PHYSICAL PROPERTIES OF MAGNETIC LIQUIDS
OF BIOMEDICAL APPLICATION
Biophys J. 2001 May; 80 (5): 2483 – 2486.
Magnetic resonance of a dextran-coated magnetic fluid
intravenously administered in mice.
Lacava
LM, Lacava ZG, Da Silva MF, Silva O, Chaves SB, Azevedo RB,
Pelegrini F, Gansau C, Buske N,
Sabolovic D, Morais PC.
Instituto de Biologia, Universidade de Brasilia, 70910-900 Brasilia (DF),
Brazil.
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 approximately 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 1014 cm – 3) the
particle-particle interaction responds for the nonlinear behavior, while at the
lower concentration regime (below 1014 cm – 3) the
particle-particle interaction is ruled out and the system recovers the
linearity due to the demagnetizing field effect alone.
Biomol Eng. 2001 Jan; 17 (2) : 41 – 49.
Raman spectroscopy in magnetic fluids.
Morais PC, da Silva SW, Godoy Soler
MA, Buske N.
Instituto de Fisica, Nucleo de
Fisica Aplicada, Universidade de Brasilia,
C.P. 04455, CEP 70919-970 -DF,
Brasilia, Brazil. E – mail: pcmor@fis.unb.br
In this work Raman spectroscopy was
used to investigate uncoated magnetic fluids (UMF's) and coated magnetic fluids
(CMF's). The coating agents were N-oleoylsarcosine, dodecanoic acid, and
ethoxylated polyalcohol. The Raman probe is the hydroxyl (OH) group chemisorbed
at the magnetic nanoparticle surface and the measurements were performed in the
typical OH bending and OH stretching regions. The room temperature Raman data
obtained from the UMF's and CMF's are compared to each other and with the data
obtained from liquid water. Suppression of Raman modes from the MF's are
discussed in terms of symmetry reduction and in terms of the interaction
between the chemisorbed OH-group and the surrounding medium. The relative
grafting coefficient associated to different coatings are estimated from the
Raman data. The highest grafting coefficient is achieved with a single coating
of dodecanoic acid in the hydrocarbon-based MF. The surface-grafting
coefficient of the N-oleoylsarcosine-coated MF reduces when the polar liquid
carrier replaces the non-polar liquid carrier. In comparison to liquid water,
it was found that the hydrogen bonding between the chemisorbed OH-group and the
solvent was enhanced in UMF's and reduced in CMF's.
J. Neurooncol. 1999
Jan;41(2):99-105.Related Articles, Links
Distribution of small magnetic particles in brain
tumor-bearing rats.
Pulfer SK, Ciccotto SL, Gallo JM.
Fox Chase Cancer Center,
Philadelphia, PA 19111, USA.
Small (10-20 nm) uncharged magnetic
particles (SMP) were evaluated for their ability to target intracerebral rat
glioma-2 (RG-2) tumors in vivo. In an effort to determine the influence of
particle size on blood-tumor barrier uptake, the tissue distribution of the
injected particles was evaluated following intraarterial injection (4 mg/kg
SMP) in male Fisher 344 rats bearing RG-2 tumors with a magnetic field of 0 Gs
or 6000 Gs applied to the brain for 30 min. Animals were sacrificed at 30 min
or 6 h post-injection after which tissues were collected and analyzed for
magnetite content. In the presence of a magnetic field, SMP localized in brain
tumor tissue at levels of 41-48% dose/g tissue after 30 min and 6 h
respectively, significantly greater than non-target tissues. In the absence of
a magnetic field only 31-23% dose/g tissue was achieved for the same time
points. Tumor targeting of the SMP for brain tumor was demonstrated by large
target selectivity indexes (ts) of 2-21
for normal brain tissue, indicating a 2-21 fold increase in concentrations
compared to normal brain. In comparison with larger (1 micron) diameter
magnetic particles, SMP concentrated in brain tumor at significantly higher
levels than magnetic neutral dextran (p = 0.0003) and cationic aminodextran (p
= 0.0496) microspheres previously studied. TEM analysis of brain tissue
revealed SMP in the interstitial space of tumors, but only in the vasculature
of normal brain tissue. These results suggest that changes in the vascular
endothelium of tumor tissue promote the selective uptake of SMP and provide a
basis for the design of new small drug-loaded particles as targeted drug delivery
systems for brain tumors.
Biophys J. 2000 Feb; 78
(2):1018-23.
Electron paramagnetic resonance study of the migratory
and Pachycondyla marginata abdomens.
Wajnberg E, Acosta-Avalos D, El-Jaick
LJ, Abracado L,
Coelho JL, Bakuzis AF, Morais PC, Esquivel DM.
Centro Brasileiro de Pesquisas Fisicas,
Rio de Janeiro (RJ), 20290-180,
Brazil. E – mail: elianew@cbpf.br
Electron paramagnetic resonance was
used to investigate the magnetic material present in abdomens of Pachycondyla
marginata ants. A g congruent with 4.3 resonance of high-spin ferric ions and a
very narrow g congruent with 2 line are observed. Two principal resonance broad
lines, one with g > 4.5 (LF) and the other in the region of g congruent with
2 (HF), were associated with the biomineralization process. The resonance field
shift between these two lines, HF and LF, associated with magnetic
nanoparticles indicates the presence of cluster structures containing on
average three single units of magnetite-based nanoparticles. Analysis of the
temperature dependence of the HF resonance linewidths supports the model
picture of isolated magnetite nanostructures of approximately 13 nm in diameter
with a magnetic energy of 544 K. These particles are shown to present a
superparamagnetic behavior at room temperature. The use of these
superparamagnetic particle properties for the magnetoreception process of the
ants is suggested.
J. Magn Reson. 1998
Sep;134(1):180-3.
Investigation of the anisotropy in frozen nickel
ferrite ionic magnetic fluid
using magnetic resonance
Saenger
JF, Skeff Neto K, Morais PC, Sousa MH, Tourinho FA.
Instituto de Fisica, Nucleo de Fisica Aplicada, Universidade de Brasilia.
Magnetic resonance is used to obtain
the temperature dependence of the magnetic anisotropy of noninteracting NiFe2O4
nanoparticles from 100 to 250 K. The 10.3 nm particles are dispersed as a
stable ionic magnetic fluid which is frozen under the action of an external
field to perform angular variation measurements. The thermal fluctuation of the
easy axis and magnetic moment about the direction of the external field is
included in order to obtain the anisotropy from the angular dependence of the
resonance field. Copyright 1998 Academic Press.
J. Neurooncol. 1999
Jan;41(2):99-105.Related Articles, Links
Distribution of small magnetic particles in brain
tumor-bearing rats.
Pulfer SK, Ciccotto SL, Gallo JM.
Fox Chase Cancer Center,
Philadelphia, PA 19111, USA.
Small (10-20 nm) uncharged magnetic
particles (SMP) were evaluated for their ability to target intracerebral rat
glioma-2 (RG-2) tumors in vivo. In an effort to determine the influence of
particle size on blood-tumor barrier uptake, the tissue distribution of the
injected particles was evaluated following intraarterial injection (4 mg/kg
SMP) in male Fisher 344 rats bearing RG-2 tumors with a magnetic field of 0 Gs
or 6000 Gs applied to the brain for 30 min. Animals were sacrificed at 30 min
or 6 h post-injection after which tissues were collected and analyzed for magnetite
content. In the presence of a magnetic field, SMP localized in brain tumor
tissue at levels of 41-48% dose/g tissue after 30 min and 6 h respectively,
significantly greater than non-target tissues. In the absence of a magnetic
field only 31-23% dose/g tissue was achieved for the same time points. Tumor
targeting of the SMP for brain tumor was demonstrated by large target
selectivity indexes (ts) of 2-21 for
normal brain tissue, indicating a 2-21 fold increase in concentrations compared
to normal brain. In comparison with larger (1 micron) diameter magnetic
particles, SMP concentrated in brain tumor at significantly higher levels than
magnetic neutral dextran (p = 0.0003) and cationic aminodextran (p = 0.0496)
microspheres previously studied. TEM analysis of brain tissue revealed SMP in
the interstitial space of tumors, but
only in the vasculature of normal brain tissue. These results suggest that
changes in the vascular endothelium of tumor tissue promote the selective
uptake of SMP and provide a basis for the design of new small drug-loaded
particles as targeted drug delivery systems for brain tumors.
Lab Invest. 1994
Dec;71(6):895-903.Related Articles, Links
Biodegradation of magnetite dextran nanoparticles in
the rat.
A histologic and biophysical study.
Okon E., Pouliquen D., Okon P.,
Kovaleva Z. V.,
Stepanova T.P., Lavit S. G.,
Kudryavtsev B. N., Jallet P.
Laboratoire de Biophysique, Faculte
de Medecine, Angers, France.
BACKGROUND: Superparamagnetic iron
oxide particles represent a new class of contrast agents that increase the
detectability of hepatic and splenic tumors by magnetic resonance imaging
(MRI). Magnetite dextran nanoparticles, a preparation with a small mean
particle diameter in solution and null zeta potential present high safety
margin and efficacy. The purpose of this investigation was to define the main
steps of the metabolism of the iron oxide crystals.
EXPERIMENTAL DESIGN: Rats were intravenously administered a single
small dose of 59Fe-labeled MD3 (3 mg Fe/kg), and the biodistribution of 59Fe
was investigated in the different organs from 2 hours to 25 days postinjection.
Magnetic susceptibility studies were conducted in parallel to light microscopy
and immunohistochemistry from day 1 to day 14 after administration. RESULTS:
Most of the dose accumulated in the carcass (45%), liver (7%), and spleen (7%)
in the first 2 hours. In the spleen, a continuously iron uptake was observed up
to 48 hours (44%), then decreased to 25 days (22%). The splenic magnetic
susceptibility dropped sharply during the first days and then more slightly
until day 14. In the liver and blood, the 59Fe-level decreased at 24 hours and
then increased until day 25 (11% and 27%, respectively). Histochemistry
features essentially confirmed the radiotracer data and showed that iron oxide
cores were accumulated into the Kupffer cells and the macrophages of the
splenic marginal zone. With time, the number of the granules was decreased
whereas the fine iron granules appeared in the cytoplasm. Immunopositive
staining for ferritin was markedly increased in the liver hepatocytes to 3 days
after injection, and in the splenic marginal zone macrophages to 14 days after
injection.
CONCLUSIONS: The data point to the
early biodegradation of the iron oxide crystals. MD3 thus appear as an
interesting biodegradable new contrast agent first devoted to magnetic
resonance imaging of liver and spleen diseases that could be further extended
to heart, kidneys, and other organs.
A novel formulation for superparamagnetic iron oxide (SPIO) particles enhancing MR lymphography: comparison of physicochemical properties and the in vivo behaviour.
Lind
K., Kresse M., Debus N. P., Muller R. H.
Department
of Pharmaceutical Technology, The Free University of Berlin, Germany.
The major aim of this study was to prove or disprove the theories concerning the correlation between physicochemical properties of superparamagnetic iron oxide (SPIO) particles and their accumulation in the lymph nodes. New SPIO particles were produced using starch as stabilising polymer shell. The synthesis was done in a two-step procedure using conventional wet-chemical precipitation technique and subsequent coating of the iron oxide cores. The particles were physicochemically characterised and their lymphotrophy studied in rats using well described lymphotropic dextran-coated SPIO particles as reference. Despite the short blood half-lives of approximately 13 min and the relatively large sizes (approximately 60-90 nm), the starch SPIO particles proved at least as efficient in lymph node accumulation as the small 25 nm dextran SPIO particles having a half-life of 90 min. The currently accepted theories concerning the connection between particle properties and their uptake into lymph nodes are not generally valid, or have at least to be limited for dextran-coated SPIO particles. Lymph node targeting could be achieved despite the present theories consider small size (<30 nm) and long circulation times in the blood as prerequisites. Histological examination showed, that SPIO particles could only be found in lymph node areas where macrophages could be marked which enclosed the particles. Localisation in marginal areas of the lymph nodes indicates endothelial transcytosis as the major accumulation pathway.
Cellular uptake and trafficking of a
prototypical magnetic iron oxide label in vitro.
Department
of Radiology, Massachusetts General Hospital, Boston 02114, USA.
RATIONALE AND OBJECTIVES.Target-specific magnetic resonance (MR) contrast agents are being developed to improve the accuracy of MR imaging. The purpose of this study was to determine the mechanism of cell uptake, and modes of intracellular trafficking of a prototypical iron oxide label (RMA) used in the synthesis of some target-specific MR contrast agents.
METHODS. The prototypical agent (RMA) consisted of a dextran-coated
monocrystalline iron oxide that was modified with rhodamine (fluorescent label)
and opsonized with albumin. Fluorescence microscopy was performed in a
phagocytic C6 cell line and in murine bone marrow macrophages.
Immunohistochemistry against lysosomal markers was used to confirm the
intracellular location of the label. RESULTS. RMA was identified inside cells
after incubation at concentrations as low as 4.0 x 10 – 10 M Fe,
typically observed with receptor mediated endocytosis and several orders of
magnitude lower than that expected with fluid phase pinocytosis. Cell uptake
could be inhibited by excess protein but not by dextran. RMA localized
initially to tubular and to round intracellular organelles and co-localized
with an antibody against a murine lysosomal glycoprotein antibodies (LGP-A) in
macrophages. Three days after incubation, RMA was concentrated in perinuclear
vesicles, which most likely represent terminal lysosomes where final breakdown
appears to occur.
CONCLUSIONS. The mechanism of cellular uptake of a prototypical
opsonized iron oxide label is consistent with receptor-mediated endocytosis.
Immediately after cell contact, RMA localizes to the lysosomal compartment and
at long time points reside in vesicles that by morphology and distribution
appear to be terminal lysosomes. Iron oxides therefore demonstrate metabolism
via the lysosomal pathway.
MR lymphography using iron oxide
nanoparticles in rats: pharmacokinetics
in the lymphatic system after intravenous
injection.
Rety
F., Clement O., Siauve N., Cuenod C. A., Carnot F., Sich M., Buisine A., Frija
G.
Laboratoire
de Recherche en Imagerie,
INSERM
U 494, School of Medicine, Necker Enfants-Malades, 75015 Paris, France.
The
objective of the study was to quantify the kinetics of the superparamagnetic
nanoparticle ferumoxtran (AMI 227, Sinerem(R), Combidex(R)) in the efferent
lymph of the subdiaphragmatic lymph nodes and in various node groups of the rat
to elucidate the uptake mechanism. The thoracic lymph duct was catheterized in
24 rats after an IV injection of 40 micromol Fe/kg ferumoxtran. Three rats were
studied at several time points between 1.5 and 24 hours. At each time point,
0.3 ml of lymph were collected over 45 minutes. Lymph nodes were differentiated
into five groups. The iron concentration in the samples and in plasma was
measured by relaxometry at 0.47 T and atomic absorption spectrometry. Cytology
was performed on the lymph. High concentrations of nanoparticles were found in
the thoracic lymph soon after injection (90 minutes). No particle was found in
the lymph cells, indicating that ferumoxtran was extracellular in the lymph
fluid. The maximum concentration was reached later in all node groups, at 12 hours,
and then plateaued. The transcapillary pathway and subsequent lymph drainage of
the particles seem to play a major role in the delivery to the lymph nodes.
Development of superparamagnetic
nanoparticles for MRI:
effect of particle size, charge and surface nature on biodistribution.
Chouly
C, Pouliquen D, Lucet I, Jeune JJ, Jallet P.
Laboratoire
de Biophysique, Faculte de Medecine, Angers, France.
Twelve
superparamagnetic Magnetite-Dextran (MD) nanoparticles potentially useful as
contrast agents for Magnetic Resonance Imaging (MRI), with different sizes,
charges and surface natures, were produced and internally labelled with (59)Fe
in order to investigate the effect of their physicochemical properties on their
biodistribution in mice. In a first step, neutral MD particles of a size
33-90.6 nm were studied. Next, the influence of charge was investigated with
negative and positive particles (MDL, MDD, MDDEAE). The former (-25, -30 mV)
were small, around 30 nm in size whereas the latter (+20 mV) were larger (104
nm). The effect of surface nature was evaluated using MD particles coated with
polyoxyethylene-polyoxypropylene copolymers (Synperonic: these MDP particles
were neutral and larger in size (65.9-76.4 nm). Experiments showed that 20 min
post-injection (2 mg Fe/kg), liver uptake was enhanced when the mean diameter
increased: 22% for the smallest and 42% for the largest. It was up to 3 X lower
for electrically neutral particles than for charged particles. Coated particles
presented higher vascular persistence. The diagnostic potential for liver,
lymph node or vascular imaging were discussed.
Erratum in: Invest Radiol 2000 Dec;35(12):706.
Characterization of ultrasmall magnetite
[correction of paramagnetic
magnetite] particles as superparamagnetic
contrast agents in MRI.
Grimm
J., Karger N., Lusse S., Winoto-Morbach S., Krisch B., Muller-Hulsbeck S.,
Heller M.
Klinik
fur Diagnostische Radiologie,
Christian-Albrects
Universitat zur Kiel, Germany. E – mail: grimm@rad.uni-kiel.de
RATIONALE AND OBJECTIVES: Very small dextran-coated magnetite particles were developed. These particles can be used either as immunospecific contrast agents for MRI by coupling to antibodies or as an interstitial contrast agent. METHODS: The particles were synthesized from iron chloride/dextran solutions. Size was evaluated by electron microscopy and photon correlation spectroscopy. The iron concentration was determined by x-ray spectroscopy. T1 and T2 values as well as relaxivities RI and R2 were evaluated with a clinical MR scanner at 1.5 T. Biocompatibility assays were performed with the cell line U937 in methylcellulose cultures.
RESULTS: Superparamagnetic, dextran-coated magnetite particles with a
hydrodynamic diameter of 10 nm were developed. The iron core size was 7 nm;
R1,7 L/mmol x s; and R2, 19 L/mmol x s. These particles are smaller than those
currently available commercially and therefore show a smaller R1 to R2 ratio.
Biocompatibility tests have shown no toxic side effects so far.
CONCLUSIONS: Ultrasmall magnetite particles with a dextran coating were developed; the physical properties of these particles evaluated in vitro are described in this study.
Preparation of magnetoliposomes and its in vivo behavior on ICR mice.
Wu
K. S., Tang J. T. , Liu X., Zhang Q.
Department
of Pharmaceutics, School of Pharmaceutical Sciences, Peking
University
Health Science Center, Beijing 100083, China.
AIM: To prepare magnetoliposome (MLP) containing dextran-encapsulated
magnetite (Fe3O4), and to examine its physicochemical
properties and its in vivo behavior on ICR mice.
METHODS: Reverse phase evaporation method was used to formulate MLP and
the Fe 2 + concentration was measured by o-phenanthroline method.
Then the basic properties of MLP and in vivo distribution were studied with the
aid of 3H isotope as biomarker.
RESULTS: The mean diameter of MLP was 602.5 nm and the final
concentration of encapsulated Fe3O4 was 88.1 mg x L (-1).
Under natural conditions most of the MLP was taken up by spleen after the
administration via tail vain, but its uptake was reduced under the magnetic
field. There was a great difference in vivo distribution between the left and
right lobes of the liver and the left and right kidneys in magnetic fields.
CONCLUSION: Reverse phase evaporation method was utilized to prepare magnetoliposomes. The formulation was stable and encapsulated high amount of magnetite. The delivery system could be oriented to certain tissues under magnetic field and satisfying magnetic responsiveness was observed.
Detection and
quantitation in rat tissues of the superparamagnetic magnetic resonance
contrast agent dextran magnetite as demonstrated by electron spin resonance
spectroscopy.
Iannone A., Federico M., Tomasi A., Magin R. L., Casasco A., Calligaro
A., Vannini V.
Instituto di Patologia Generale, Modena, Italy.
RATIONALE AND OBJECTIVES. The compound studies in this article is a
superparamagnetic macromolecular complex of magnetite cores coated with
hydrophilic dextran, which is under active investigation as a contrast agent
for magnetic resonance imaging (MRI) in liver and spleen. The biodistribution
of paramagnetic compounds is problematic and is usually studied by
histochemical reactions or by radiolabeling the compound under study. The
purpose of this article is to show how electron spin resonance (ESR)
spectroscopy detects dextran magnetite (DM) particles in tissues.
METHODS. DM injected intravenously in the experimental animal was
detected in some reticulo-endothelial organs by ESR. The spectroscopic study
was validated using electron microscopy and electron-probe microanalysis.
RESULTS. DM exhibits an ESR spectrum; ESR delineated the distribution of DM distribution in liver, spleen, bone marrow, and blood as a function of time. The blood clearance was biphasic, dependent on the size of particles.
CONCLUSIONS. ESR spectroscopy is a highly sensitive and reproducible
method of studying DM distribution.
Pharm Res. 1995 Aug;12(8):1176-83.Related Articles,
Links
Preparation and characterization of dextran magnetite-incorporated thermosensitive liposomes: an on-line flow system for quantifying magnetic responsiveness.
Viroonchatapan E., Ueno M., Sato H., Adachi I., Nagae H., Tazawa K.,
Horikoshi I.
Department of Hospital Pharmacy,
Toyama Medical and Pharmaceutical University, Japan.
PURPOSE. Dextran magnetite (DM)-incorporated thermosensitive liposomes,
namely thermosensitive magnetoliposomes (TMs), were prepared and characterized
in order to investigate their possibility for magnetic drug targeting.
METHODS. TMs containing calcein were prepared at various DM
concentrations by reverse-phase evaporation of dipalmitoylphosphatidylcholine
(DPPC). They were evaluated for their physicochemical properties including
size, DM capture, magnetite distribution within liposomes, and
temperature-dependent calcein release. Moreover, a novel on-line flow apparatus
with a sample injector, a coil of tubing placed in an electromagnet, and a
fluorescence detector was developed for quantifying the magnetic responsiveness
of TMs. This device allowed us a real-time measurement of percentage holding of
TMs by magnetic field.
RESULTS. Due to water-soluble property of DM, higher contents of
magnetite up to 490 mg per mmol DPPC were successfully incorporated into the
liposomes with DM than with conventional magnetite (Fe3O4).
Thermosensitivity and lipid integrity of TMs were not influenced by inclusion
of DM. Using the on-line flow system, percentage holding of TMs by magnetic
field was shown to vary with several factors; it increases as the magnetic
field strength increases, the fluid flow rate decreases, the magnetite content
increases, and the liposome concentration increases. Typically, at 490 mg
incorporated magnetite per mmol DPPC, 0.5 ml/min-fluid flow rate, and high
magnetic field strength (> or = 10 kiloGauss), approximately 100% of TMs
were found to be held.
CONCLUSIONS. The TMs were suggested to be useful in future cancer treatment by magnetic targeting combined with drug release in response to hyperthermia.