Hongzhe Sun

Targeted Drug Delivery via the Transferrin Receptor-Mediated Endocytosis Pathway

The membrane transferrin receptor-mediated endocytosis or internalization of the complex of transferrin bound iron and the transferrin receptor is the major route of cellular iron uptake. This efficient cellular uptake pathway has been exploited for the site-specific delivery not only of anticancer drugs and proteins, but also of therapeutic genes into proliferating malignant cells that overexpress the transferrin receptors. This is achieved either chemically by conjugation of transferrin with therapeutic drugs, proteins, or genetically by infusion of therapeutic peptides or proteins into the structure of transferrin. The resulting conjugates significantly improve the cytotoxicity and selectivity of the drugs. The coupling of DNA to transferrin via a polycation or liposome serves as a potential alternative to viral vector for gene therapy. Moreover, the OX26 monoclonal antibody against the rat transferrin receptor offers great promise in the delivery of therapeutic agents across the blood-brain barrier to the brain.

Coordination chemistry of metals in medicine: target sites for bismuth

Abstract Bismuth compounds are used for the treatment of gastrointestinal disorders and may also be useful for the treatment of other diseases. Bi(III) exhibits a highly variable coordination number (3–10) and often an irregular coordination geometry. The coordination chemistry of Bi(III) with carboxylates and aminocarboxylates is dominated by intermolecular interactions which leads to polymeric structures. Bi(III) binds strongly to the thiolate sulfur of the tripeptide glutathione, however these adducts are also kinetically labile which allows rapid translocation of Bi(III) inside cells. The major biological target for Bi(III) appears to be proteins and enzymes. Bi(III) binds to both Zn(II) sites (e.g. metallothionein) and Fe(III) sites (e.g. transferrin and lactoferrin) in proteins and enzymes and inhibits the bacterial Ni enzyme urease.

Microwave synthesis of BiPO4 nanostructures and their morphology-dependent photocatalytic performances.

A facile and rapid microwave irradiation method was explored for the synthesis of bismuth phosphate (BiPO(4)) nanostructures with various morphologies and phases in different solvents. The BiPO(4) products were characterized by powder X-ray diffraction (XRD), Raman spectroscopy, scanning electron microscopy (SEM), transmission electron microscopy (TEM), high resolution transmission electron microscopy (HRTEM), UV-vis diffuse reflection spectroscopy (DRS). The effect of the solvents on the formation of the BiPO(4) nanostructures was discussed on the basis of experimental results. The different BiPO(4) nanostructures exhibited different optical properties, BET surface areas and photocatalytic activities on the degradation of methyl orange (MO) under UV and visible light irradiation. The experimental results suggested that the photocatalytic activity was closely relative with the crystalline phase and band gap of BiPO(4). Hexagonal BiPO(4) nanoparticles with narrow band gap showed the highest photocatalytic performance.

A biomimetic zinc activated ion channel

A novel biomimetic zinc activated ion channel was prepared by incorporating a zinc responsive peptide, zinc finger, into a single polymeric nanochannel.

The role of the transferrin-transferrin-receptor system in drug delivery and targeting

Exploration of the potential of site-specific and target-oriented drug delivery systems has gained interest recently. Indeed, the efficient cellular mechanism of transferrin uptake has been exploited for the delivery not only of anticancer drugs and proteins, but also of therapeutic genes into proliferating malignant cells that overexpress transferrin receptors. In particular, the transferrin receptor offers great promise in the delivery of therapeutic agents across the blood-brain barrier to the brain.

Interactions of Bismuth Complexes with Metallothionein(II)

Bismuth complexes are widely used as anti-ulcer drugs and can significantly reduce the side effects of platinum anti-cancer drugs. Bismuth is known to induce the synthesis of metallothionein (MT) in the kidney, but there are few chemical studies on the interactions of bismuth complexes with metallothionein. Here we show that Bi3+ binds strongly to metallothionein with a stoichiometry bismuth:MT = 7:1 (Bi7MT) and can readily displace Zn2+ and Cd2+. Bismuth is still bound to the protein even in strongly acidic solutions (pH 1). Reactions of bismuth citrate with MT are faster than those of [Bi(EDTA)]−, and both exhibit biphasic kinetics.1H NMR data show that Zn2+ is displaced faster than Cd2+, and that both Zn2+ and Cd2+ in the β-domain (three metal cluster) of MT are displaced by Bi3+ much faster than from the α-domain (four metal cluster). The extended x-ray absorption fine structure spectrum of Bi7MT is very similar to that for the glutathione and N-acetyl-l-cysteine complexes [Bi(GS)3] and [Bi(NAC)3] with an inner coordination sphere of three sulfur atoms and average Bi–S distances of 2.55 Å. Some sites appear to contain additional short Bi–O bonds of 2.2 Å and longer Bi–S bonds of 3.1 Å. The Bi3+ sites in Bi7MT are therefore highly distorted in comparison with those of Zn2+ and Cd2+.

Template‐Free Fabrication of Bi2O3 and (BiO)2CO3 Nanotubes and Their Application in Water Treatment

Uniform bismuth oxide (Bi(2)O(3)) and bismuth subcarbonate ((BiO)(2)CO(3)) nanotubes were successfully synthesized by a facile solvothermal method without the need for any surfactants or templates. The synergistic effect of ethylene glycol (EG) and urea played a critical role in the formation of the tubular nanostructures. These Bi(2)O(3) and (BiO)(2)CO(3) nanotubes exhibited excellent Cr(VI)-removal capacity. Bi(2)O(3) nanotubes, with a maximum Cr(VI)-removal capacity of 79 mg g(-1), possessed high removal ability in a wide range of pH values (3-11). Moreover, Bi(2)O(3) and (BiO)(2)CO(3) nanotubes also displayed highly efficient photocatalytic activity for the degradation of RhB under visible-light irradiation. This work not only demonstrates a new and facile route for the fabrication of Bi(2)O(3) and (BiO)(2)CO(3) nanotubes, but also provides new promising adsorbents for the removal of heavy-metal ions and potential photocatalysts for environmental remediation.

The First Specific TiIV-Protein Complex: Potential Relevance to Anticancer Activity of Titanocenes

The transfer of titanium ions from titanium citrate and titanocene dichloride to the blood plasma protein transferrin was proven unequivocally by UV/Vis and NMR spectroscopy. The results may provide insight intoan important step in the mechanism of action of titanium anticancer drugs.

A histidine-rich and cysteine-rich metal-binding domain at the C terminus of heat shock protein A from helicobacter pylori: Implication for nickel homeostasis and bismuth susceptibility

HspA, a member of the GroES chaperonin family, is a small protein found in Helicobacter pylori with a unique histidine- and cysteine-rich domain at the C terminus. In this work, we overexpressed, purified, and characterized this protein both in vitro and in vivo. The apo form of the protein binds 2.10 ± 0.07 Ni2+ or 1.98 ± 0.08 Bi3+ ions/monomer with a dissociation constant (Kd) of 1.1 or 5.9 × 10-19 μm, respectively. Importantly, Ni2+ can reversibly bind to the protein, as the bound nickel can be released either in the presence of a chelating ligand, e.g. EDTA, or at an acidic pH (pH½ 3.8 ± 0.2). In contrast, Bi3+ binds almost irreversibly to the protein. Both gel filtration chromatography and native electrophoresis demonstrated that apo-HspA exists as a heptamer in solution. Unexpectedly, binding of Bi3+ to the protein altered its quaternary structure from a heptamer to a dimer, indicating that bismuth may interfere with the biological functions of HspA. When cultured in Ni2+-supplemented M9 minimal medium, Escherichia coli BL21(DE3) cells expressing wild-type HspA or the C-terminal deletion mutant clearly indicated that the C terminus might protect cells from high concentrations of external Ni2+. However, an opposite phenomenon was observed when the same E. coli hosts were grown in Bi3+-supplemented medium. HspA may therefore play a dual role: to facilitate nickel acquisition by donating Ni2+ to appropriate proteins in a nickel-deficient environment and to carry out detoxification via sequestration of excess nickel. Meanwhile, HspA can be a potential target of the bismuth antiulcer drug against H. pylori.

Recent advances in bioinorganic chemistry of bismuth

Bismuth has been used in medicine for over two centuries for the treatment of various diseases, in particular for gastrointestinal disorders, owing to its antimicrobial activity. Recent structural characterization of bismuth drugs provides an insight into assembly and pharmacokinetic pathway of the drugs. Mining potential protein targets inside the pathogen via metallomic/metalloproteomic approach and further characterization on the interactions of bismuth drugs with these targets laid foundation in understanding the mechanism of action of bismuth drugs. Such studies would be beneficial in rational design of new potential drugs.