Open access peer-reviewed chapter

Theoretical Insight into the Medicinal World of Organometallics: Macro versus Nano

Written By

Ruby Srivastava

Submitted: 07 October 2016 Reviewed: 08 February 2017 Published: 05 July 2017

DOI: 10.5772/67781

From the Edited Volume

Recent Progress in Organometallic Chemistry

Edited by Mohammed Muzibur Rahman and Abdullah Mohamed Asiri

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Abstract

Due to the unique physicochemical properties, organometallic complexes have been widely used in the medicinal world. These complexes have specific properties such as structural diversity, redox/catalytic activities, and possibility of ligand exchange. As the cancer therapies provided by these complexes are not always effective and have desired side effects, new treatment methods are needed for the successful therapies. Recent advances suggest that nanotechnology has also profound impact on the disease prevention, diagnosis, and treatment. The delivery system based on nanotechnology has faster drug absorption, controlled dosage release, and minimal side-effects. This technology is used for the treatment of cancer till now, but soon, it will find applications to other diseases also. The use of nanotechnology in the field of drug delivery is to develop a system that improves the solubility and bioavailability of hydrophobic drugs. It is used to increase specificity, developing delivery system for slow release, and to design delivery vehicles that can improve the circulatory presence of drugs. As the photophysics of organometallic complexes is still not clear, this topic is included to discuss the latest developments in this field, which allows the photochemical reactions at the nanolevel.

Keywords

  • organometallic complexes
  • nanotechnology
  • photophysics
  • drug delivery
  • upconversion luminescence

1. Introduction

Organometallic chemistry deals with three basic aspects as environmental concern, biological aspect, and medicinal chemistry. Medicinal organometallic chemistry continues to be a major application for these compounds in biology. Medicinal organic chemistry has therapeutics, diagnostics, and theranostics effects. Medicinal organometallic complexes consist of platinum, ruthenium, iron, titanium, and gold among other metals. Fundamental studies have been carried out on the organometallic complexes in which the mechanism of action exert their medicinal effect (e.g., induce cell death in cancer cells), the synthesis of new organometallic compounds and the development of combination therapies containing organometallic components. Research has shown significant progress in utilization of transition metal complexes as

1.1. Anticancer agents

The development of metal complexes with platinum as a central atom such as cisplatin or carboplatin had an enormous impact on current cancer chemotherapy. Cisplatin has become one of the most widely used drugs and is highly effective in treating several cancers such as ovarian and testicular cancers. The limitations of cisplatin have stimulated research in the field of platinum antitumor chemistry by including the reduction in toxicity of cisplatin (nausea, ear damage, vomiting, loss of sensation in hands, and kidney toxicity), acquired drug resistance observed in certain tumors and inefficiency of the drug against some of the commonest tumors (e.g., colon and breast). Due to its particular chemical structure, cisplatin offers little possibility for improvement in tumor specificity and thereby reducing side effects. The other alternative complexes have at least one direct, covalent metal-carbon bond, having structural variety, diverse stereochemistry, provide control over major kinetic properties, kinetically stable, usually uncharged, and having low oxidation state of metal atom, so they can be used as ideal candidates for anticancer candidates [14]. Some examples are: metallocenes [59], organometallic ruthenium half-sandwich complexes [1014], organometallic osmium half-sandwich complexes [1517], organometallic iridium and rhodium complexes [1821], rhenium organometallics [2224], ruthenium, osmium, iridium, and platinum organometallics as scaffolds for protein kinase inhibitors, metal NHC complexes [25, 26], and metal carbonyl complexes [27, 28].

1.2. Antibacterial agents

The biggest challenge in the antibacterial market is the issues related to the drug-resistant pathogens. The remedy is now to search for new compounds with new mode of action to overcome the resistant strains. This can be done by either the organic derivatization of old drugs or completely new organometallic drugs, for example, new tamoxifen [1921, 29], platensimycin [2224], etc.

1.3. Anti-infectant agents

Transition metal as silver is being used as the antimicrobial agent due to its low toxicity as compared to the other metals. For example: silver (1) sulfazine, which is used to treat burns to prevent the bacterial infections. Silver nitrate is given to the infants to prevent the development of ophthalmia neonatorum. Chlorhexidine-silver sulfadiazine is an anti-infective metal complex against catheter infections. Organometallic complexes of Pt [3032], Rh, Ir, Pd, and Os metal with active organic molecules have been reported to exhibit trypanocidal activity. Metal complexes of Pt (II) and Ru (II) with o-vanillin-(4-methyl thiosemicarbazone), and o-vinillin-(4-phenyl thiosemicarbazone), metal complexes of Ga (III), Al (III), and Fe are among the various other drugs [3336].

1.4. Anti-inflammatory agents

These complexes are also used as anti-inflammatory and antiarthritic agents. Several injectable transition metal complexes as sodium aurothiomalate, aurothioglucose, sodium aurothiopropanol and gold and silver nanoparticles conjugated with heparin derivative possess antiangiogenesis properties [3739]. Gold has been used for the treatment of peripheral psoriatic arthropathy. As a product of oxygen metabolism, superoxide anion can trigger oxidative injury to tissues. This activity is associated with riper fusion and inflammatory diseases as well as neurological disorders such as Parkinson’s disease and Alzheimer’s disease. However, excess use of these complexes in arthritis causes pain and fever. NO is excellent ligand for transition metal ions and these metal nitrosyls having therapeutic values. Sodium nitroprusside is used to treat cardiovascular diseases by releasing NO with limited usage due to the toxicity of CN. Ruthenium poly aminocarboxylate complexes are also efficient NO scavengers [40, 41].

1.5. Anti-diabetic agents

Diabetes is the most suffering disease among human beings. This is the disease in which the body do not produce insulin hormone, which is used for absorption of glucose in cells. The control of glucose level is done by vanadium complexes with organic ligands which are less toxic and have improved solubility and lipophilicity [42]. These complexes show involvement in the activation of prominent key components of insulin-signaling pathways [43]. Chromium supplementation also improves glycemia among patients of diabetes [44]. Similarly, higher zinc intake also lowers the risk of type 2 diabetes in women [45].

1.6. Neurological drugs

Neurological disorders are also treated by transition metal complexes. Lithium is used for Huntington’s chorea, tardive dyskinesia, spasmodic torticollis, Tourette’s syndrome, L-dopa induced hyperkinesia, Parkinsonism, organic brain disorders, drug induced delusional disorders, migraine and cluster headache, periodic hypersomnolence, epilepsy, Meniere’s disease, and periodic hypokalemic paralysis. Lithinium inhibit the scavenging pathways for capturing inositol in the resynthesis of polyphosphoinositides in the brain. Zinc is also used as transmitter in neuronal signaling pathways.

1.7. Delivery probes and diagnostic tools

Organometallic complexes have unique properties as redox activity, Lewis acidity, electrophilicity, valency, geometry magnetic spectroscopic, and radiochemical properties which can be used to measure cellular functions. Gold nanorods has been used for photoacoustic molecular imaging with simultaneous multiple targeting as they are less reactive and less toxic. The nanoparticles injected in the tumor cells increases their ability to absorb radiation of specific wavelength. The property is used in lymphotropic nanoparticle-enhanced magnetic resonance imaging of prostate cancer. As iron oxide has superparamagnetic properties so they can act as negative contrast agent in magnetic resonance imaging (MRI) which is used to detect the sensitivity of inflamed tissues.

Transition metals exhibit different oxidation states and can interact with several negatively charged molecules. Due to their vital role in medicinal chemistry, we have included both the macro and the nanoorganometallic complexes and their structural and photophysical behavior in detail.

Metallocene compounds have two π-bonded cyclopentadienyl (Cpa) ligands on a metal atom. These compounds are also called “sandwich complexes” due to their symmetrical nature. Other metal complexes with cyclic π-perimeters are also named as metallocenes. Compounds with only one π-perimeter are classified as “half sandwich metallocenes.” The bis-cyclopentadienyl complexes are divided in two categories: (a) “classical” with parallel Cp rings and (b) “bent” metallocenes, which have other ligands bonded to the metal in addition to the Cp rings. Ferrocene was the first organometallic compound with antiproliferative properties, so the medicinal properties of the complex were investigated [3]. Ferrocene is nontoxic compound and can be injected, inhaled, or taken orally. It cannot cause major health problems [4, 5]. Another ferrocene-containing compound chloroquine (derivative) is used as antimalarial drug. Ferroquine has an activity-like chloroquine on the malaria parasite P. falciparum. The p-methoxybenzyl substituted titanocene show very good activity against renal cell cancer and pleura mesothelioma cell lines. Ruthenium complexes have low toxicity and it has the same mechanism (ligand exchange kinetics) to those of platinum(II) antitumor drugs [10]. A class of ruthenium(II)-arene complexes that are weakly cytotoxic in vitro, [Ru(η6-p-arene)Cl2(1,3,5-triaza-7-phosphaadamantane)] termed as RAPTA, interact strongly with proteins, with the ability to discriminate binding to different proteins, but show a relatively low propensity to bind DNA, which is considered to be the main target of many metal-based drugs. Dyson et al. recently described the preparation of a series of RAPTA-type complexes with fluoro-substituted η6-arene ligands [46] (Figure 1). The active Pt-drug seems to be cis-coordinated by bidentate amine ligands or two amines (at least one -NH group on the amine) and two leaving groups with an intermediate binding strength (e.g., Cl, SO42−, citrate or oxalate) to platinum. Nonplatinum metals may have some different chemical behavior (oxidation state, redox potential, coordination geometry, additional coordination sites, binding preferences to biomolecules as the HSAB (hard and soft (Lewis) acids and bases), rate of hydrolysis or kinetics of ligand exchange reactions and the ability to replace essential metals. Due to these differences, the nonplatinum metal-based compounds may have different mechanisms of action, biodistribution, and biological activity.

Figure 1.

Schematic diagram of few organometallic complexes.

Studies were carried out on complexes with iron, cobalt or gold, titanium, ruthenium, or gallium central atoms, which have shown the promising results in preclinical studies. Other metal complexes which have shown potential anticancer activity are the complexes of Rh (I), Rh (III) [22, 23, 47], Ir (I), Ir (II), Ir (IV) [48, 20, 21], Os (II), and Os(III) [18, 4952]. Ferrocifenes [53] exhibit anticancer activity against hormone dependent and hormone-independent breast cancers. Ferrocene derivatives as curcuminoids [54], androgen derivatives [55], and antiandrogens derived from the nilutamide lead structure [56], indolones [57], and ferrocenophane polyphenols [58] has also been used for antiproliferative activities.

Transition metal carbene complexes also feature a divalent organic ligand, which is coordinated to the metal center. As these complexes are highly stable and easily derivatize, they can be the suitable candidates for drug development [8, 59].

Metal NHC complexes are also having pharmacological properties as novel antibacterial and antitumor drugs. Their mode of action is both coordinated metal–respective biological target-dependent thioredoxin reductase or other enzymes containing (seleno) cysteine residues in their active site for gold or DNA for copper NHC complexes (half-sandwich) [60, 32], ruthenium [27], or manganese [28, 61] bioorganometallic species and complex containing an acetylsalicylic acid (aspirin) derived ligand emerged as cytotoxic drugs.

An enormous work has been carried out by my mentor Prof. G. Narahari Sastry and group in the field of anticancer treatment. The research group has focused their attention to the biochemical aspects of the clinical application of aromatase inhibitors with designing strategies on toxicity profile, pharmacokinetics, relative potency of aromatase inhibitors, and pharmacophores models [6273].

As the side effects of these complexes are unavoidable, the research was shifted to the nanotechnology which will have a profound impact on disease prevention, diagnosis, and treatment.

Few advantages of nanotechnology techniques are:

  1. Protect drug from degradation

  2. Easily changeable physical properties due to nanosizes

  3. Reduced dose size

  4. Ease of drug targeting due to nanosize

  5. Allow delivery of insoluble drugs

  6. Longer circulation time

  7. Maintain its therapeutic activity

  8. Improve the oral bioavailability of the agents

  9. Passive targeting of drugs to the macrophages (liver and spleen)

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2. Nanoorganometallic complexes

Recent advances suggest that nanotechnology will give a better solution for disease prevention, diagnosis, and treatment. It is an ideal targeting system, should have long circulating time, be present at appropriate concentrations at the target site, and should not lose its activity or therapeutic efficacy while in circulation. The increased vascular permeability coupled with an impaired lymphatic drainage in tumor allows an enhanced permeability and retention effect of the nanosystems in the tumor or inflamed tissue. Nanotechnology offers a solution for using the numerous chemical entities for treating brain disorders that are not clinically useful because of the presence of the blood-brain barrier.

The advantage of nanoparticles with potential MRI-related medical applications comprise of various materials, such as metals (gold, silver, and cobalt) or metal oxides (Fe3O4, TiO2 and SiO2) (Figure 2). Magnetic nanoparticles coated with dimercapto succinic acid (DMSA) were toxic to neurons in a dose-dependent manner. Cobalt (Co), gold (Au@Fe), and platinum (Pt@Fe) are the other types of nanomaterials that show potential application in antimicrobial and anticancer treatment. Several studies on nanoparticles shown them to be cytotoxic [72], genotoxic [73], and potentially carcinogenic [74] and are used to induce apoptosis and inhibit cell proliferation [75].

Figure 2.

Schematic representation of the targeted contrast agent used for MRI approaching of the cancer cell and specific proteins.

These nanomaterials contain the sphere and core-shell structures, two-dimensional (2D) grapheme nanosheets have great potential for high drug loading efficiency and conjugation of proteins, drugs, and fluorescent probes.

The molecular imaging applies to various techniques such as positron emission tomography (PET), computed tomography (CT), or ultrasound and magnetic resonance imaging (MRI) which gives the best spatial resolution and is either noninvasive or minimally invasive. As MRI is not applied in full potential due to low specificity, so it can be alternatively taken to use as cell markers. The unique paramagnetic and superparamagnetic properties of nanoparticles (NP) can be utilized for the detection with MRI in small quantities. Nanoparticles with potential MRI-related medical applications comprise various materials, such as metals (gold, silver, and cobalt) or metal oxides (Fe3O4, TiO2, and SiO2). While diagnostic is a common medical application of nanoparticles, they can also be used for therapy [7680] (Figure 3).

Figure 3.

Representation of toxicological mechanisms of NM to eukaryotic cells.

Nanoparticles can be categorized in two parts:

2.1. Inorganic nanoparticles

Silver (Ag), iron oxide (Fe3O4), titanium oxide (TiO2), copper oxide (CuO), and zinc oxide (ZnO) are used for highly potent antibacterial effect. The property is exhibited through reactive oxygen species (ROS) generation or by physical structure and metal-ion release. Though the mechanism is not clear, nonetheless high surface energy may compromise their efficacy. Another important aspect is that how to define and determine the silver minimal inhibitory concentration (MIC) and breaking point, the ease of emergence of resistant strains [8183]. Silver really kills biofilm or planktonic cells and finally the side effects of silver and its complexes [8487] remains the same. Yet till now it is the most promising antibacterial nanometal. Titanium oxide (TiO2) has shown its efficiency against various viral species and parasites [8890]. Copper oxide (CuO) is less expensive and used for efficacy enhancement [9193]. Iron oxide (Fe3O4) [94], zinc oxide (ZnO) and Magnesium oxide (MgO) [9597] nanoparticles show antibacterial activities. Gold nanoparticles and nanorods have been used as bactericidal in photothermally functionalized form [98]. Pt nanoparticles diffuse through membranes and induce DNA damage, accumulation of cells at the S-phase of the cell cycle, and apoptosis [99]. The properties of Al2O3 are unclear about the antibacterial treatment [100], while SiO2, Au, Fe2O3, and TiO2 are biocompatible.

Even cytotoxic NM can be converted into biocompatible materials through slight variation in their surface structure. Therefore, we can say that nanomaterials possess a broad level of biological properties that are highly dependent upon their size, structure, quantity, and receptor cell type. Though, the nanomaterials that penetrate the body through the skin by respiration or by inhalation directly affect the major body organs (lungs, heart, and brain).

2.2. Organic nanoparticles

Quaternary ammonium compounds, imidazole derivatives, alkyl pyridiniums, copolymers of N-vinylimidazole and phenacyl methacrylate, benzoic acid, phenol, and p-Hydroxy benzoate esters, quaternary phosphonium or sulfonium groups, triclosan, 5-chloro-8-hydroxy-quinoline, chitosan, or quaternary phosphonium are the polymeric nanoparticles that are used to kill microorganisms either by releasing antibiotics, antimicrobial peptides, and antimicrobial agents or by contact-killing cationic surfaces. Organic antibacterial materials are less stable than inorganic materials at high temperatures [101, 102]. Still some phenomena such as several NM killing pathways, effects of NM’s treatment combinations and bacterial intrinsic pathways of programmed cell death in NM’s dependent killing are yet to be understood.

As we all know, hepatocellular carcinoma (HCC) is the leading cause of cancer-associated death and the conventional treatment is still not satisfactory due to chemoresistance and recurrence. In a recent study, Pt nanocluster assembly (Pt-NA) composed of assembled Pt nanoclusters was synthesized incorporating a pH-sensitive polymer and HCC-targeting peptide [103].

The advantage of Pt nanocluster medicine is that Pt-NA is active in peripheral blood and readily targets tumor cells including CLSC because of (i) the surface-targeting peptide; (ii) protonation of pH-sensitive polymers in an acidic intracellular environment triggers Pt-NA disassembly into extremely small Pt nanoclusters; and (iii) the resulting extremely small Pt nanoclusters with large specific surface accelerate the release of toxic Pt ions inside the cells for an effective cancer treatment (Figure 4).

Figure 4.

Schematic representation of HCC targeted Pt nanocluster assembly (Pt-NA). Adapted with permission from American Chemical Society [103].

Numerous efforts have been devoted to synthesize nanostructured materials with specific morphology as their size and shape play an important role in determining their functions. It was seen that the cationic nanoparticles with metals (gold, silver, and cobalt) or metal oxides (Fe3O4, TiO2, and SiO2) were moderately toxic than their anionic nanoparticles. The studies reflect that DMSA coated nanoparticles are nontoxic to HeLa cells or RAW macrophages. The incorporation of chlorotoxin onto functionalized Fe3O4 nanoparticles resulted in a significant increase in the total uptake within the brain tumors of mice. Substituted magnetic spinel ferrites of the general formula MFe2O4 (where M = Zn2+, Mn2+, Co2+, Ni2+, and Mg2+) offer the opportunity to fine-tune the magnetic properties of the inorganic nanoparticle core as a function of the kind of divalent ion.

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3. Photophysics of the bioactive molecules

In the recent years, new experimental and theoretical developments have occurred in the field of photoactivatable metal complexes which play active role in the field of medicine and biotechnology. Some metal-DNA complexes possess favorable emission properties, while some complexes also provide site-directed therapy. These properties help in oncology, where metal-based precursors generate excited state drugs with different mechanisms.

In this section, the computational techniques (time-dependent density functional theory) and ultrafast-pulsed radiation techniques will be discussed.

The delivery of light depends on the efficiency of light source. It should be efficient to activate the complex. The irradiation should occur in the strong MLCT transitions. However, in medicinal world the UV radiations are harmful but red region is preferred as it deeply penetrates the tissues. Two and three photon absorption can be achieved as the desirable condition is to activate complexes that absorb at shorter wavelength using laser beam that penetrates tissues deeply.

The use of organometallics has become a topic of interest for design of tractable therapeutic agents and theranostics [104]. The most promising organometallic complexes (and motifs) usedin cancer therapy is RAPTA-C: [Ru(η6-p-cymene)Cl2(pta)] (pta = 1,3,5-triaza-phosphatricyclo[3.3.1.1]-decane; Chart 1), along with its osmium analogue and their corresponding functionalized derivatives [105]. These complexes exhibit antimetastatic properties in vivo. The quite strongly bonded phosphine and arene ligands, the chloride ligands rapidly interchange with water molecules. Arene-ruthenium derivatives can react with N- and S-donors so that they can bind to both nucleotides and proteins [106].

Chart 1.

Structure of [Ru(η6-p-cymene) Cl2(pta)] (left) and [(η5-Cp)Ti((η5-C5H4-(CH2)4-PPh2-[Ru(η6-p-cymene)Cl2(pta)] (right).

Porphyrins and their metalloderivatives are used for photodynamic therapy [107] and optical imaging and as theranostic agents [108]. Gold (III), Palladium (II), Palladium (III) inside the porphyrin rings and their derivatives can act as anticancer agents [109]. It is based on the concept of “optical bi-theranostic” (two modalities for therapy and one for optical imaging). Further as the intramolecular interactions between the two moieties alter their activities so this should be considered for designing and testing. Ruthenium and Iridium possess favorable photophysical properties which allow functional imaging of cells and tissues (e.g., DNA interactions) and provide site-directed therapy. The electronic transitions can be metal-centered (MC), ligand-centered (LC) or involve both the metal and the ligands: metal-to-ligand charge transfer (MLCT) (for readily oxidized metal ions and ligands with low-lying acceptor orbitals), or ligand-to-metal charge transfer (LMCT) (for readily reduced metal ions with strong donor ligands) (Figure 5).

Figure 5.

Schematic representation of the orbital and excited state diagram for (d6) metal complex. Spin is represented by arrows (↑↓) for electronic transitions. (a) Spin up is represented for electronic transition in singlet state whereas spin down is represented for electronic transition in triplet state. (b) Jablonski diagram.

A lot of research is carried out in the delivery of small molecules, which can act as second messengers and transmit signals into cells, for example, NO, carbon monoxide (CO), and hydrogen sulfide (H2S). Photoactive Pt (IV) diazido complexes also offer potential dual mode activity; excited singlet and triplet states can release reactive or biologically active ligands and form Pt (II) species which can bind to DNA. The introduction of extended conjugation into the amine ligands of square–planar Pt (II) complexes has allowed two-photon activation of ligand exchange using red and near-infrared (NIR) light. The wavelength for two-photon activation of cis-[PtCl2(MOPEP)2], where MOPEP is the π-conjugated ligand 4-[2-(4 methoxyphenyl)ethynyl]pyridine, is shorter than twice the single-photon absorption wavelength [110].

Another important optical phenomenon is “upconversion luminescence,” which is discussed here.

3.1. Upconversion luminescence

It is a nonlinear optical phenomenon, which absorb two or more photons and emit one photon. Compared with traditional luminescent materials, upconversion nanostructures have many advantages, such as weak background interference, long lifetime, low excitation energy, and strong tissue penetration, which are used in bioimaging and sensing. Similarly producing shorter wavelength light from longer wavelength irradiation involves the use of upconverting nanoparticles. For example: YF3 doped with lanthanide ions (Yb3+and Tm3+). Lanthanide-doped upconversion nanoparticles are used to mediate nitric oxide (NO) release from Roussin’s black salt anion [Fe4S3(NO)7] in NIR light from a simple diode laser operating at 980 nm [110]. Cr (III) sensitizers around a central Er (III) acceptor also favor efficient nonlinear energy transfer and upconversion luminescence [111].

3.2. Imaging and binding of photo-triggered DNA

The simple and powerful strategy for selective destruction of cancer cells is to target the metal complexes to the tumor cells by photoactivation. Peptides releases the aqua species, [(η6-p-cym)Ru(bpm)(H2O)]2+in the visible range which bind to DNA. The other example is the cyclometalated iridium (III) polypyridine indole complexes, which have the intense luminescence (λem= 540–616 nm, τ = 0.13–5.15 μs) [112]. Another interesting feature of these complexes is that they can deliver CO in the body [113], for example, MnI carbonyl complex [Mn(pqa)(CO)3]+ (pqa =(2-pyridylmethyl)(2-quinolylmethyl)amine) [114] and manganese complexes [115]. The release of CO from these complexes is visibly monitored by time-resolved IR spectroscopy [116]. This property is also used to deliver other biologically active species also. [Rh(bpy)2(chrysi)]3+ targets single-base mismatches in DNA by noncovalent binding in UV/visible region. As there is deficiency of mismatch repair in cancer cells, this technique can be used to detect the cancer cells [117, 118]. The other luminescent N-heterocylic carbene (NHC) cyclometalated platinum(II) complexes, which are localized in cytoplasmic structures, do not interact with nucleotides [119].

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4. Conclusions

Unfortunately, like the macro organometallic complexes, the nanoparticles also carry some serious adverse effects. Though the adverse effects of nanoparticles depend on individual factors such as genetics, existing disease conditions, exposure, nanoparticle chemistry, size, shape, agglomeration state, and electromagnetic properties, the key to understanding the toxicity of nanoparticles is their size. Thus, it is very essential to understand the basic nature, structure, and the photophysics behind these particles. Nanoparticles are smaller than mammalian cells and cellular organelles, which allows them to penetrate these biological structures and disrupt their normal function. Nanoparticles are effective in glycoma treatment. This brain cancer is particularly difficult to treat as neurosurgery is ineffective, while chemotherapy suffers from the inability of therapeutics to cross the blood. Although the lack of self-error-correcting mechanism result in defect sites in these nanostructures, the high efficiency and relative simplicity of the novel approach demonstrates the potential power of using irreversible covalent bonds to generate adverse range of shape-persistent and robust nanostructures that is likely to enrich the repertoire of self-assembled nanomaterials and multidrug delivery. Finally, toxicity of nanoparticles could also be potentially utilized to destroy the cancer cells. Bioorganometallic compounds offer hope in the fight against the deadly diseases such as Malaria, HIV/AIDS, and EVD that have continued to devastate humans. There are expected challenges in this area of collaborative research as organometallic compounds are ideally synthesized under inert atmosphere in the absence of oxygen and water. These challenges are not too difficult to surmount, we therefore implore researchers to orient more into this relatively new multidisciplinary research area in the search for novel and potent anticancer and other drug candidates with reduced side effects, which can be a great service to the mankind.

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Acknowledgments

The author acknowledges the financial assistance by the DST WOS‐A (CS‐1005/2014). The author is also thankful to her mentor Dr. G. Narahari Sastry, Head, Center for Molecular Modeling for the support.

References

  1. 1. Jakupec MA, Galanski M, Arion VB, Hartinger CG, Keppler BK. Antitumour metal compounds: More than theme and variations. Dalton Transactions. 2008;2:183-194. DOI:10.1155/2015/859730
  2. 2. Dyson PJ, Sava G. Metal-based antitumour drugs in the post genomic area. Dalton Transactions. 2006;16:1929-1933. DOI:10.1039/c1dt10522a
  3. 3. Wang D, Lippard S J. Cellular processing of platinum anticancer drugs. Nature Reviews Drug Discovery. 2005;4:307-320. DOI:10.1038/nrd1691
  4. 4. Lippert B. Cisplatin, Chemistry and Biochemistry of a Leading Anticancer Drug; Zurich, Switzerland: Verlag Helvetica Chimica Acta; 1999. p. 563. DOI:10.1038/nrd1691
  5. 5. Gasser G, Ott I and Metzler-Nolte N. Organometallic anticancer compound. Journal of Medicinal Chemistry. 2011;54:3-25. DOI: 10.1021/jm100020w
  6. 6. Köpf-Maier P, Köpf H. Organometallic Anticancer Compounds. Drugs Future. 1986;11:297-320. DOI:10.1021/jm100020w
  7. 7. Köpf-Maier P, Köpf H, Neuse EW. Ferrocenium salts; the first antineoplastic iron compounds. Angewandte Chemie, International Edition England. 1984;23:456-457. DOI:10.1021/jm100020w
  8. 8. Köpf-Maier P, Köpf H. Non-platinum-group metal antitumor agents: History, current status, and perspectives. Chemical Reviews. 1987; 89:1137-1152. DOI: 10.1021/cr00081a012
  9. 9. Köpf-Maier P, Köpf H. Transition and main-group metal cyclopentadienyl complexes: preclinical studies on a series of antitumor agents of different structural type. Structural Bonding [Berlin]. 1988;70:105-185
  10. 10. Dale LD, Tocher JH, Dyson TM, Edwards DI, Tocher DA. Studies on DNA damage and induction of SOS repair by novel multifunctional bioreducible compounds. II. A metronidazole adduct of a ruthenium-arene compound. Anti-Cancer Drug Design. 1992;7:3-14. DOI: 10.2337/dc08-1913
  11. 11. Melchart M, Sadler PJ. Ruthenium arene anticancer complexes. In Jaouen G, editor. Bioorganometallics. Weinheim, Germany: Wiley-VCH; 2006. pp. 39-64
  12. 12. Peacock AFA, Sadler PJ. Medicinal organometallic chemistry: Designing metal arene complexes as anticancer agents. Chemistry, an Asian Journal. 2008;3:1890-1899. DOI: 10.1002/asia.200800149
  13. 13. Dougan SJ, Sadler PJ. The design of organometallic ruthenium arene anticancer agents. Chimia. 2007;61:704-715. DOI: http://dx.doi.org/10.2533/chimia
  14. 14. Süss-Fink G. Arene ruthenium complexes as anticancer agents. Dalton Transactions. 2010;39:1673-1688. DOI: 10.1002/1521-3773
  15. 15. Peacock AFA, Habtemariam A, Fernandez R, Walland V, Fabbiani FPA, Parsons S, Aird RE, Jodrell DI, Sadler PJ. Tuning the reactivity of osmium[II] and ruthenium[II] arene complexes under physiological conditions. Journal of the American Chemical Society. 2006;128:1739-1748. DOI: 10.1021/ja055886r
  16. 16. Peacock, AFA, Habtemariam A, Moggach SA, Prescimone A, Parsons S, Sadler P J. Chloro half-sandwich osmium [II] complexes: Influence of chelated N,N-ligands on hydrolysis, guanine binding, and cytotoxicity. Inorganic Chemistry. 2007;46:4049-4059. DOI: 10.1021/ic062350d
  17. 17. Peacock AFA, Parsons S, Sadler PJ. Tuning the hydrolytic aqueous chemistry of osmium arene complexes with N, O-chelating ligands to achieve cancer cell cytotoxicity. Journal of the American Chemical Society. 2007;129:3348-3357. DOI: 10.1021/ja068335p
  18. 18. Dorcier A, Ang WH, Bolãno S, Gonsalvi L, Juillerat-Jeannerat L, Laurenczy G, Peruzzini M, Phillips AD, Zanobini F, Dyson PJ. In vitro evaluation of rhodium and osmium RAPTA analogues: The case for organometallic anticancer drugs not based on ruthenium. Organometallics. 2006;25:4090-4096. DOI: 10.1021/om060394o
  19. 19. Liu Z, and Sadler PJ. Organoiridium complexes: Anticancer agents and catalysts. Accounts of Chemical Research. 2014;47(4):1174-1185. DOI: 10.1021/ar400266c
  20. 20. Scharwitz MA, Ott I, Geldmacher Y, Gust R, Sheldrick WS. Cytotoxic half-sandwich rhodium [III] complexes: Polypyridyl ligand influence on their DNA binding properties and cellular uptake. Journal of Organometallics Chemistry. 2008;693:2299-2309. DOI: 10.1016/j.jorganchem.2008.04.002
  21. 21. Lau JSY, Lee PK, Tsang KHK, Ng CHC, Lam YW, Cheng SH, Lo KKW. Luminescent cyclometalated iridium[III] polypyridine indole complexes;synthesis, photophysics, electrochemistry, protein-binding properties, cytotoxicity, and cellular uptake. Inorganic Chemistry. 2009;48:708-718. DOI:10.1007/s11426-010-4120-y
  22. 22. Zhang J, Vittal JJ, Henderson W, Wheaton JR, Hall IH, Hor TSA, Yan YK. Tricarbonylrhenium [I] complexes of phosphine-derivatized amines, amino acids and a model peptide: Structures, solution behavior and cytotoxicity. Journal of Organometallics Chemistry. 2002; 650:123-132. DOI:10.4172/2155-9821.1000141
  23. 23. Wang W, Yan YK, Hor TSA, Vittal JJ, Wheaton JR, Hall IH. Synthesis, X-ray structures, and cytotoxicity of rhenium[I] carbonyl 2-[dimethylamino]ethoxide complexes. Polyhedron 2002;21:1991-1999. DOI: 10.1016/s0277-5387[02]01045-8
  24. 24. Yan YK, Cho SE, Shaffer KA, Rowell JE, Barnes BJ, Hall IH. Cytotoxicity of rhenium[I] alkoxo and hydroxo carbonyl complexes in murine and human tumor cells. Pharmazie 2000;55:307-313. DOI:10.1007/s11010-014-2201-5
  25. 25. Melaiye A, Sun Z, Hindi, K, Milsted A, Ely D, Reneker DH, Tessier CA, Youngs WJ. Silver[I]-imidazole cyclophane gem-diol complexes encapsulated by electrospun tecophilic nanofibers: Formation of nanosilver particles and antimicrobial activity. Journal of the American Chemical Society. 2005;127:2285-2291. DOI:10.1021/ja040226s
  26. 26. Kascatan-Nebioglu A, Melaiye A, Hindi, K, Durmus S, Panzner MJ, Hogue LA, Mallett RJ, Hovis CE, Coughenour M, Crosby SD, Milsted A, Ely DL, Tessier CA, Cannon CL, Youngs WJ. Synthesis from caffeine of a mixed N-heterocyclic carbene-silver acetate complex active against resistant respiratory pathogens. Journal of Medicinal Chemistry. 2006;49:6811-6818. DOI:10.1021/jm060711t
  27. 27. Reddy VD, Dayal D, Cosenza SC, Reddy MVR, Pearl WC Jr, Adams RD. Glycal-ruthenium carbonyl clusters: syntheses, characterization, and anticancer activity. Journal of Organometallics Chemistry. 2009;694:959-967. DOI:10.1016/j.jorganchem.2008.11.025
  28. 28. Niesel J, Pinto A, N’Dongo HWP, Merz K, Ott I, Gust R, Schatzschneider U. Photoinduced CO release, cellular uptake and cytotoxicity of a tris[pyrazolyl] methane manganese tricarbonyl complex. Chemical Communications. 2008;15:1798-1800. DOI: 10.1039/B719075A
  29. 29. Buriez O, Heldt JM, Labbé E, Vessières A, Jaouen G, Amatore C. Reactivity and antiproliferative activity of ferrocenyl-tamoxifen adducts with cyclodextrins against hormone-independent breast-cancer cell lines. Chemistry. 2008;14(27):8195-203. DOI: 10.1002/chem.200800507
  30. 30. Patra M, Gasser G, Pinto A, Merz K, Ott I, Bandow JE, Metzler-Nolte N. Synthesis and biological evaluation of chromium bioorganometallics based on the antibiotic Platensimycin lead structure. ChemMedChem. 2009;4:1930-1938. DOI: 10.1002/cmdc.200900347
  31. 31. Patra M, Gasser G, Wenzel M, Merz K, Bandow JE, Metzler-Nolte N. Synthesis and biological evaluation of ferrocene-containing bioorganometallics inspired by the antibiotic Platensimycin lead structure. Organometallics. 2010;29:4312-4319. DOI: 10.1021/om100614c
  32. 32. Patra M, Gasser G, Wenzel M, Merz K, Bandow JE, Metzler-Nolte N. Sandwich and half-sandwich derivatives of Platensimycin: Synthesis and biological evaluation, Organometallics. 2012;31(16):5760-5771. DOI: dx.doi.org/10.1021/om201146c
  33. 33. Bassetti S, Hu J, Agostino Jr. RB, Sherertz RJ. Prolonged antimicrobial activity of catheter containing chlorhexidine silver sulfadiazine extends protection against catheter infection in vivo. Antimicrobial Agents and Chemotherapy. 2001;45(5):1535. DOI:10.1128/AAC.45.5.1535-1538.2001
  34. 34. Clarke MJ. Ruthenium metallopharmaceuticals. Coordination Chemistry. 2003;236:299-233. DOI: 10.1186/s12951-015-0129-x
  35. 35. Rafique S, Idrees M, Nasim A, Akbar H, and Athar A. Transition metal complexes as potential therapeutic agents. Biotechnology and Molecular Biology Reviews. 2010;5(2):38-45. DOI: http://www.academicjournals.org /BMBR
  36. 36. Singh RV, Chaudhary A. Biologically relevant tetra azamacrocyclic complexes of manganese. Spectral, antimicrobial, antifertility, and anti-inflammatory approach. Journal of Inorganic Biochemistry. 2004;98(11):1712-1721. DOI: 10.1016/j.jinorgbio.2004.07.007
  37. 37. Kemp MM, Kumar A, Mousa S, Dyskin E, Yalcin M, Ajayan P, Linhardt RJ, Mousa SA. Gold and silver nanoparticles conjugated with heparin derivative possess anti-angiogenesis properties. Nanotechnology. 2009;20(45):455104. DOI:10.1088/0957-4484/20/45/455104
  38. 38. Nash P, Clegg DO. Proriatic arthritis therapy: NSAID and traditional DMARDS. Annals of the Rheumatic Diseases. 2005;64:74-77. DOI: 10.1136/ard.2004.030783
  39. 39. Pedersen MO, Larsen A, Pedersen DS, Stoltenberg M, Penkova M. Metallic gold treatment reduces proliferation of inflammatory cells, increases expression of VEGF and FGF, and stimulates cell proliferation in the subventricular zone following experimental traumatic brain injury. Histology Histopathology. 2009;5:573-586. DOI:10.14670/HH-24.573
  40. 40. Mosi R, Seguin B, Cameron B, Amankawa L. Mechanistic studies on AMD6221: A ruthenium based nitric oxide scavenger. Biochemical and Biophysical Research Communications. 2009;292:519-529. DOI: 10.1006/bbrc.2002.6685
  41. 41. Spasojevic I, Batinic-Harberle I, Reboculus. Electrostatic contribution in the catalysis of O2- dismutation by superoxide dismutase mimics. Journal of Medicinal Chemistry. 2003;278:6831-6837. DOI:10.1074/jbc.M211346200
  42. 42. Bagonza J, Rutebemberwa E, Bazeyo W. Adherence to anti diabetic medication among patients with diabetes in eastern Uganda; a cross sectional study. BMC Health Services Research. 2015;15:168-175. DOI: 10.1186/s12913-015-0820-5
  43. 43. Balk EM, Tatsioni A, Lichtenstein AH, Lau J, Pittas AG. Effect of chromium supplementation on glucose metabolism and lipids. A systematic review of randomized controlled trials. Diabetes Care. 2007;30(8):2154-2163. DOI: https://doi.org/10.2337/dc06-0996
  44. 44. Mehdi MZ, Pandey SK, Theberge JF, Srivastava AK. Insulin signal mimicry as a mechanism for the insulin-like effects of vanadium. Cell Biochemical and Biophysics. 2006;44(1):73-81. DOI: 10.1385/CBB:44:1:073
  45. 45. Sun Q, van Dam RM, Willett WC, Hu FB. Prospective study of zinc intake and risk of type 2 diabetes in women. Diabetes Care. 2009;32(4):629-634. DOI: 10.2337/dc08-1913
  46. 46. Renfrew AK, Phillips AD, Tapavicza E, Scopelliti R, Rothlisberger U, Dyson PJ. Tuning the efficacy of ruthenium-[II]-Arene [RAPTA] antitumor compounds with fluorinated arene ligands. Organometallics 2009;28:5061-5071. DOI:10.1021/om900345n
  47. 47. Leonidova A. Gasser G. The underestimated potential of organometallic rhenium complexes as anticancer agents. Biology. 2014;9(10):2180-2193. DOI: 10.1021/cb500528c
  48. 48. Ali Nazif M, Bangert JA, Ott I, Gust R, Stoll R, Sheldrick WS. Dinuclear organoiridium [III] mono- and bis-intercalators with rigid bridging ligands: synthesis, cytotoxicity and DNA binding. Journal of Inorganic Biochemistry. 2009;103(10):1405-1414. DOI: 10.1016/j.jinorgbio.2009.08.003
  49. 49. Kostrhunova H, Florian J, Novakova O, Peacock AFA, Sadler PJ, Brabec V. DNA interactions of monofunctional organometallic osmium[II] antitumor complexes in cell-freemedia. Journal of Medicinal Chemistry. 2008;51:3635-3643. DOI:10.1021/jm701538w
  50. 50. Van Rijt, SH, Peacock AFA, Johnstone RDL, Parsons S, Sadler PJ. Organometallic osmium[II] arene anticancer complexes containing picolinate derivatives. Inorganic Chemistry. 2009; 48:1753-1762. DOI:10.1021/ic8020222
  51. 51. Schmid WF, John RO, Arion VB, Jakupec MA, Keppler BK. Highly antiproliferative ruthenium[II] and osmium[II] arene complexes with paullone-derived ligands. Organometallics. 2007;26:6643-6652. DOI:10.1039/c5dt02410b
  52. 52. Dorcier A, Dyson PJ, Gossens C, Rothlisberger U, Scopelliti R, Tavernelli I. Binding of organometallic ruthenium[II] and osmium[II] complexes to an oligonucleotide: A combined mass spectrometric and theoretical study. Organometallics. 2005;24:2114-2123. DOI:10.1002/ejic.201100250
  53. 53. Osella D, Mahboobi H, Colangelo D, Cavigiolio G, Vessieres A, Jaouen G. FACS analysis of oxidative stress induced on tumour cells by SERMs. Inorganica Chimica Acta. 2005;358:1993-1998. DOI: http://dx.doi.org/10.1016/j.ica.2004.11.027
  54. 54. Arezki A, Brule E, Jaouen G. Synthesis of the first ferrocenyl derivatives of curcuminoids. Organometallics. 2009;28:1606-1609. DOI:10.1039/c0md00231c
  55. 55. Top S, Thibaudeau C, Vessieres A, Brule E, Le Bideau F, Joerger JM, Plamont MA. Samreth S, Edgar A, Marrot J, Herson P, Jaouen G. Synthesis and structure activity relationship of organometallic steroidal androgen derivatives. Organometallics. 2009;28:1414-1424. DOI:10.1021/om800698y
  56. 56. Payen O, Top S, Vessieres A, Brule E, Plamont MA, McGlinchey M J, Mueller-Bunz H, Jaouen G. Synthesis and structure-activity relationships of the first ferrocenyl-aryl-hydantoin derivatives of the nonsteroidal antiandrogen nilutamide. Journal of Medicinal Chemistry. 2008;51:1791-1799. DOI:10.1021/jm701264d
  57. 57. Spencer J, Mendham AP, Kotha AK, Richardson SCW, Hillard EA, Jaouen G, Male L, Hursthouse MB. Structural and biological investigation of ferrocene-substituted 3-methylidene-1,3-dihydro-2H-indol-2-ones. Dalton Transactions. 2009;6:918-921. DOI: 10.1039/B816249B
  58. 58. Plazuk D, Vessieres A, Hillard EA, Buriez O, Labbe E, Pigeon P, Plamont MA, Amatore C, Zakrzewski J, Jaouen GA. [3]Ferrocenophane polyphenol showing a remarkable antiproliferative activity on breast and prostate cancer cell lines. Journal of Medicinal Chemistry. 2009;52:4964-4967. DOI:10.1021/jm900297x
  59. 59. Raubenheimer HG, Cronje S. Carbene complexes of gold: Preparation, medical application and bonding. Chemical Society Reviews. 2008;37:1998-2011. DOI:10.1039/b708636a
  60. 60. Jones GB, Mathews JE. Tricarbonyl arene chromium[0] based antitumor agents. Bioorganic Medical Chemistry Letters. 1995;5:93-96. DOI:10.1016/j.ejphar.2010.01.011
  61. 61. Neundorf I, Hoyer J, Splith K, Rennert R, N’Dongo HWP, Schatzschneider U. Cymantrene conjugation modulates the intracellular distribution and induces high cytotoxicity of a cell-penetrating peptide. Chemical Communications. 2008;21:5604-5606. DOI: 10.1021/jm100020w
  62. 62. Murthy N, Rao AR, Sastry GN. Aromatase inhibitors: A new paradigm in breast cancer treatment. Current Medicinal Chemistry. Anti-Cancer Agents. 2004;4:523-534. DOI: 10.1007/s00044-011-9688-z
  63. 63. Srinivas E, Murthy JN, Ram Rao AR, Sastry GN. Recent advances in molecular modeling and medicinal chemistry aspects of phospho-glycoprotein. Current Drug Metabolism. 2006;7:205-217. DOI:10.2174/138920006775541534
  64. 64. Kulkarrni RG, Achaiah G, Sastry GN. Novel targets for anti-inflammatory and antiarthritic agents. Current Pharmaceutical Design. 2006;12(19):2437-2454. PMID:16842190
  65. 65. Kamal A, Naseer M, Khan A, Reddy KS, Rohini K, Sastry GN, Sateesh B, Sridhar B. Synthesis, structure analysis, and antibacterial activity of some novel 10-substituted 2-(4-piperidyl/phenyl)-5,5-dioxo[1, 2, 4] triazolo[1, 5-b][1, 2, 4] benzothiadiazine derivatives. Bioorganic & Medicinal Chemistry Letters. 2007;17:5400-5405. DOI: 10.1016/j.bmcl.2007.07.043
  66. 66. Kamal A, Rajender, Reddy DR, Reddy MK, Balakishan G, Shaik TB, Chourasia M, Sastry GN. Remarkable enhancement in the DNA-binding ability of C2-fluoro substituted pyrrolo[2, 1-c][1, 4]benzodiazepines and their anticancer potential. Bioorganic & Medicinal Chemistry. 2009;17:1557-1572. DOI:10.1016/j.bmc.2008.12.068
  67. 67. Kamal A, Bharathi EV, Ramaiah MJ, Dastagiri D, Surendranadha Reddy J, Viswanath, A, Sultana F, Pushpavalli SNCVL, Bhadra MP, Srivastava HK, Sastry GN, Juvekar A, Sen S, Zingde S. Quinazolinone linked pyrrolo[2, 1-c] [1, 4] benzodiazepine (PBD) conjugates: Design, synthesis and biological evaluation as potential anticancer agents. Bioorganic & Medicinal Chemistry. 2010;18:526-542. DOI:10.1002/jcc.21277
  68. 68. Kamal A, Shetti RVCRNC, Ramaiah MJ, Swapna P, Reddy KS, Mallareddy A, Narasimha Rao MP, Chourasia M, Sastry GN, Juvekar A, Zingde S, Sarma P, Pushpavallib SNCVL, Bhadra MP. Carbazole–pyrrolo[2, 1-c][1, 4]benzodiazepine conjugates: design, synthesis, and biological evaluation. Medicinal Chemistry Communications. 2011;2:780-788. DOI: 10.1039/C1MD00072A
  69. 69. Bohari MH, Srivastava HK, Sastry GN. Analogue-based approaches in anti-cancer compound modelling: The relevance of QSAR models, Bohari et al. Organic and Medicinal Chemistry Letters. 2011;1:1-12. DOI: 10.1186/2191-2858-1-3
  70. 70. Sreshty AS, Surolia A, Sastry GN, Suryanarayana Murty U. Deorphanization of Malonyl CoA:ACP transacylase drug target in plasmodium falciparum (PfFabD) using bacterial antagonists: A ‘Piggyback’ approach for antimalarial drug discovery. Molecular Informatics. 2012;31: 281-299. DOI: 10.1002/minf.201100051
  71. 71. Venkatesh R, Ramaiah MJ, Gaikwad HK, Janardhan S, Bantu RS, Nagarapu L, Sastry GN, Ganesh AR, Bhadra MP. Luotonin-A based quinazolinones cause apoptosis and senescence via HDAC inhibition and activation of tumor suppressor proteins in HeLa Cells. European Journal of Medicinal Chemistry. 2015;94:87-101. DOI: http://dx.doi.org/10.1016/j.ejmech.2015.02.057
  72. 72. Ponti E, Sabbioni B. Munaro et al. Genotoxicity and morphological transformation induced by cobalt nanoparticles and cobalt chloride: An in vitro study in Balb/3T3 mouse fibroblasts. Mutagenesis. 2009;24:439-445. DOI: 10.1093/mutage/gep027
  73. 73. Dey S, Bakthavatchalu V, Tseng MT et al. Interactions between SIRT1 and AP-1 reveal a mechanistic insight into the growth promoting properties of alumina [Al2O3] nanoparticles in mouse skin epithelial cells. Carcinogenesis. 2008;29(10):1920-1929. DOI: 10.1093/carcin/bgn175
  74. 74. Sangiliyandi G, Han JW, Eppakayala V, Jeyaraj M, Kim JH. Cytotoxicity of biologically synthesized silver nanoparticles in MDA-MB-231 Human Breast Cancer Cells BioMed Research International Volume 2013;1-10. DOI:10.1155/2013/535796
  75. 75. Simon M, Barberet P, Delville MH, Moretto P, and Seznec H. Titanium dioxide nanoparticles induced intracellular calcium homeostasis modification in primary human keratinocytes. Towards an in vitro explanation of titanium dioxide nanoparticles toxicity. Nanotoxicology. 2011;5(2):125-139. DOI:10.3109/17435390.2010.502979
  76. 76. Blasiak B, Frank CJM van Veggel, Tomanek B. Applications of nanoparticles for MRI cancer diagnosis and therapy. Journal of Nanomaterials. 2013;2013:1-12. DOI: http://dx.doi.org/10.1155/2013/148578
  77. 77. Meyer MHF, Stehr M, Bhuju S et al. Magnetic biosensor for the detection of Yersinia pestis. Journal of Microbiological Methods. 2007;68(2):218-224. DOI: http://dx.doi.org/10.1155/2013/148578
  78. 78. Kirsch JE. Basic principles of magnetic resonance contrast agents. Topics in Magnetic Resonance Imaging. 1991;3(2):1-18. DOI:10.1155/2013/148578
  79. 79. Cai W, Gao T, Hong H, Sun J. Applications of gold nano-particles in cancer. Nanotechnology, Science and Applications. 2008;1:17-32. DOI: https://doi.org/10.2147/NSA.S3788
  80. 80. Duguet E, Vasseur S, Mornet S, Devoisselle JM. Magnetic nanoparticles and their applications in medicine. Nanomedicine. 2006;1(2):157-168. DOI:10.2217/17435889.1.2.157
  81. 81. Elblbesy M. Hemocompatibility of albumin nanoparticles as a drug delivery system—An in vitro study. Journal of Biomaterials and Nanobiotechnology. 2016;7:64-71. DOI:10.4236/jbnb.2016.72008
  82. 82. Fahmy TM, Fong PM, Goyal A, Saltzman WM. Targeted for drug delivery. Materials Today. 2005;8(8):18-26. DOI: http://dx.doi.org/10.1016/S1369-7021[05]71033-6
  83. 83. Fahmy TM, Samstein RM, Harness CC, Saltz-man WM. Surface modification of biodegradable polyesters with fatty acid conjugates for improved drug targeting. Biomaterials. 2005;26(28):5727-5736. DOI:10.1016/j.biomaterials.2005.02.025
  84. 84. Couvreur P, Barratt G, Fattal E, Legrand P, Vauthier C. Nanocapsule technology: A review. Critical Reviews in Therapeutic Drug Carrier Systems. 2002;19(2):99-134. DOI: 10.5681/apb.2012.007
  85. 85. Roger J, Pons JN, Massart R, Halbreich A, Bacri JC. Some biomedical applications of ferrofluids. The European Physical Journal Applied Physics. 1999;5(3):321-325. DOI: http://dx.doi.org/10.1155/2013/148578
  86. 86. Alexis F, Rhee JW, Richie JP, Radovic-Moreno AF, Langer R, Farokhzad OC. New frontiers in nanotechnology for cancer treatment. Urologic Oncology. 2008;26(1):74-85. DOI:http://doi.org/10.1016/j.urolonc.2007.03.017
  87. 87. Zhang L, Gu FX, Chan JM, Wang AZ, Langer RS, Farokhzad OC. Nanoparticles in medicine: Therapeutic applications and developments. Clinical Pharmacology and Therapeutics. 2008;83(5):761-769. DOI:10.1038/sj.clpt.6100400
  88. 88. Phanapavudhikul P, Shen S, Ng WK, Tan RBH. Formulation of Fe3O4/acrylate co-polymer nanocomposites as potential drug carriers. Drug Delivery. 2008;15(3):177-183. DOI: http://dx.doi.org/10.1080/10717540801952597
  89. 89. Arap W, Pasqualini R, Ruoslahti E. Cancer treatment by targeted drug delivery to tumor vasculature in a mouse model. Science. 1998;279(5349):377-380. DOI: 10.1126/science.279.5349.377
  90. 90. Dagar S, Sekosan M, Lee BS, Rubinstein I, Ony H. VIP receptors as molecular targets of breast cancer: Implications for targeted imaging and drug delivery. Journal of Controlled Release. 2001;74(1-3):129-134. DOI:10.1016/S0168-3659[01]00326-1
  91. 91. Sousa F, Mandal S, Garrovo C et al. Functionalized gold nanoparticles: A detailed in vivo multimodal microscopic brain distribution study. Nanoscale. 2010;2(12):2826-2834. DOI: http://dx.doi.org/10.1039/c0nr00345j
  92. 92. Wen PY, Kesari S. Malignant gliomas in adults. New England Journal of Medicine. 2008;359(5):492-507. DOI:10.1056/NEJMra0708126
  93. 93. Ullrich NJ, Pomeroy SL. Pediatric brain tumors. Neurologic Clinics. 2003;21(4):897-913. DOI:10.1016/S0733-8619(03)00014-8
  94. 94. Herńandez-Pedro NY, Rangel-López E, Magãna-Maldonado R et al. Application of nanoparticles on diagnosis and therapy in gliomas. BioMed Research International. 2013;2013:1-20. DOI: http://dx.doi.org/10.1155/2013/351031
  95. 95. Park JY, Baek MJ, Choi ES et al. Paramagnetic ultrasmall gadolinium oxide nanoparticles as advanced T1 MRI contrast agent: Account for large longitudinal relaxivity, DOI:10.1021/nn900761s
  96. 96. Lefebure S, Dubois E, Cabuil V, Neveu S, Massart R. Monodisperse magnetic nanoparticles: Preparation and dispersion in water and oils. Journal of Materials Research. 1998;13(10):2975-2981. DOI:10.1557/JMR.1998.0407
  97. 97. Mejías R, Pèrez-Yagüe S, Roca AG et al. Liver and brain imaging through dimercaptosuccinic acid-coated iron oxide nanoparticles. Nanomedicine. 2010;5(3):397-408. DOI:10.2217/nnm.10.15
  98. 98. Siegal T, Horowitz A, Gabizon A. Doxorubicin encapsulated in sterically stabilized liposomes for the treatment of a brain tumor model: Biodistribution and therapeutic efficacy. Journal of Neurosurgery. 1995;83(6):1029-1037. DOI:10.3171/jns.1995.83
  99. 99. Kircher MF, de la Zerda A, Jokerst JV et al. A brain tumor molecular imaging strategy using a new triple-modality MRI-photoacoustic-Raman nanoparticle. Nature Medicine. 2012;18(5):829-834. DOI:10.1038/nm.2721
  100. 100. Khlebtsov N, Dykman L. Biodistribution and toxicity of engineered gold nanoparticles: A review of in vitro and in vivo studies. Chemical Society Reviews. 2011;40(3):1647-1671. DOI:10.1038/nm.2721
  101. 101. De Jong WH, Hagens WI, Krystek P, Burger MC, Sips AJAM, Geertsma RE. Particle size-dependent organ distribution of gold nanoparticles after intravenous administration. Biomaterials. 2008;29(12):1912-1919. DOI: 10.1016/j.biomaterials.2007.12.037
  102. 102. Sonavane G, Tomoda K, and Makino K. Biodistribution of colloidal gold nanoparticles after intravenous administration: Effect of particle size. Colloids and Surfaces B. 2008;66(2):274-280. DOI: 10.1016/j.colsurfb.2008.07.004
  103. 103. Xia H, Li F, Hu X, Park W, Wang S, Jang Y, Du Y, Baik S, Cho S, Kang T, Kim DH, Ling D, Hui KM, Hyeon T. pH-Sensitive Pt nanocluster assembly overcomes cisplatin resistance and heterogeneous stemness of hepatocellular carcinoma. ACS Central Science. 2016;2:802−811. DOI: 10.1021/acscentsci.6b00197
  104. 104. Bardhan R, Lal S, Joshi A, Halas N. Theranostic nanoshells: From probe design to imaging and treatment of cancer. Journal of Accounts of Chemical Research. 2011;44:936−946. DOI: 10.1021/ar200023x
  105. 105. Scrase TG, O Neill MJ, Peel AJ, Senior PW, Matthews PW, Shi H, Boss SR, Barker PD. Selective lability of Ruthenium(II) arene amino acid complexes. Inorganic Chemistry. 2015;54:3118−3124. DOI: 10.1021/ic502051y
  106. 106. Clavel CM, Paunescu E, Nowak-Sliwinska P, Griffioen AW, Scopelliti R, Dyson PJ. Discovery of a highly tumor-selective organometallic ruthenium [II]–arene complex. Journal of Medicinal Chemistry. 2014;57:3546−3558. DOI:10.1021/jm5002748
  107. 107. Allardyce CS, Dyson PJ, Ellis DJ, Heath SL. Ligand substitutions between ruthenium–cymene compounds can control protein versus DNA targeting and anticancer activity. Chemical Communications. 2001;1396−1397. DOI:10.1039/b705449a
  108. 108. Ang WH, Daldini E, Juillerat-Jeanneret L, Dyson PJ. Strategy to tether organometallic ruthenium-arene anticancer compounds to recombinant human serum albumin. Inorganic Chemistry. 2007;46:9048−9050. DOI:10.1021/ic701474m
  109. 109. Sun RW, Li CK, Ma DL, Yan JJ, Lok CN, Leung CH, Zhu N, Che CM. Stable anticancer gold[III]-porphyrin complexes: Effects of porphyrin structure. Chemistry. 2010;16[10]:3097-3113. DOI: 10.1002/chem.200902741
  110. 110. Garcia JV et al. NIR-triggered release of caged nitric oxide using upconverting nanostructured materials. Small. 2011;8:3800-3805. DOI:10.1002/smll.201201213
  111. 111. Aboshyan-Sorgho L, Besnard C, Pattison P, Kittilstved KR, Aebischer A, Bünzli J-CG, Hauser A, Piguet C. Near-infrared → visible light upconversion in a molecular trinuclear d–f–d complex. Angewandte Chemie International Edition. 2011;50:4108-4112. DOI:10.1002/anie.201100095
  112. 112. Wecksler SR, Mikhailovsky A, Korystov D, Buller F, Kannan R, Tan L-S, Ford PC. Single- and two-photon properties of a dye-derivatized Roussin’s red salt ester [Fe2[μ-RS]2[NO]4] with a large TPA cross section. Inorganic Chemistry. 2007;46:395-402. DOI:10.1021/ic0607336
  113. 113. Schatzschneider U. PhotoCORMs: Light-triggered release of carbon monoxide from the coordination sphere of transition metal complexes for biological applications. Inorganic Chemistry Acta. 2011;374:19-23. DOI:10.1016/j.ica.2011.02.068
  114. 114. Gonzalez MA, Yim MA, Cheng S, Moyes A, Hobbs AJ, Mascharak PK. Manganese carbonyls bearing tripodal polypyridine ligands as photoactive carbon monoxide-releasing molecules. Inorganic Chemistry. 2011;51:601-608. DOI:10.1021/ic2021287
  115. 115. Pfeiffer H, Rojas A, Niesel J, Schatzschneider U. Sonogashira and ‘Click’ reactions for the N-terminal and side-chain functionalization of peptides with [Mn[CO]3[tpm]]+-based CO releasing molecules [tpm = tris[pyrazolyl]methane]. Dalton Transactions. 2009;22:4292-4298. DOI:10.1039/b819091g
  116. 116. Huber W, Linder R, Niesel J, Schatzschneider U, Spingler B, Kunz PC. A comparative study of tricarbonylmanganese photoactivatable CO releasing molecules [PhotoCORMs] by using the myoglobin assay and time-resolved IR spectroscopy. European Journal of Inorganic Chemistry. 2012;19:3140-3146. DOI:10.1002/ejic.201200115
  117. 117. Zeglis BM, Pierre VC, Barton JK. 2007 Metallo-intercalators and metallo-insertors. Chemical Communications. 2007;44:4565-4579. DOI:10.1039/b710949k
  118. 118. Zeglis BM, Barton JK. DNA base mismatch detection with bulky rhodium intercalators: Synthesis and applications. Nature Protocols. 2007;2:357-371. DOI:10.1038/nprot.2007.22
  119. 119. Wai-Yin Sun R, Lok-Fung Chow A, Li XH, Yan JJ, Sin-Yin Chui S, Che C-M. Luminescent cyclometalated platinum[II] complexes containing N-heterocyclic carbene ligands with potent in vitro and in vivo anti-cancer properties accumulate in cytoplasmic structures of cancer cells. Chemical Science. 2011;2:728-736. DOI:10.1039/c0sc00593b

Written By

Ruby Srivastava

Submitted: 07 October 2016 Reviewed: 08 February 2017 Published: 05 July 2017