TRIPASS XR تري باس

 

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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.

Chapter IX

VITAMIN B6 AS LIVER-TARGETING

GROUP IN DRUG DELIVERY

Guo-Ping Yan∗ , Xiao-Yan Wang and Li-Li Mei

School of Material Science and Engineering, Wuhan Instituite of Technology,

Wuhan 430073, P. R. China.

ABSTRACT

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)

∗

 Correspondence concerning this article should be addressed to: Guo-Ping Yan, School of Material Science and

Engineering, Wuhan Instituite of Technology, Wuhan 430073, P. R. China. E-mail address:

guopyan@hotmail.com.

154 Guo-Ping Yan, Xiao-Yan Wang, Li-Li Mei

INTRODUCTION

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

(MRI) contrast agents and anticancer conjugates [4-7]. The research progress of livertargeting 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 exhibited liver-targeting

properties [8-19].

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].

HOOCCH2

-

OOCCH2

CH2COOH

CH2COO- CH2COOGd3+

N N N

Figure 1. Structural formula of Gd-DTPA.

-

OOCCH2

-

OOCCH2 CH2COOH

CH2COOGd3+

N

N N

N

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

the diethylenetriamine backbone of Gd-DTPA and Gd-DOTA to obtain the tissue or organspecific contrast agents. For example, liver-targeting agents such as gadobenate dimeglumine

(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].

N

H3 C

-

OPOCH2

N

H+

CH2OPO -

N

H+

CH3

Mn

O

O O

O

O

O

C

C

N

OH OH

O O

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

Vitamin B6 as Liver-targeting Group in Drug Delivery 157