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Dextran

Dextran is a branched polysaccharide made of many glucose molecules joined into chains of varying lengths. The straight chain consists of α1->6 glycosidic linkages between glucose molecules, while branches begin from α1->3 linkages (and in some cases, α1->2 and α1->4 linkages as well). (For information on the numbering of carbon atoms in glucose, see the glucose article.) Dextran is synthesized from sucrose by Leuconostoc mesenteroides streptococcus, and are also produced by bacteria and yeast. Dental plaque is rich in dextrans. more...

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Uses

Microsurgery uses

These agents are used commonly by microsurgeons to decrease vascular thrombosis. The antithrombotic effect of dextran is mediated through its binding of erythrocytes, platelets, and vascular endothelium, increasing their electronegativity and thus reducing erythrocyte aggregation and platelet adhesiveness. Dextrans also reduce factor VIII-Ag Von Willebrand factor, thereby decreasing platelet function. Clots formed after administration of dextrans are more easily lysed due to an altered thrombus structure (more evenly distributed platelets with coarser fibrin). By inhibiting α-2 antiplasmin, dextran serves as a plasminogen activator and therefore possesses thrombolytic features. Outside from these features, larger dextrans, which do not pass out of the vessels, are potent osmotic agents, and thus have been used urgently to treat hypovolemia. The hemodilution caused by volume expansion with dextran use improves blood flow, thus further improving patency of microanastomoses and reducing thrombosis. Still, no difference has been detected in antithrombotic effectiveness in comparison of intraaterial and intravenous administration of dextran. Dextrans are available in multiple molecular weights ranging from 10,000 Da to 150,000 Da. The larger dextrans are excreted poorly from the kidney and therefore remain in the blood for as long as weeks until they are metabolized. Subsequently, they have prolonged antithrombotic and colloidal effects. In this family, dextran-40 (MW: 40,000 Da), has been the most popular member for anticoagulation therapy. Close to 70% of dextran-40 is excreted in urine within the first 24 hours after intravenous infusion while the remaining 30% will be retained for several more days. Although there are relatively few side-effects associated with dextran use, these side-effects can be very serious. These include anaphylaxis, volume overload, pulmonary edema, cerebral edema, or platelet dysfunction. An uncommon but significant complication of dextran osmotic effect is acute renal failure. The pathogenesis of this renal failure is the subject of many debates with direct toxic effect on tubules and glomerulus versus intraluminal hyperviscosity being some of the proposed mechanisms. Patients with history of diabetes mellitus, renal insufficiency, or vascular disorders are most at risk. Brooks and others recommend the avoidance of dextran therapy in patients with chronic renal insufficiency and CrCl<40 cc per minute.

Other medical uses

It is used in some eye drops as a lubricant, and in certain intravenous fluids. Dextran in intravenous solution provides an osmotically neutral fluid that once in the body is digested by cells into glucose and free water. It is occasionally used to replace lost blood in emergency situations, when replacement blood is not available, but must be used with caution as it does not provide necessary electrolytes and can cause hyponatremia or other electrolyte disturbances. It also increases blood sugar levels.

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Magnetic resonance of a dextran-coated magnetic fluid intravenously administered in mice
From Biophysical Journal, 5/1/01 by Lacava, L M

ABSTRACT Magnetic resonance was used to investigate the kinetic disposition of magnetite nanoparticles (9.4 nm core diameter) from the blood circulation after intravenous injection of magnetite-based dextran-coated magnetic fluid in female Swiss mice. In the first 60 min the time-decay of the nanoparticle concentration in the blood circulation follows the one-exponential (one-compartment) model with a half-life of (6.9 +/- 0.7) min. The X-band spectra show a broad single line at g == 2, typical of nanomagnetic particles suspended in a nonmagnetic matrix. The resonance field shifts toward higher values as the particle concentration reduces, following two distinct regimes. At the higher concentration regime (above 10^sup 14^ cm^sup -3^) the particle-particle interaction responds for the nonlinear behavior, while at the lower concentration regime (below 10^sup 14^ cm^sup -3^) the particle-particle interaction is ruled out and the system recovers the linearity due to the demagnetizing field effect alone.

INTRODUCTION

Magnetic resonance has been widely used in the investigation of nanomagnetic particles immersed in nonmagnetic matrices (Dormann et al., 1977; Komatsu et al., 1979; Morais et al., 1987). In recent years, the technique has been successfully used in the study of ionic (Tronconi et al., 1993) and surfacted (Sastry et al., 1995) magnetic fluids (MFs). Effects of particle concentration (Tronconi et al., 1993), ionic strength (Morais et al., 1995), and temperature (Morais et al., 1996) have been investigated using the nanomagnet as the resonant probe. Important information concerning the surface charge-discharge process (Morais et al., 1995), particle-particle interaction (Bakuzis et al., 1996), magnetic anisotropy (Saenger et al., 1998), and Brownian relaxation (Morais et al., 1997) in ionic MFs has been obtained through magnetic resonance investigations. In particular, magnetic resonance has been proved to be an excellent technique to investigate the relative contribution of both the anisotropy field and the exchange field of field-oriented nanomagnetic particles suspended in frozen nonmagnetic matrices (Bakuzis et al., 1999).

Despite the complexity of living beings, magnetic resonance has been recently used to investigate biomineralized nanomagnetite particles in the migratory ant Pachycondyla marginata abdomens (Wajnberg et al., 2000). The capability of the technique to sense as few as 100 pmol of nanomagnetic materials and to probe the size and the shape of nanomagnetic-based structures makes magnetic resonance a powerful tool in the investigation of nanomagnets introduced in living beings (Da Silva et al., 1997). In the present study a biocompatible MF sample based on dextran-coated nanomagnetite is given as an intravenous bolus dose to mice, while magnetic resonance is used to investigate the disposition of the nanomagnetic-based material out of blood circulation. The methodology for the kinetic data analysis, based on the magnetic resonance signal, is proposed in this study as well. Finally, it is shown that the time evolution (nanoparticle concentration decay) of the magnetic resonance field is in very good agreement with the kinetic analysis.

MATERIALS AND METHODS

The dextran-coated magnetic fluid (DC-MF) sample used to carry out the experiments was obtained by chemical co-precipitation of Fe(II) and Fe(III) ions in alkaline medium to produce 9.4 nm average-diameter magnetite particles, following surface coating with a single layer of dextran. After surface coating the nanomagnetite particles with dextran, the DC-MF sample was diluted in water and stabilized at neutral pH, in a concentration of =4.9 X 10^sup 16^ particle/cm^sup 3^. The interest in this sample is mainly due to the extremely reduced toxicity it presents when in vivo tests are performed (Lacava et al., 1999). In order to carry out the resonance experiments 100 (mu)l of the DC-MF sample was given as an intravenous bolus dose to female Swiss mice (average of 30 g in weight). The DC-MF sample was administered to 36 animals and =10 (mu)l of blood was collected from a set of three animals every 5 min after administration of the DC-MF sample, up to 60 min. The resonance data (area under the absorption curve and resonance field) were averaged out at each time point using three animals. Three extra animals were not treated with the DC-MF sample and were used as control; 10-(mu)l blood samples from the control were used in the experiment, before (pure) and after mixing with the DC-MF sample. The DC-MF samples were administered through the animal's tail vein. Likewise, all the blood samples (total blood) were collected by tailbleeding the animals. The blood samples collected from the animals were transferred to heparinized sample holders. Different amounts of the DC-MF sample were mixed with the blood samples in order to obtain the calibration curve, i.e., the area under the resonance absorption curve versus the nanoparticle concentration, in the range of 5 X 10^sup 12^ to 5 x 10^sup 15^ particle/cm^sup 3^. Room-temperature magnetic resonance spectra were obtained from the blood samples using Bruker ESP-300 equipment tuned to =9.4105 GHz. Indeed, three different samples were investigated in this study: the blood samples collected from the animals (MFB) some time after (5-60 min) intravenous administration of the magnetite-based DC-MF sample, the DC-MF samples mixed with blood from the control (MFM), and the pure blood samples collected from the control (PBC).

RESULTS AND DISCUSSION

Fig. 1 shows typical room-temperature resonance spectra (first derivative of the absorption curves) of the MFB sampies as a function of time (5, 30, and 60 min). The MFM samples presented similar magnetic resonance spectra (not shown). The PBC samples showed no typical resonance signal, even when the equipment sensitivity was set two orders of magnitude higher than the highest sensitivity (60 min spectrum) used to obtain the spectra shown in Fig. 1. Note in Fig. 1 that the signal-to-noise ratio decreases as the resonance field shifts to higher values (see vertical bars), i.e., as the blood collecting time increases from 5 to 60 min. After 60 min the concentration of the nanomagnetite particles in the blood circulation has been reduced by about three orders of magnitude.

Open circles in Fig. 2 represent the time-decay (disposition) of the nanomagnetite particle concentration in the MFB samples. Determination of the nanoparticle concentration in the MFB samples is obtained from the area under the magnetic resonance absorption curve. Calibration involving the area under the magnetic resonance absorption curve versus nanomagnetite concentration was previously performed using the MFM samples, as shown in the inset of Fig. 2. Dilution of the original DC-MF sample (4.9 X 10^sup 16^ particle/cm^sup 3^) in water was also realized (resonance data not shown) in order to obtain DC-MF samples in the same particle concentration range as the calibration curve (Fig. 2, inset). When compared to the MFM samples the resonance linewidth of the water-diluted samples present deviation of

C(t) = C^sub 0^ exp(-kt) (1)

CONCLUSIONS

In summary, magnetic resonance has been proposed as a spectroscopic technique in the study of the kinetic disposition of nanomagnetite-based dextran-coated magnetic fluid intravenously administered in mice. The resonance data show a nanoparticle concentration decay of about three orders of magnitude one hour after intravenous injection of a bolus dose. The data show a first-order kinetic welldescribed by the one-compartment model, with a half-life of (6.9 +/- 0.7) min. The resonance field dependence of the nanoparticle concentration shows a strong nonlinear behavior as the particle concentration goes above 10^sup 14^ cm^sup -3^. Such nonlinear behavior was explained in terms of the dipolar interaction between nanomagnetite particles. Despite the complexity of the particle-particle interaction and in contrast to its influence upon the magnetic resonance field, the intensity of the resonance signal (area under the absorption curve) was successfully used to probe the timedecay of the nanoparticle concentration in blood circulation, in a wide range of particle concentration.

This work was partially supported by the Brazilian agencies FAP-DF and FINATEC, and by the International Brazilian/French (CNPq/INSERM) cooperation agreement.

Received for publication 16 October 2000 and in final form 24 January 2001.

REFERENCES

Bakuzis, A. F., P. C. Morals, and F. Pelegrini. 1999. Surface and exchange anisotropy fields in MnFe^sub 2^O^sub 4^ nanoparticles: size and temperature effects. J. Appl. Phys. 85:7480-7482.

Bakuzis, A. F., P. C. Morals, and F. A. Tourinho. 1996. Investigation of the magnetic anisotropy in manganese ferrite nanoparticles using magnetic resonance. J. Magn. Reson. A. 122:100-103.

Da Silva, M. F., F. Gendron, J. C. Bacri, J. Roger, J. N. Pons, M. Rabineau, D. Sabolovic, and A. Halbretch. 1997. Quantification of maghemite nanoparticles in biological media by ferromagnetic resonance and its alteration by conjugation with biological substances. In Scientific and

Clinical Applications of Magnetic Carriers. U. Hafeli, W. Schutt, J. Teller, and M. Zborowski, editors. Plenum Press, New York 171-176.

Dormann, J. L., P. Gibart, G. Suran, and C. Sella. 1977. Magnetic properties of granular Fe-SiO^sub 2^. Physics B & C. 86:1431-1433.

Kneller, E. 1969. Fine particle theory. In Magnetism and Metallurgy, Vol. 1. A. E. Berkowitz and E. Kneller, editors. Academic Press, New York. 365-471.

Komatsu, T., N. Soga, and M. Kunugi. 1979. ESR study of NiFe204 precipitation process from silicate-glasses. J. Appl. Phys. 50: 6469-6474.

Lacava, L. M., L. P. Silva, S. B. Chaves, G. S. Correia, Z. G. M. Lacava, and R. B. Azevedo. 1999. Morphological effects of a dextran-magneticfluid in the liver. Acta Microscopica Suppl. C. 8:745-746.

Morals, P. C., M. C. F. L. Lara, and K. Skeff Neto. 1987. Electron spin resonance in superparamagnetic particles dispersed in a non-magnetic matrix. Phil. Mag. Lett. 55:181-183.

Morals, P. C., M. C. F. L. Lara, A. L. Tronconi, F. A. Tourinho, A. R. Pereira, and F. Pelegrini. 1996. Magnetic particle-particle interaction in frozen magnetic fluids. J. Appl. Phys. 79:7931-7935.

Morais, P. C., F. A. Tourinho, G. R. R. Goncalves, and A. L. Tronconi. 1995. Ionic strength effect on magnetic fluids: a resonance study. J. Magn. Magn. Mater. 149:19-21.

Morais, P. C., A. L. Tronconi, F. A. Tourinho, and F. Pelegrini. 1997. Investigation of the Brownian relaxation and hydrodynamic radius in magnetic nanoparticles. Solid State Commun. 101:693-697.

Nagata, K., and A. Ishihara. 1992. ESR of ultrafine magnetic particles. J. Magn. Magn. Mater. 104:1571-1573.

Nony, P., M. Cucherat, and J.-P. Boissel. 1998. Revisiting the effect compartment through timing errors in drug administration. Trends Pharmacol. Sci. 19:49-54.

Saenger, J. F., K. Skeff Neto, P. C. Morais, M. H. Sousa, and F. A. Tourinho. 1998. Investigation of the anisotropy in frozen nickel ferrite ionic magnetic fluid using magnetic resonance. J. Magn. Reson. 134: 180-183,

Sastry, M. D., Y. Babu, P. S. Goyal, R. V. Mehta, R. V. Upadhyay, and D. Srinivas. 1995. Electron magnetic resonance of ferrofluids: evidence for anisotropic resonance at 77 K in samples cooled in a magnetic field. J. Magn. Magn. Mater. 149:64-66.

Tronconi, A. L., P. C. Morais, F. Pelegrini, and F. A. Tourinho. 1993. Electron paramagnetic resonance study of ionic water-based manganese ferrite ferrofluids. J. Magn. Magn. Mater. 122:90-92.

Wajnberg, E., D. Acosta-Avalos, L. J. El-Jaick, L. Abracado, J. L. A. Coelho, A. F. Bakuzis, P. C. Morais, and D. M. S. Esquivel. 2000. Electron paramagnetic resonance study of the migratory ant Pachycondyla marginata abdomens. Biophys. J. 78:1018-1023.

L. M. Lacava,* Z. G. M. Lacava,* M. F. Da Silva,^ O. Silva,^^ S. B. Chaves,* R. B. Azevedo,* F. Pelegrini,^^ C. Gansau,(sec) N. Buske,(sec) D. Sabolovic,(para) and P. C. Morais^

Address reprint requests to Dr. P. C. Morais, Instituto de Fisica, Nucleo de Fisica Aplicada, Universidade de Brasilia, 70919-970 Brasilia (DF), Brazil. Tel.: 55-61-273-6655; Fax: 55-61-272-3152; E-mail: pcmor@fis.unb.br.

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