A biocompatible method of decorporation: Bisphosphonate-modified magnetite nanoparticles to remove uranyl ions from blood

Article abstract of DOI:10.1021/ja0651355

We report on the use of bisphosphonate to functionalize Fe₃O₄ magnetic nanoparticles via dopamine (DA) linkage. Using tetraethyl-3-aminopropane-1,1-bisphosphonate (BP) as the functional molecule, we created a system with an Fe_3<

Full text of DOI:10.1021/ja0651355

Published on Web 09/21/2006
A Biocompatible Method of Decorporation: Bisphosphonate-Modified
Magnetite Nanoparticles to Remove Uranyl Ions from Blood
Ling Wang,† Zhimou Yang,† Jinhao Gao,† Keming Xu,† Hongwei Gu,† Bei Zhang,‡
Xixiang Zhang,‡ and Bing Xu*,†
Departments of Chemistry and Physics, The Hong Kong UniVersity of Science & Technology, Clear Water Bay,
Hong Kong, China
Received July 18, 2006; E-mail: chbingxu@ust.hk
Scheme 1. (A) Synthesis of the Surface-Modified Magnetite
Nanoparticles and (B) the Removal of UO2 from Blood
This communication describes the use of bisphosphonate-
modified magnetite nanoparticles to remove radioactive metal toxins
(e.g., UO22+) with high efficiency from water or blood. Although
metal ions (except cadmium, mercury, and lead) are essential for
living cells, their accumulation beyond optimal concentrations in
tissues or organs usually results in various diseases and disorders
because they chelate to essential functional groups, displace other
metal ions, or destroy the active conformation of biological
molecules.1 In addition to their metal toxicity, radioactive heavy
metals, such as isotopes of uranium, cesium, and americium, could
inflict radiological risks to human. Thus, it is important to develop
a safe and effective procedure to remove radionuclides from the
body (decorporation) after radiological contamination that would
arise from either accidents or possible malicious attacks. The
existing methods (e.g., ion exchange, chemical precipitation,
membrane filtration, and liquid extraction) for the removal or
recovery of heavy metal ions, including transuranics from aqueous
phases, however, remain unsuitable for the purpose of decorpora-
tion. Despite its own limitation for in vivo use, the magnetically
assisted chemical separation (MACS) process,2 which utilizes
magnetic microparticles coated with a selective extractant for the
efficient recovery of radionuclides, provides a useful guide to
develop a method of decorporation based on biocompatible
magnetic nanoparticles.
The recent successful synthesis of monodispersed magnetic
nanoparticles,3,4 particularly iron oxide nanoparticles,3,5 provides a
basis on which to explore further applications of magnetic nano-
particles in biomedicine due to the inherent biocompatibility of iron
oxide.6 Several groups have demonstrated exciting and promising
biological applications of magnetic nanoparticles7,8 and confirmed
superior performances of magnetic nanoparticles to magnetic
microparticles in applications, such as separation of proteins and
detection of pathogens.8,9 These works, together with our result that
bisphosphonate-containing hydrogel effectively lowers the toxicity
of UO22+-contaminated wounds on mice,10 led us to develop a
2+
Scheme 1A shows the synthetic route for making the conjugate
of 4 and Fe3O4 nanoparticles. Compound 1 reacted with 2 to give
3 with 67% yield after purification. Then 3 was further hydroge-
nated to remove the benzyl group and treated with bromotrimeth-
ylsilane (TMSBr) to eliminate diethyl ester to yield 4. Then Fe3O4
nanoparticles (in hexane phase) reacted with 4 (in aqueous solution,
pH ∼ 5) under vigorous stirring overnight or under sonication for
30 min to form Fe-O bonds that linked 4 to the Fe3O4. After the
reaction, the resulting product, 5, became water soluble and was
easily separated from the organic phase for further characterization
and testing.
As shown in the TEM images (Figure 1), 5 remains as crystalline
nanocrystals (similar to the as-prepared Fe3O4 nanoparticles) and
exhibits slight aggregation as the result of surface modification by
the attachment of 4. Time-of-flight second ion mass spectra (ToF-
SIMS) confirm the DA-BP moieties on the surface of Fe3O4,11
which displays not only the fragments of iron-coordinated 4 (FeO2‚
4+, m/e ) 540) but also the fragment of the iron-coordinated
dihydroxylbenzyl moiety (FeO2C7H6+, m/e ) 178), further proving
that 4 forms covalent bonds with Fe atoms on the surface of the
Fe3O4 nanoparticles. The weight analysis11 estimates an average
of 54 molecules of 4 on one Fe3O4 nanoparticle.
conjugate of dopamine and bisphosphonate (4, DA-BP, which
2+
binds tightly to iron oxide and coordinates to a uranyl ion (UO2
)
with high affinity) to modify magnetite Fe3O4 nanoparticles for
decorporating UO22+. Using the simple procedure illustrated in
Scheme 1, we found that the designed magnetic nanoparticles, 5,
2+
can remove 99 and 69% of UO2 from water and blood,
respectively. In addition to it being the first example of the removal
of radionuclides from a biological fluid by nanoparticles, this result
suggests that these functionalized, biocompatible magnetic nano-
particles can act as useful and effective agents of decorporation
for selective and rapid removal of radioactive metal toxins in vivo.
Scheme 1B illustrates the procedure of using 5 to remove uranyl
ions in water or blood, which consists of three major steps: mixing,
binding, and removing/decorporating. Before using 5 to decorporate
2+
UO2 from blood, we first tested the binding ability of 5 with
uranyl ion in water ([UO22+] ) 10-4 M). After being mixed with
uranyl ion contaminated samples (i.e., UO22+ in water), 5 selectively
† Department of Chemistry.
‡ Department of Physics.
2+
coordinated with UO2 to form 6 in water. A small bar magnet
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10.1021/ja0651355 CCC: $33.50 © 2006 American Chemical Society

C O M M U N I C A T I O N S
to provide a very efficient protocol to remove uranyl ions from
blood. Although the phosphates and proteins in the biological
2+
systems (e.g., blood) also bind to UO2 competitively, the high
affinity between the bisphosphonate and uranyl ions (due to
chelating effect12) allows successful decorporation. This work
provides a potential platform to develop biocompatible methodology
(e.g., using magnetite nanoparticles and appropriate ligands) for
decorporating radioactive hazards from the human body. In addition,
the principle demonstrated in this work should also allow the
detection, recovery, and decorporation of other heavy metal toxins
from biological systems via tailoring the ligands or utilizing other
novel nanomaterials.13
Acknowledgment. This work was partially supported by RGC
(Hong Kong) and HIA (HKUST).
Figure 1. Transmission electron micrograph (TEM) images of (A) as-
prepared Fe3O4 nanoparticles, (B) 5, and (C) 6; (D) electron diffraction
patterns (EDP) of 6.
Supporting Information Available: Detail of the syntheses, the
calibration, the magnetic measurement, and the calculation. This
material is available free of charge via the Internet at http://pub.acs.org.
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In summary, we successfully synthesized a bisphosphonate
derivative, DA-BP, which modifies the magnetite nanoparticles
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