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In: Vitamin B: New Research ISBN: 978-1-60021-782-1
Editor: C. M. Elliot, pp. 153-174 © 2008 Nova Science Publishers, Inc.
Guo-Ping Yan∗ , Xiao-Yan Wang and Li-Li Mei
School of Material Science and Engineering, Wuhan Instituite of Technology,
Vitamin B6 includes a series of compounds containing the pyridoxal structure, such
as pyridoxol, pyridoxamine, pyridoxaldehyde and their derivatives. The pyridoxal
structure，the catalytically active form of vitamin B6, possesses specific hepatocyte
uptake by the pyridoxine transporter at the sinusoidal pole because the pyridoxine
transporters that exist in hepatocytes can selectively recognize and bind to the pyridoxal
structure, and transport it into the cells via a member transport system. Thus pyridoxine
can be adopted as a liver-targeting group and be incorporated into the low molecular
weight compounds and macromolecules for the use as magnetic resonance imaging
(MRI) contrast agents and anticancer conjugates. The research progress of liver-targeting
drug delivery system is discussed briefly. Previous researches have demonstrated that the
incorporation of pyridoxine into these molecules can increase their uptake by the liver,
and that these molecules containing pyridoxine groups exhibit liver-targeting properties.
Keywords: vitamin B6, liver-targeting, drug delivery, magnetic resonance imaging (MRI)
Engineering, Wuhan Instituite of Technology, Wuhan 430073, P. R. China. E-mail address:
154 Guo-Ping Yan, Xiao-Yan Wang, Li-Li Mei
Vitamin B6, also known as pyridoxine, is water-soluble and is required for both mental
and physical health. Vitamin B6 includes a series of compounds containing the pyridoxal
structure, such as pyridoxol, pyridoxamine, pyridoxaldehyde and their derivatives.
The liver has both a unique blood supply (arterial, venous and portal-venous) and
specific cells that are capable of transporting/accumulating bulk amounts of both endo- and
exobiotic substances [1-3]. The pyridoxine transporters that exist in hepatocytes at the
sinusoidal pole can selectively recognize and bind to the pyridoxal structure, and transport it
into the cells via a member transport system. The pyridoxal structure, the catalytically active
form of vitamin B6, possesses specific hepatocyte uptake by the pyridoxine transporter. Thus
pyridoxine can be adopted as a liver-targeting group and be incorporated into the low
molecular weight compounds and macromolecules for the use as magnetic resonance imaging
that the incorporation of pyridoxine into these molecules can increase their uptake by the
liver, and that these molecules containing pyridoxine groups exhibited liver-targeting
LIVER-TARGETING MRI CONTRAST AGENTS
Over the last three decades, nuclear magnetic resonance (NMR) has been perhaps the
most powerful method for the non-invasive investigation of human anatomy, physiology and
pathophysiology. Developed in 1973 by Paul Lauterbur [20], magnetic resonance imaging
(MRI) has become widely used as the diagnosis and treatment of human diseases in hospitals
around the world, since it received FDA approval for clinical use in 1985. It is a non-invasive
clinical imaging modality, which relies on the detection of NMR signals emitted by hydrogen
protons in the body placed in a magnetic field. In 2003, Paul C. Lauterbur and Sir Peter
Mansfield won the Nobel Prize in physiology and medicine for their discoveries concerning
MRI because it can be widely used for the diagnosis and treatment of human diseases, such
as necrotic tissue, infarcted artery and malignant disease [21,22].
One important way to improve the contrast in MRI is to introduce contrast agents. MRI
contrast agents are a unique class of pharmaceuticals that enhance the image contrast between
normal and diseased tissue and indicate the status of organ function or blood flow after
administration by increasing the relaxation rates of water protons in tissue in which the agent
accumulates [8,9]. Paramagnetic substances, superparamagnetic and ferromagnetic materials
have been used as MRI contrast agents because paramagnetic substances have a net positive
magnetic susceptibility, having the ability to become magnetized in an external magnetic
field. Some MRI exams include the use of contrast agents. The categorizations of currently
available contrast agents have been described according to their effect on the image,
magnetic behavior and biodistribution in the body, respectively [23].
Subsequently proper ligands have been designed and complexed with paramagnetic
metal ions to form strong water-soluble chelates as the first generation MRI contrast agents,
Vitamin B6 as Liver-targeting Group in Drug Delivery 155
for example, gadolinium diethylenetriaminepentaacetic acid (Gd-DTPA, Magnevist®,
Schering AG, Germany) (Figure 1) [24]. Some clinically used MRI contrast agents are small
ionic molecules such as Gd-DTPA and gadolinium 1,4,7,10-tetraazacyclododecane-N, N’,
N’’, N’’’-tetraacetic acids (Gd-DTOA, Dotarem®, Guerbet SA, France) (Figure 2) [25,26] that
can diffuse freely through the extracellular space and excreted rapidly by the kidney. Then
their biodistribution are nonspecific although Gd-DTPA works well in organs such as the
brain and spinal cord, where the normal brain parenchyma has a barrier to permeability of the
contrast agent and pathologic conditions such as cancer do not. The injection of large
quantities of the ionic complex will raise ion concentration in vivo and cause localized
disturbances in osmolality, which, in turn leads to cellular and circulatory damage. Most
commonly, Gd-DTPA and Gd-DOTA have been modified to form neutral molecules, which
thus exhibited much lower osmolality and higher LD50s in animals [27-31].
Figure 1. Structural formula of Gd-DTPA.
Figure 2. Structural formula of Gd-DOTA.
Nowadays ideal MRI contrast agent is focused on the neutral tissue- or organ-targeting
materials with high relaxivity and specificity, low toxicity and side effect, suitable long
intravascular duration and excretion times, high contrast enhancement with low doses in vivo,
and minimal cost of procedure [8,9,27,28]. In general, tissue or organ-specific contrast agents
consist of two components: a magnetic label capable of altering the signal intensity on MR
images and a target-group molecule having a characteristic affinity for a specific type of cell
or receptor. Some suitable residues have been incorporated into either the acetic side-arms or
(Gd-BOPTA, Gadobenate, Multihance®, Bracco Imaging, Italy) and gadolinium
ethoxybenzyltriamine pentaacetic acid (Gd-EOB-DTPA, Gadoxetate; Eovist®, Schering AG,
156 Guo-Ping Yan, Xiao-Yan Wang, Li-Li Mei
Germany) have been developed, which can accumulate in the liver site, increasing contrast
concentration, and producing greater signal in the MR images [32-42].
Low Molecular Weight Liver-Targeting MRI Contrast Agents
Manganese dipyridoxyl-diphosphate (mangafodipir, Mn-DPDP, Teslascan®, Nycomed
Amersham Imaging, Princeton, NJ) is a contrast agent developed for imaging of the
hepatobiliary system (Figure 3). Unlike Gd-DTPA, Mn-DPDP is an intracellular agent that is
taken up specifically by hepatocytes and pancreas, and excreted in the bile since the ligand
consists of two linked pyridoxal-5’-phosphate groups, the catalytically active form of vitamin
B6. Thus, it was thought that Mn-DPDP was a potential candidate for specific hepatocyte
uptake by the pyridoxine transporter at the sinusoidal pole. However, it was reported that the
complex dissociated both in the blood and in the liver and the uptake mechanism did not
depend on the pyridoxine transporter [4-6].
Figure 3. Structural formula of Mn-DPDP.
Other liver-targeting DTPA derivates containing vitamin B6 groups have also been
prepared according to the liver-targeting property of Mn-DPDP. A series of DTPA
derivatives ligands containing pyridoxol groups have been synthesized by the reaction of
DTPA dianhydride with the pyridoxol derivatives with the different space groups. Compared
with Gd-DTPA, their non-ionic bulky Gd3+ complexes have higher relaxivities, lower
stability constants and the liver-targeting property. Moreover, Gd-DTPA and Gd-DOTA are
modified to form neutral molecules, which thus exhibit much lower osmolality, while these
neutral agents have been shown to have higher LD50s in animals [7,43,44].
Macromolecular Liver-Targeting MRI Contrast Agents
Macromolecular MRI contrast agent can be prepared by the incorporation of a low
molecular weight paramagnetic metal cheated complex such as Gd-DTDA or Gd-DOTA, to
the backbone or the pendant chains of macromolecule. It usually exhibits more effective
relaxation than that of the low molecular weight metal complex alone and improves the
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