James C. Dabrowiak

Cytotoxicity of mesoporous silica nanomaterials.

We here measure the toxicity of MCM-41, a mesoporous silica nanomaterial, two of its functionalized analogs, AP-T, which has grafted aminopropyl groups and MP-T, which has grafted mercaptopropyl groups, and spherical silica nanoparticles (SiO(2)), toward human neuroblastoma (SK-N-SH) cells. Since the particles studied are not soluble in aqueous media, the metric used to report the cytotoxicity of these materials is a new quantity, Q(50), which is the number of particles required to inhibit normal cell growth by 50%. Determining the number of particles per gram of material applied to the cells required both the calculated and experimentally determined surface areas of these nanomaterials. This study shows that Q(50) increases in the order, MCM-41<MP-T<AP-T approximately SiO(2), showing that on a per particle basis, MCM-41 is the most cytotoxic material studied. For the three mesoporous silica materials in this study, cytotoxicity appears related to the adsorptive surface area of the particle, although the nature of the functional group cannot be ruled out. Silica nanospheres have the lowest surface area of the particles studied but since they exhibit a Q(50) value similar to that of AP-T, shape may also be important in the cytotoxicity of these materials.

Metals in Medicine

Feature Boxes. Preface. Acknowledgments. 1 Inorganic Chemistry Basics. 1.1 Crystal field theory. 1.2 Molecular orbital theory. 1.3 Absorption spectra of metal complexes. 1.4 Magnetic properties of metal complexes. 1.5 Reactions of metal complexes. Problems. References. Further reading. 2 Metallo-Drugs and Their Action. 2.1 Introduction. 2.2 Proteins as targets for metallo-drugs. 2.3 DNA as a target for metallo-drugs. 2.4 Reaction of metal complexes in the biological milieu. 2.5 Evaluating the pharmacological effects of agents. 2.6 From discovery to the marketplace. Problems. References. Further reading. 3 Cisplatin. 3.1 Physical and chemical properties of cisplatin. 3.2 Formulation, administration and pharmacokinetics. 3.3 Reaction of cisplatin in biological media. 3.4 Uptake, cytotoxicity and resistance. 3.5 Interaction of cisplatin with cellular targets. Problems. References. Further reading. 4 Platinum Anticancer Drugs. 4.1 Carboplatin. 4.2 Oxaliplatin. 4.3 New platinum agents. Problems. References. Further reading. 5 Ruthenium, Titanium and Gallium for Treating Cancer. 5.1 Ruthenium compounds for treating cancer. 5.2 Titanium compounds for treating cancer. 5.3 Gallium for treating cancer. Problems. References. Further reading. 6 Gold Compounds for Treating Arthritis, Cancer and Other Diseases. 6.1 Chemistry of gold in biological media. 6.2 Gold compounds for treating arthritis. 6.3 Gold complexes for treating cancer. 6.4 Gold complexes for treating AIDS and other diseases. Problems. References. Further reading. 7 Vanadium, Copper and Zinc in Medicine. 7.1 Vanadium for treating diabetes. 7.2 Role of copper and other metal ions in Alzheimers disease. 7.3 Copper in Wilsons and Menkes diseases. 7.4 Zinc-bicyclam: a chemokine receptor antagonist. Problems. References. Further reading. 8 Metal Complexes for Diagnosing Disease. 8.1 Technetium in diagnostic nuclear medicine. 8.2 Metal compounds as contrast agents for MRI. 8.3 Radionuclides for palliative care and cancer treatment. Problems. References. Further reading. 9 Nanomedicine. 9.1 Nanoscience for treating disease. 9.2 Nanomedicine in diagnosing disease. 9.3 Potential health risks of nanoparticles. Problems. References. Further reading. Index.

Pt(IV) complexes as prodrugs for cisplatin

The antitumor effects of platinum(IV) complexes, considered prodrugs for cisplatin, are believed to be due to biological reduction of Pt(IV) to Pt(II), with the reduction products binding to DNA and other cellular targets. In this work we used pBR322 DNA to capture the products of reduction of oxoplatin, c,t,c-[PtCl(2)(OH)(2)(NH(3))(2)], 3, and a carboxylate-modified analog, c,t,c-[PtCl(2)(OH)(O(2)CCH(2)CH(2)CO(2)H)(NH(3))(2)], 4, by ascorbic acid (AsA) or glutathione (GSH). Since carbonate plays a significant role in the speciation of platinum complexes in solution, we also investigated the effects of carbonate on the reduction/DNA-binding process. In pH 7.4 buffer in the absence of carbonate, both 3 and 4 are reduced by AsA to cisplatin (confirmed using ((195))Pt NMR), which binds to and unwinds closed circular DNA in a manner consistent with the formation of the well-known 1, 2 intrastrand DNA crosslink. However, when GSH is used as the reducing agent for 3 and 4, ((195))Pt NMR shows that cisplatin is not produced in the reaction medium. Although the Pt(II) products bind to closed circular DNA, their effect on the mobility of Form I DNA is different from that produced by cisplatin. When physiological carbonate is present in the reduction medium, ((13))C NMR shows that Pt(II) carbonato complexes form which block or impede platinum binding to DNA. The results of the study vis-à-vis the ability of the Pt(IV) complexes to act as prodrugs for cisplatin are discussed.

The binding of copper ions to daunomycin and adriamycin

Using visible absorption, CD, 1H nmr, and epr spectroscopy, the Cu(II) binging properties of daunomycin, adriamycin, and N-trifluoroacetyl daunomycin in water and ethanol have been explored. The drugs form two water soluble complexes having Cu-drug stoichiometries of 1:1 and 1:2, and with apparent pKas of formation of 5.6 and 6.5, respectively. At pH values above ∼8, the drugs form insoluble polymeric complexes with Cu(II). Similar species are also observed in ethanol. The structure of the compounds have been interpreted in terms of binding of the deprotonated hydroxyquinone portion of the drug to the copper ion. No evidence for the binding of the amino group on daunosamine was found.

A spectroscopic investigation of the metal binding site of bleomycin A2. The Cu(II) and Zn(II) derivatives

Using a combination of ultraviolet-visible absorption, 1H NMR and ESR techniques we have established that N(1) of the imidazole and N(1) of the pyrimidine residues of bleomycin A2 bind to Cu(II) and Zn(II). The observations coupled with the earlier results that the alpha-amino group of the alpha-amino carboxamide function and the carbamoyl moiety are also Cu(II)-ligating groups makes it possible to reconstruct the detailed geometry and stereochemistry of the metal binding site of bleomycin A2.

The coordination chemistry of bleomycin: a review

Abstract It is evident that bleomycin is a “something for everyone antibiotic.” The mechanism, which involves an important anticancer drug, a metal ion, and DNA, attracts a broad spectrum of scientific intellects and publications on the antibiotic can be found in a variety of different journals. For the inorganic chemist the challenges with bleomycin are just beginning. While the large size of the molecule complicates the study of metal binding phenomena, the drug is small enough to be studied using the structural techniques normally employed by the coordination chemist, e.g., 1 H and 13 C nmr. Although significant progress toward understanding the structure and chemistry of the important metallobleomycins has been made, much remains yet to be done. It is hoped that by placing in perspective the accomplishments of the past, this review will help to more clearly define the course of future experimentation on the antibiotic.

DNA-capped nanoparticles designed for doxorubicin drug delivery

The anticancer drug, doxorubicin (DOX), was loaded onto DNA-capped gold nanoparticles (AuNP) designed for specific DOX intercalation. Drug binding was confirmed by monitoring DNA melting temperature, AuNP plasmon resonance maximum, and hydrodynamic radius increase, as a function of [DOX]/[DNA] ratio. The capacity for drug release to target DNA was confirmed.

Multifunctional DNA-Gold Nanoparticles for Targeted Doxorubicin Delivery

In this report we describe the synthesis, characterization, and cytotoxic properties of DNA-capped gold nanoparticles having attached folic acid (FA), a thermoresponsive polymer (p), and/or poly(ethylene glycol) (PEG) oligomers that could be used to deliver the anticancer drug doxorubicin (DOX) in chemotherapy. The FA-DNA oligomer used in the construction of the delivery vehicle was synthesized through the reaction of the isolated folic acid N-hydroxysuccinimide ester with the amino-DNA and the conjugated DNA product was purified using high performance liquid chromatography (HPLC). This approach ultimately allowed control of the amount of FA attached to the surface of the delivery vehicle. Cytotoxicity studies using SK-N-SH neuroblastoma cells with drug loaded delivery vehicles were carried out using a variety of exposure times (1-48 h) and recovery times (1-72 h), and in order to access the effects of varying amounts of attached FA, in culture media deficient in FA. DOX loaded delivery vehicles having 50% of the DNA strands with attached FA were more cytotoxic than when all of the strands contained FA. Since FA stimulates cell growth, the reduced cytotoxicity of vehicles fully covered with FA suggests that the stimulatory effects of FA can more than compensate for the cytotoxic effects of the drug on the cell population. While attachment of hexa-ethylene glycol PEG(18) to the surface of the delivery vehicle had no effect on cytotoxicity, 100% FA plus the thermoresponsive polymer resulted in IC50 = 0.48 ± 0.01 for an exposure time of 24 h and a recovery time of 1 h, which is an order of magnitude more cytotoxic than free DOX. Confocal microscopic studies using fluorescence detection showed that SK-N-SH neuroblastoma cells exposed to DOX-loaded vehicles have drug accumulation inside the cell and, in the case of vehicles with attached FA and thermoresponsive polymer, the drug appears more concentrated. Since the biological target of DOX is DNA, the latter observation is consistent with the high cytotoxicity of vehicles having both FA and the thermoresponsive polymer. The study highlights the potential of DNA-capped gold nanoparticles as delivery vehicles for doxorubicin in cancer chemotherapy.

4 Platinum Antitumour Agents

Publisher Summary This chapter focuses on platinum antitumor agents. Biologically active platinum complexes have been under investigation for nearly two decades. The large data base on structure–activity relationships has revealed a number of principles as well as raised new questions. Mechanistically, the aquation of the compounds and their ability to cause intrastrand cross-links in defined regions of DNA appear to be the chemical events most closely associated with antitumour activity. The reaction kinetics of the compounds in aqueous systems, which may be influenced by chelate effects, steric hindrance of bulky ligands or metal oxidation state have been studied for some complexes and are amenable to reasonably precise investigation in the future. The pharmacological behavior of the complexes in animals and in humans is, however, much less well defined. Although the pharmacokinetics of a number of compounds have been studied, conclusions regarding toxic effects have only been inferred, and reasons for varying antitumour effects are even less well understood. With intense motivation, both from the oncologic and commercial communities for clinical success, attention is heavily focused on the most active compounds in terms of antitumour effects.

Modification and Uptake of a Cisplatin Carbonato Complex by Jurkat Cells

The interactions of Jurkat cells with cisplatin, cis-[Pt(15NH3)2Cl2](1), are studied using 1H-15N heteronuclear single quantum coherence (HSQC) NMR and inductively coupled plasma mass spectrometry. We show that Jurkat cells in culture rapidly modify the monocarbonato complex cis-[Pt(15NH3)2(CO3)Cl]- (4), a cisplatin species that forms in culture media and probably also in blood. Analysis of the HSQC NMR peak intensity for 4 in the presence of different numbers of Jurkat cells reveals that each cell is capable of modifying 0.0028 pmol of 4 within ∼0.6 h. The amounts of platinum taken up by the cell, weakly bound to the cell surface, remaining in the culture medium, and bound to genomic DNA were measured as functions of time of exposure to different concentrations of drug. The results show that most of the 4 that has been modified by the cells remains in the culture medium as a substance of molecular mass <3 kDa, which is HSQC NMR silent, and is not taken up by the cell. These results are consistent with a hitherto undocumented extracellular detoxification mechanism in which the cells rapidly modify 4, which is present in the culture medium, so it cannot bind to the cell. Because there is only a slow decrease in the amount of unmodified 4 remaining in the culture medium after 1 h, -1.1 ± 0.4 μM h-1, the cells subsequently lose their ability to modify 4. These observations have important implications for the mechanism of action of cisplatin.