosis, influenza, hepatitis B and C, human immunodeficiency virus infection and AIDS, etc. Dextran derivatives indeed change the pathology of infections dependent on DC-SIGN and mannose receptors. Complete knowledge of specific dextran-lectin interactions may also be important for development of future dextran applications in biological research and medicine.

Flocculation performance of different cationic amphiphilic dextran derivatives in zirconium silicate suspension

The flocculation efficiency of some cationic amphiphilic dextran derivatives has been investigated in zirconium silicate suspensions with respect to settling time, polycation dose, its chemical structure and molar mass. The presence of pendent cationic groups and the length of the alkyl substituent at the nitrogen of pendent groups were crucial for the efficacy of flocculation process, in terms of the optimum polymer dose and the flocculation window width. Within the range of 10–400kDa, no significant effect was observed on the separation efficacy. The negative values of the zeta potential at the optimum polymer dose point to contributions from charge patch mechanism and hydrophobic associations for the flocculation process. This kind of polymers has been also proved to be efficient flocculants for kaolin and 25/75 zirconium silicate/ kaolin mixture suspensions. Furthermore, the presence of kaolin in the above mentioned mixture led to acceleration of the particles flocculation.

PH- and reduction-responsive polymeric lipid vesicles for enhanced tumor cellular internalization and triggered drug release.

Enhanced tumor cellular internalization and triggered drug release are two main concerns in the development of nanoparticles for antitumor drug delivery. In this article, a new kind of smart pH- and reduction-dual-responsive drug- loaded PEG coated polymeric lipid vesicle (PPLV) that can achieve both enhanced tumor cellular internalization and triggered drug release has been designed and prepared. The PPLVs were formed from amphiphilic dextran derivatives. The antitumor drug, doxorubicin (DOX), was loaded in the cores of the PPLVs. The newly developed PPLVs had a nanosized structure (∼40 nm) with PEG coating, so they were neutral and had high colloidal stability in the blood circulation. The in vitro physicochemical characterizations showed that the PPLVs lose their PEG coating and expose the positive surface charge under acidic environments. The in vitro cellular uptake study indicated that the acidic-treated PPLVs can efficiently enter tumor cells. It has been demonstrated by in vitro DOX release profiles that the PPLVs can achieve a triggered drug release in response to the reduction environment. The MTT assay demonstrated that DOX-loaded PPLVs treated with pH 5.0 solution had higher antitumor activity than DOX-loaded PPLVs treated with pH 7.4 solution. These results suggested that the PPLVs were promising nanoparticles for smart antitumor drug delivery applications.

Bioreducible carboxymethyl dextran nanoparticles for tumor-targeted drug delivery.

Bioreducible carboxymethyl dextran (CMD) derivatives are synthesized by the chemical modification of CMD with lithocholic acid (LCA) through a disulfide linkage. The hydrophobic nature of LCA allows the conjugates (CMD-SS-LCAs) to form self-assembled nanoparticles in aqueous conditions. Depending on the degree of LCA substitution, the particle diameters range from 163 to 242 nm. Doxorubicin (DOX), chosen as a model anticancer drug, is effectively encapsulated into the nanoparticles with high loading efficiency (>70%). In vitro optical imaging tests reveal that the fluorescence signal of DOX quenched in the bioreducible nanoparticles is highly recovered in the presence of glutathione (GSH), a tripeptide capable of reducing disulfide bonds in the intracellular compartments. Bioreducible nanoparticles rapidly release DOX when they are incubated with 10 mm GSH, whereas the drug release is greatly retarded in physiological buffer (pH 7.4). DOX-loaded bioreducible nanoparticles exhibit higher toxicity to SCC7 cancer cells than DOX-loaded nanoparticles without the disulfide bond. Confocal laser scanning microscopy observation demonstrate that bioreducible nanoparticles can effectively deliver DOX into the nuclei of SCC7 cells. In vivo biodistribution study indicates that Cy5.5-labeled CMD-SS-LCAs selectively accumulate at tumor sites after systemic administration into tumor-bearing mice. Notably, DOX-loaded bioreducible nanoparticles exhibit higher antitumor efficacy than reduction-insensitive control nanoparticles. Overall, it is evident that bioreducible CMD-SS-LCA nanoparticles are useful as a drug carrier for cancer therapy.

Micelle-like association of polysaccharides with hydrophobic end groups

New dextran derivatives with hydrophobic end groups were synthesized by reductive amination of dextran chain ends, followed by chemical modification of the dextran main chain by attachment of cationic groups and/or by crosslinking. Properties of the aggregates formed by hydrophobic association of the end groups were studied by fluorescence, dynamic light scattering, atomic force microscopy and transmission electron microscopy and depended on the length of the dextran chain (6, 10, 25kDa) and the hydrophobicity of the end group (alkyl, dialkyl, bile acid). All neutral derivatives were able to form micelle-like aggregates above a critical aggregation concentration (0.008–0.159g/dL). Polarity of the micelle hydrophobic core was close to or lower than that of neutral low molecular surfactants (polarity parameter I1/I3≈0.8–1.13), aggregation number was 20–30 and hydrodynamic radius 20–30nm. Attachment of cationic groups to the dextran main chain increased critical aggregation concentration and core polarity, but cationic polymeric surfactants with good association ability could be obtained by an appropriate choice of the content and hydrophobicity of the cationic groups. Cross-linking of the micelle shell with divinylsulfone increased micelle stability to dilution.

Dextran derivative-based pH-sensitive liposomes for cancer immunotherapy

pH-Sensitive dextran derivatives having 3-methylglutarylated residues (MGlu-Dex) were prepared by reacting dextran with 3-methyl-glutaric anhydride. MGlu-Dex changed the protonation state and their characteristics from hydrophilic to hydrophobic in neutral and acidic pH regions. Surface modification of egg yolk phosphatidylcholine liposomes with MGlu-Dex produced highly pH-sensitive liposomes that were stable at neutral pH but which were destabilized strongly in the weakly acidic pH region. MGlu-Dex-modified liposomes were taken up efficiently by dendritic cells and delivered entrapped ovalbumin (OVA) molecules into the cytosol. When MGlu-Dex-modified liposomes loaded with OVA were administered subcutaneously to mice, the antigen-specific humoral and cellular immunity was induced more effectively than the unmodified liposomes loaded with OVA. Furthermore, administration of MGlu-Dex-modified liposomes loaded with OVA to mice bearing E.G7-OVA tumor significantly suppressed tumor growth and extended the mice survival. Results suggest that MGlu-Dex-modified liposomes are promising for the production of safe and potent antigen delivery systems that contribute to the establishment of efficient cancer immunotherapy.

Smart pH- and reduction-dual-responsive folate-PEG-coated polymeric lipid vesicles for tumor-triggered targeted drug delivery.

To improve their therapeutic index, designed nanocarriers should preferentially accumulate in tumor tissues and then rapidly enter tumor cells to release the encapsulated drugs in a triggered manner. In this article, a new kind of a smart pH- and reduction-dual-responsive drug delivery system based on folate-PEG-coated polymeric lipid vesicles (FPPLVs) formed from amphiphilic dextran derivatives was designed and prepared successfully. PEG chains with pH-sensitive hydrazone bonds, stearyl alcohol (SA) chains with reduction-sensitive disulfide bonds and folate were connected to a dextran main chain. The newly developed FPPLVs had a nano-sized structure (∼50 nm) with a PEG coating. The in vitro DOX release profiles showed that the FPPLVs achieved a triggered drug release in response to acidic pH and reducing environments due to the cleavage of hydrazone bonds and disulfide bonds. It has also been demonstrated by an in vitro cellular uptake study that the FPPLVs lose their PEG coating as well as expose the folate in acidic conditions, which allows them to efficiently enter tumor cells through ligand-receptor interactions. In vitro cytotoxicity measurements also confirmed that FPPLVs exhibited pronounced antitumor activity against HeLa cells. These results suggest that FPPLVs are promising carriers for smart antitumor drug delivery applications.

Impact of in situ granulation and temperature quenching on crystal habit and micromeritic properties of ibuprofen-cationic dextran conjugate crystanules

Ibuprofen was recrystallized in the presence of aqueous solution of cationic dextran derivative, Diethylaminoethyl Dextran (Ddex) using the melt-in situ granulation-crystallization technique in order to produce a stable amorphous ibuprofen-Ddex conjugates with improved morphological, micromeritic and thermo-analytical characteristics without the use of organic solvent. Ddex was used in this study because of its ability to form conjugates with various drug molecules and enhance their physicochemical characteristics and therapeutic activities. Cationic dextrans are also biocompatible and biodegradable. Mechanism of conjugation as well as the impact of conjugation on the ibuprofen crystal habit was investigated. Gaussian type normal particle size distribution was obtained and the size of the crystals in the crystanule conjugates decreased steadily, with increasing concentration of Ddex, to a minimum of 480 nm (440-folds reduction, p<0.05, n=20) at Ddex molar concentration of 0.01 mM. FT-IR spectra showed electrostatic interaction and hydrogen bonding between ibuprofen and Ddex which was confirmed with the (1)H NMR and (13)C NMR spectra. DSC curves exhibited single peaks from the binary ibuprofen-Ddex conjugate crystanules suggesting compatibility and formation of an eutectic product. The conjugate crystanules showed broad and diffuse endothermic peaks with a glass transition temperature (T(g)) of 58.3 and 59.14°C at Ddex molar concentrations of 1.56 × 10(-4) and 3.125 × 10(-4)mM respectively confirming the existence of ibuprofen-Ddex crystanule conjugates in amorphous state. Higher concentrations of Ddex decreased T(g) steadily. TGA curves showed first order degradation at low molar concentrations of Ddex up to 3.125 × 10(-4)mM which coincides with the critical granular concentration of the crystanules while higher concentrations exhibited second order degradation profile. This study provides the basis for the development of stable amorphous drug-polymer conjugates with potential practical application in controlled and extended drug release formulations.

Biocompatible polysaccharide-based cryogels

This study focuses on the development of novel biocompatible macroporous cryogels by electron-beam assisted free-radical crosslinking reaction of polymerizable dextran and hyaluronan derivatives. As a main advantage this straightforward approach provides highly pure materials of high porosity without using additional crosslinkers or initiators. The cryogels were characterized with regard to their morphology and their basic properties including thermal and mechanical characteristics, and swellability. It was found that the applied irradiation dose and the chemical composition strongly influence the material properties of the resulting cryogels. Preliminary cytotoxicity tests illustrate the excellent in vitro-cytocompatibility of the fabricated cryogels making them especially attractive as matrices in tissue regeneration procedures.

Photocrosslinkable bioadhesive based on dextran and PEG derivatives

In this study, a hybrid photopolymeric bioadhesive system consisting of urethane methacrylated dextran (Dex-U) and 3, 4-Dihydroxyphenyl-l-alanine (DOPA) modified three-arm poly (ethylene glycol) s (PEG-DOPAs) was designed. The process of photopolymerization was detected by Photo-Differential Scanning Calorimetry (Photo-DSC). The adhesion strength was evaluated by the lap shear tests. The surface tension of the solutions, burst pressures and the cytotoxicity assays were also investigated. The addition of PEG-DOPAs significantly improved the properties of Dex-U especially in the field of adhesion strength and burst pressure. And materials variation could be tailored to match the demands for tissue repair. Compared to the Dex-U systems, the maximum adhesion strength of the copolymeric system increased from 2.7±0.1MPa to 4.0±0.6MPa. Owing to its strong adhesion strength, rapid curing rate and good biocompatibility, such photocrosslinkable hydrogelsa could be applied to the areas of bioadhesive.

Separation of TiO2 particles from water and water/methanol mixtures by cationic dextran derivatives

Cationic polysaccharides with N-alkyl-N,N-dimethyl-N-(2-hydroxypropyl)ammonium chloride pendent groups attached to a dextran backbone were used to flocculate titanium dioxide (TiO2) particles suspended in water as well in water/methanol mixtures (90:10 and 50:50 v/v %). The investigations were performed with respect to the polycation dose, the suspension medium composition and the length of alkyl substituent at the quaternary nitrogen (alkyl=ethyl, octyl, dodecyl). The supernatant residual turbidity values were much lower for TiO2 particles dispersed in solvent mixtures than in water. This finding was explained by the solvent mixtures effect on the charges of both the particle surface and polyelectrolyte chains. The alkyl substituent length did not affect in a dramatic way the separation of TiO2 particles. The supernatant zeta potential dependence on the polycation dose when water/methanol mixtures were used as dispersion medium indicated a charge patch mechanism for the flocculation of TiO2 particles, which was supported by particle aggregates size measurements.

Hydrophobic modification of dextran with 1,2-epoxyalkanes in aqueous micellar medium: Competition between interfacial and bulk reactions and consequences on polymer properties

Hydrophobic modification of dextran (degree of polymerization around 125) by reaction with 1,2-epoxydodecane was investigated in micellar aqueous medium in which epoxide was dispersed under magnetic stirring in the presence of a cationic surfactant. A base catalyst, sodium hydroxide, was added in water. Dextran derivatives with degrees of substitution up to 10% were prepared. Apart from dextran modification, epoxide molecules underwent interfacial oligomerization which led to by-products that had to be extracted by dialysis followed by Soxhlet extraction. Two main reaction parameters influenced the amount of oligomeric by-products, i.e. temperature and surfactant structure. Adsorption of these compounds at air/water interface was studied by surface tension and dilational rheology measurements and compared to that observed with amphiphilic dextrans prepared in homogeneous conditions.

Intra-abdominal adhesions in ultrasound. Parts I and II.

The peritoneal adhesions and their clinical consequences, such as bowel obstruction, infertility in women and increased risk of extrauterine pregnancy, still remain an unsolved problem in contemporary intra-abdominal surgery. The frequency of occurrence of adhesions following laparotomies is estimated to reach 67–97%(1, 2). The most common causes encompass a physical trauma (including surgical or thermal one, e.g. electrocoagulation), infection, ischemia and the presence of a foreign body (stitches, talc, gauze, intestinal contents). Peritoneal adhesions are the most common cause of intestinal obstruction. The presence of adhesions increases the risk of each surgery and extends its duration, in particular, the stage of opening the abdominal cavity. Adhesions increase the probability of damaging the intestine while opening the abdominal cavity by 20%(3–5). Adhesive obstruction of the bowels may occur in 5% of patients who underwent a surgery(6). The adhesions which cause intestinal obstruction most frequently form after surgeries involving the large intestine as well as urologic and gynecological procedures. After laparoscopic procedures, adhesions appear more rarely and their preparation is easier(7–9). The methods that help decrease the risk of intra-abdominal adhesions include: non-traumatic surgeries, minimally invasive surgery, usage of gloves without talc, removal of drains and remains of dead tissues from the peritoneal cavity, restraining from suturing the defects in the peritoneum as well as administering pharmacological agents such as non-steroidal anti-inflammatory drugs, anticoagulants, vitamin E, statin, medicines with topical anesthetizing effect, dextran derivatives (Adept – 4% icodextrin solution) and Seprafilm (a biological barrier that prevents adhesions; composed of two polysaccharides: hyaluronic acid, carboxymethylcellulose). Seprafilm is very hydrophilic and does not require suturing. The differentiation between simple mechanical obstruction and strangulation obstruction constitutes a difficult clinical problem. Strangulation and necrosis of the bowel are the cause of a high perioperative mortality rate which in these cases equals 8–28%(7, 10). When diagnosing adhesive obstruction, the most valuable methods comprise: repeated physical examinations, plain abdominal x-ray, computed tomography and bowel passage with water soluble contrast agent (gastrografin). Gastrografin is a hyperosmolar agent (1900 mOsm/L) which increases the amount of water in the bowel and stimulates its peristalsis. The bowel passage of gastrografin is then both a diagnostic and therapeutic method(11–13). To prevent adhesive obstruction, it is proposed to perform internal intestinal splinting for the period of 7–14 days(14). The relevant literature relatively seldom mentions the value of ultrasound examination (US) in assessing the number and localization of intra-abdominal adhesions. It is a shame since there are more and more specialists in clinical sonography who use more and more advanced US equipment. Therefore, abdominal examinations performed to assess adhesive disease of the peritoneal cavity should be encouraged. In 1994, Duffy and diZerega proposed the application of abdominal US examination prior to laparoscopic management of adhesive obstruction in order to localize the first trocar(15). I know Professor Andrzej Smereczynski personally. I have always admired him for his stubbornness in research, consistent actions, enthusiasm and motivation. The Professor has vast experience in clinical sonography. He constantly verifies his studies and findings in the operation theatre. He checks himself and his actions. This is a rare and exceptional feature among diagnosticians. I have read both papers with huge interest(16, 17). Despite my limited, not to say, scarce knowledge and experience in the field of sonography, I recognize the diagnostic significance and value of the examination that is performed well and properly. I can think of numerous clinical situations in which sonographic assessment of adhesions would be of enormous significance, namely: The selection of the best site to perform a surgical cut or insert the first trocar in the patients with the history of surgeries (laparotomies). Such a procedure would surely reduce the risk of damaging the bowel when opening the abdomen. The help to differentiate between simple intestinal obstruction and strangulation of the mesentery that may cause bowel necrosis and requires urgent surgical intervention. Diagnosis of so-called aggressive fibromatosis of the peritoneum in the course of multiple, familial polyposis of the large intestine. The more common application of US examination in intra-abdominal adhesions would reduce the number of computed tomography examinations which are expensive and burden the patient with a high dosage of radiation. I can imagine that learning sonographic diagnosis of intraabdominal adhesions requires a long training. Nonetheless, with such a distinguished center, where Professor Smereczynski works, we might hope that more and more radiologists and other specialists, necessarily including surgeons, will take an interest in this diagnostic method. With all my heart, I wish you all the best and many successes in developing intra-abdominal adhesion sonography.

Design and Development of 99mTc-‘4+1’-Labeled Dextran-Mannose Derivatives as Potential Radiopharmaceuticals for Sentinel Lymph Node Detection

The synthesis, labeling, and biological evaluation of a dextran derivative (DCM-30-iso) as potential radiopharmaceutical for sentinel lymph node imaging is presented. DCM-30-iso bears mannose as active moiety and isocyanide as ligand for technetium through the formation of a '4+1' Tc(III) mixed-ligand complex. A second derivative without mannose (DC-25-iso) was also prepared and evaluated as control. DCM-30-iso and DC-25-iso were synthesized from dextran in four steps (>50% overall yield) and characterized by spectroscopic methods. Labeling with (99m)Tc was achieved by reaction with 2,2',2''-nitrilotris(ethanethiol) and (99m)Tc-EDTA. Radiochemical purity was above 90% and was stable for at least 4 hours postlabeling at 37°C. The identity of the (99m)Tc complex was established through comparative HPLC studies using the well-characterized analogous Re-DC-25-iso complex. Biodistribution and imaging experiments of (99m)Tc-DCM-30-iso showed high uptake in the popliteal lymph node, which could be blocked with preinjection of mannose, and very low uptake in other nodes and organs. The nonmannosylated (99m)Tc-DC-25-iso derivative showed negligible uptake in all lymph nodes. The novel dextran-mannose derivative DCM-30-iso can be successfully labeled with (99m)Tc to give a well-characterized '4+1' complex with favorable biological properties as sentinel lymph node imaging agent.