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Calcium phosphates (CaPs) in the form of hydroxyapatite (HA) have been extensively studied in the context of bone regeneration due to their chemical similarity to natural bone mineral. While HA is known to promote osteogenic differentiation, the structural properties of the ceramic have been shown to affect the extent of this effect; several studies have suggested that nanostructured HA can improve the bioactivity. However, the role shape plays in the osteogenic potential is more elusive. Here we studied the effect of HA nanoparticle shape on the ability to induce osteogenesis in human mesenchymal stromal cells (hMSCs) by developing nanoparticle films using needle-, rice- and spherical-shaped HA. We showed that the HA films made from all three shapes of nanoparticles induced increased levels of osteogenic markers (i.e. runt-related transcription factor 2 (RUNX2), bone morphogenetic protein 2 (BMP2), alkaline phosphatase (ALP), osteopontin (OPN), osteocalcin (OCN) on protein and gene level in comparison to hMSCs cultured on cover glass slides. Furthermore, their expression levels and profiles differed significantly as a function of nanoparticle shape. We also showed that nanoparticle films were more efficient in inducing osteogenic gene expression in hMSCs compared to adding nanoparticles to hMSCs in culture media. Finally, we demonstrated that hMSC morphology upon adhesion to the HA nanoparticle films is dependent on nanoparticle shape, with hMSCs exhibiting a more spread morphology on needle-shaped nanoparticle films compared to hMSCs seeded on rice- and spherical-shaped nanoparticle films. Our data suggests that HA nanoparticle films are efficient in inducing hMSC osteogenesis in basic cell culture conditions and that nanoparticle shape plays a vital role in cell adhesion and morphology and extent of induction of osteogenic differentiation.

Encephalopathy of prematurity (EoP) is a common cause of long‐term neurodevelopmental morbidity in extreme preterm infants. Diffuse white matter injury (dWMI) is currently the most commonly observed form of EoP. Impaired maturation of oligodendrocytes (OLs) is the main underlying pathophysiological mechanism. No therapies are currently available to combat dWMI. Intranasal application of mesenchymal stem cells (MSCs) is a promising therapeutic option to boost neuroregeneration after injury. Here, we developed a double‐hit dWMI mouse model and investigated the therapeutic potential of intranasal MSC therapy. Postnatal systemic inflammation and hypoxia‐ischemia led to transient deficits in cortical myelination and OL maturation, functional deficits and neuroinflammation. Intranasal MSCs migrated dispersedly into the injured brain and potently improved myelination and functional outcome, dampened cerebral inflammationand rescued OL maturation after dWMI. Cocultures of MSCs with primary microglia or OLs show that MSCs secrete factors that directly promote OL maturation and dampen neuroinflammation. We show that MSCs adapt their secretome after ex vivo exposure to dWMI milieu and identified several factors including IGF1, EGF, LIF, and IL11 that potently boost OL maturation. Additionally, we showed that MSC‐treated dWMI brains express different levels of these beneficial secreted factors. In conclusion, the combination of postnatal systemic inflammation and hypoxia‐ischemia leads to a pattern of developmental brain abnormalities that mimics the clinical situation. Intranasal delivery of MSCs, that secrete several beneficial factors in situ, is a promising strategy to restore myelination after dWMI and subsequently improve the neurodevelopmental outcome of extreme preterm infants in the future., Main Points Intranasal MSC therapy potently restores myelination after encephalopathy of prematurity.MSCs modify their secretome in situ to support OL maturation by upregulating valuable, beneficial growth factors and/or anti‐inflammatory cytokines.

Ceramic (nano)materials are promising materials for bone regeneration applications. The addition of bioinorganics such as strontium and zinc is a popular approach to further improve their biological performance. However, control over ion delivery is important to prevent off-target effects. Mesoporous silica nanoparticles (MSNs) are popular nanomaterials that can be designed to incorporate and controllably deliver multiple ions to steer specific regenerative processes. In this work, we developed MSNs loaded with strontium (MSNSr ) and surface coated with a pH sensitive calcium phosphate (MSNSr -CaP) or calcium phosphate zinc layer (MSNSr -CaZnP). The ability of the MSNs to promote osteogenesis in hMSCs under basic cell culture conditions was explored and compared to ion administration directly to the cell culture media. Here we show that MSN-CaPs can effectively induce ALP levels and osteogenic gene expression in the absence of other osteogenic stimulants, where an improved effect was observed for MSNs surface coated with multiple ions. Moreover, comparatively lower ion doses were needed when using MSNs as delivery vehicles compared to direct ion administration in the medium, likely due to their different uptake mechanisms. In summary, the MSNs developed here represent promising vehicles to deliver (multiple) bioinorganics and promote hMSC osteogenesis in basic conditions. This article is protected by copyright. All rights reserved.

The development of smart interfaces that can guide tissue formation is of great importance in the field of regenerative medicine. Nanoparticles represent an interesting class of materials that can be used to enhance regenerative treatments by enabling close control over surface properties and directing cellular responses. Moreover, nanoparticles can be used to provide temporally controlled delivery of (multiple) biochemical compounds. Here, we exploited the cargo loading and surface functionalization properties of mesoporous silica nanoparticles (MSNs) to design films that can guide human mesenchymal stem cell (hMSC) differentiation towards the osteogenic lineage. We developed biocompatible MSN-based films that support stem cell adhesion and proliferation and demonstrated that these MSN films simultaneously allowed efficient local delivery of biomolecules without effecting film integrity. Films loaded with the osteogenesis-stimulating drug dexamethasone (Dex) were able to induce osteogenic differentiation of hMSCs in vitro. Dex delivery from the films led to increased alkaline phosphatase levels and matrix mineralization compared to directly supplementing Dex to the medium. Furthermore, we demonstrated that Dex release kinetics can be modulated using surface modifications with supported lipid bilayers. Together, these data demonstrate that MSN films represent an interesting approach to create biomaterial interfaces with controllable biomolecule release and surface properties to improve the bioactivity of biomaterials.Statement of significanceEngineering surfaces that can control cell and tissue responses is one of the major challenges in biomaterials-based regenerative therapies. Here, we demonstrate the potential of mesoporous silica nanoparticles (MSNs) as drug-delivering surface coatings. First, we show differentiation of mesenchymal stem cells towards the bone lineage when in contact with MSN films loaded with dexamethasone. Furthermore, we demonstrate that modification of MSNs with supported lipid bilayer allows control over drug release dynamics and cell shape. Given the range of loadable cargos and the tunability of release kinetics, MSN coatings can be used to mimic the sequential appearance of bioactive factors during tissue regeneration, which will ultimately lead to biomaterials with improved bioactivity. (C) 2019 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.

Stem cells have great potential in the field of tissue engineering and regenerative medicine due to their inherent regenerative capabilities. However, an ongoing challenge within their clinical translation is to elicit or predict the desired stem cell behavior once transplanted. Stem cell behavior and function are regulated by their interaction with biophysical and biochemical signals present in their natural environment (i.e., stem cell niches). To increase our understanding about the interplay between stem cells and their resident microenvironments, biointerfaces have been developed as tools to study how these substrates can affect stem cell behaviors. This article aims to review recent developments on fabricating cell-instructive interfaces to control cell adhesion processes towards directing stem cell behavior. After an introduction on stem cells and their natural environment, static surfaces exhibiting predefined biochemical signals to probe the effect of chemical features on stem cell behaviors are discussed. In the third section, we discuss more complex dynamic platforms able to display biochemical cues with spatiotemporal control using on-off ligand display, reversible ligand display, and ligand mobility. In the last part of the review, we provide the reader with an outlook on future designs of biointerfaces. Statement of significance Stem cells have great potential as treatments for many degenerative disorders prevalent in our aging societies. However, an ongoing challenge within their clinical translation is to promote stem cell mediated regeneration once they are transplanted in the body. Stem cells reside within our bodies where their behavior and function are regulated by interactions with their natural environment called the stem cell niche. To increase our understanding about the interplay between stem cells and their niche, 2D materials have been developed as tools to study how specific signals can affect stem cell behaviors. This article aims to review recent developments on fabricating cell-instructive interfaces to control cell adhesion processes towards directing stem cell behavior. (c) 2021 The Author(s). Published by Elsevier Ltd on behalf of Acta Materialia Inc. This is an open access article under the CC BY-NC-ND license ( http://creativecommons.org/licenses/by-nc-nd/4.0/ )

Inorganic nanoparticles have unique physical properties and, in addition, are highly modifiable, making them versatile platforms for a range of medical applications including in diagnostics and cancer therapy. Within regenerative medicine, inorganic nanoparticles have been utilized, among others, as constituents within biomaterials. This is a rapidly evolving field where their large diversity in terms of content, shape, modifications, and morphology allows the development of new generations of biomaterials with changeable features at the nanoscale. In this chapter inorganic nanoparticles (including metallic and ceramic nanoparticles) and their uses in regenerative medicine are shortly introduced followed by a description of the use of inorganic nanoparticles to trace stem cells, and to create new types of materials, ranging from nanocoatings to organic-inorganic hybrid nanomaterials. Their potential bioactivity, as well as other valuable features for their use in tissue repair therapies is discussed.

Roger Rosenbrand,1 David Barata,1 Pichaporn Sutthavas,1 Ronny Mohren,2 Berta Cillero-Pastor,2 Pamela Habibovic,1 Sabine van Rijt1 1Department of Instructive Biomaterials Engineering, MERLN Institute for Technology-Inspired Regenerative Medicine, Maastricht University, 6229 ER MD, Maastricht, the Netherlands; 2Maastricht Multimodal Molecular Imaging Institute (M4I), Division of Imaging Mass Spectrometry, Maastricht University, 6229 ER Maastricht, the Netherlands Background: Nanoparticles have emerged as promising cell-labeling tools, as they can be precisely tailored in terms of chemical and physical properties. Mesoporous silica nanoparticles (MSNs), in particular, are easily tunable with regard to surface and core chemistry, and are able to confine dyes and drug molecules efficiently. Purpose: The aim of this study was to investigate the effect of lipid and polyethylene glycol (PEG) surface modifications on MSN stem-cell-tracking abilities. Methods: Lipid and PEG surface functionalized MSNs were synthesized and the effect of surface functionalization on cell internalization, proliferation, differentiation and cell proteomics was investigated in patient derived mesenchymal stem cells (MSCs). Results: MSNs and lipid surface-modified MSNs were internalized by >80% of the MSC population, with the exception of nanoparticles modified with short PEG chains (molecular weight 750 [MSN-PEG750]). Lipid-modified MSNs had higher labeling efficiency with maximum uptake after 2 hours of exposure and were in addition internalized 17 times higher compared to unmodified MSNs, without negatively affecting differentiation capacity. Using a mass-spectrometry-based label-free quantitative proteomics approach, we show that MSN labeling leads to the up- and downregulation of proteins that were unique for the different surface-modified MSNs. In addition, functional enrichments were found in human MSCs labeled with MSNs, MSN-PEG750, and lipid-modified MSNs. Summary: Here we show that organic modifications with lipids and PEGylation can be used as a promising strategy to improve MSN labeling capabilities. In particular, we show that lipid modifications can optimize such probes in three distinct ways: significantly improved signal strength, a barrier for sustained release of additional probes, and improved stem-cell-labeling efficiency. Keywords: mesoporous silica nanoparticles, cell tracking, mesenchymal stem cells, lipid surface modification

Microfluidics, the science of engineering fluid streams at the micrometer scale, offers unique tools for creating and controlling gradients of soluble compounds. Gradient generation can be used to recreate complex physiological microenvironments, but is also useful for screening purposes. For example, in a single experiment, adherent cells can be exposed to a range of concentrations of the compound of interest, enabling high-content analysis of cell behaviour and enhancing throughput. In this study, we present the development of a microfluidic screening platform where, by means of diffusion, gradients of soluble compounds can be generated and sustained. This platform enables the culture of adherent cells under shear stress-free conditions, and their exposure to a soluble compound in a concentration gradient-wise manner. The platform consists of five serial cell culture chambers, all coupled to two lateral fluid supply channels that are used for gradient generation through a source-sink mechanism. Furthermore, an additional inlet and outlet are used for cell seeding inside the chambers. Finite element modeling was used for the optimization of the design of the platform and for validation of the dynamics of gradient generation. Then, as a proof-of-concept, human osteosarcoma MG-63 cells were cultured inside the platform and exposed to a gradient of Cytochalasin D, an actin polymerization inhibitor. This set-up allowed us to analyze cell morphological changes over time, including cell area and eccentricity measurements, as a function of Cytochalasin D concentration by using fluorescence image-based cytometry. Electronic supplementary material The online version of this article (10.1007/s10544-017-0222-z) contains supplementary material, which is available to authorized users.

Nanoparticles allow for controlled and targeted drug delivery to diseased tissues and therefore bypass systemic side effects. Spatiotemporal control of drug release can be achieved by nanocarriers that respond to elevated levels of disease-specific enzymes. For example, matrix metalloproteinase 9 (MMP9) is overexpressed in tumors, is known to enhance the metastatic potency of malignant cells, and has been associated with poor prognosis of lung cancer. Here, we report the synthesis of mesoporous silica nanoparticles (MSNs) tightly capped by avidin molecules via MMP9 sequence-specific linkers to allow for site-selective drug delivery in high-expressing MMP9 tumor areas. We provide proof-of-concept evidence for successful MMP9-triggered drug release from MSNs in human tumor cells and in mouse and human lung tumors using the novel technology of ex vivo 3D lung tissue cultures. This technique allows for translational testing of drug delivery strategies in diseased mouse and human tissue. Using this method we show MMP9-mediated release of cisplatin, which induced apoptotic cell death only in lung tumor regions of Kras mutant mice, without causing toxicity in tumor-free areas or in healthy mice. The MMP9-responsive nanoparticles also allowed for effective combinatorial drug delivery of cisplatin and proteasome inhibitor bortezomib, which had a synergistic effect on the (therapeutic) efficiency. Importantly, we demonstrate the feasibility of MMP9-controlled drug release in human lung tumors.

In this review, we discuss recent developments in the field of nanoparticles and their use in tissue regeneration approaches. Owing to their unique chemical properties and flexibility in design, nanoparticles can be used as drug delivery systems, to create novel features within materials or as bioimaging agents, or indeed these properties can be combined to create smart multifunctional structures. This review aims to provide an overview of this research field where the focus will be on nanoparticle-based strategies to stimulate bone regeneration; however, the same principles can be applied for other tissue and organ regeneration strategies. In the first section, nanoparticle-based methods for the delivery of drugs, growth factors and genetic material to promote tissue regeneration are discussed. The second section deals with the addition of nanoparticles to materials to create nanocomposites. Such materials can improve several material properties, including mechanical stability, biocompatibility and biological activity. The third section will deal with the emergence of a relatively new field of research using nanoparticles in advanced cell imaging and stem cell tracking approaches. As the development of nanoparticles continues, incorporation of this technology in the field of regenerative medicine will ultimately lead to new tools that can diagnose, track and stimulate the growth of new tissues and organs.

Iodido osmium(II) complexes [Os(η(6)-arene)(XY)I](+) (XY = p-hydroxy or p-dimethylaminophenylazopyridine, arene = p-cymene or biphenyl) are potently cytotoxic at nanomolar concentrations toward a panel of human cancer cell lines; e.g., IC(50) = 140 nM for [Os(η(6)-bip)(azpy-NMe(2))I](+) toward A2780 ovarian cancer cells. They exhibit low toxicity and negligible deleterious effects in a colon cancer xenograft model, giving rise to the possibility of a broad therapeutic window. The most active complexes are stable and inert toward aquation. Their cytotoxic activity appears to involve redox mechanisms.

The design and synthesis of three asymmetrical platinum(II) analogues of cisplatin with substituents on the amine, varying in polarity and steric bulk is presented. Their biological activities, as studied using in vitro cytotoxicity studies in cisplatin sensitive and the corresponding cisplatin resistant cell lines, cellular uptake experiments and in a reaction with model DNA base GMP, are presented. All compounds exhibit promising cytotoxicity in the cisplatin sensitive cell lines albeit lower than cisplatin. On the other hand, the complexes partly overcome cisplatin resistance in the resistant cell lines. A direct correlation between cytotoxicity and cellular uptake was found. Conversely, the rate of reaction of all compounds with the model base GMP was found to be very similar and faster than cisplatin. It was therefore concluded that the difference in activity observed for these complexes is due to differential cellular uptake rather than the reactivity towards the cellular target of platinum complexes, nuclear DNA.

Respiratory diseases are an increasing burden for the ageing population. Although our understanding of these diseases has improved significantly over the past decades, diagnostic and therapeutic options for treating lung diseases, such as chronic obstructive pulmonary disease, idiopathic pulmonary fibrosis and lung cancer, remain limited. Multidisciplinary approaches that bridge the gap between medicinal and materials sciences will likely contribute to promising new therapeutic and diagnostic solutions. One such multidisciplinary approach is the use of nanoparticles as carriers for the delivery of drugs. The advantages of using nanoparticles to deliver drugs include: increased drug concentration at the disease site; minimised drug degradation and loss; ease of creating inhalable formulations; and the possibility of specific cell targeting. This article gives a brief overview on the emerging field of nanocarriers as drug delivery vehicles for the treatment of lung diseases.

The problems of acquired resistance associated with platinum drugs may be addressed by chemotherapeutics based on other transition metals as they offer the possibility of novel mechanisms of action. In this study, the cellular uptake and induction of apoptosis in A549 human non-small cell lung cancer cells of three promising osmium(II) arene complexes containing azopyridine ligands, [Os(η(6)-arene)(p-R-phenylazopyridine)X]PF6, where arene is p-cymene or biphenyl, R is OH or NMe2, and X is Cl or I, were investigated. These complexes showed time-dependent (4–48 h) potent anticancer activity with highest potency after 24 h (IC50 values ranging from 0.1 to 3.6 μM). Cellular uptake of the three compounds as quantified by ICP-MS, was independent of their logP values (hydrophobicity). Furthermore, maximum cell uptake was observed after 24 h, with evident cell efflux of the osmium after 48 and 72 h of exposure, which correlated with the corresponding IC50 values. The most active compound 2, [Os(η(6)-p-cymene)(NMe2-phenylazopyridine)I]PF6, was taken up by lung cancer cells predominately in a temperature-dependent manner indicating that energy-dependent mechanisms are important in the uptake of 2. Cell fractionation studies showed that all three compounds accumulated mainly in cellular membranes. Furthermore, compound 2 induced apoptosis and caused accumulation in the S-phase of the cell cycle. In addition, 2 induced cytochrome c release and alterations in mitochondrial membrane potential even after short exposure times, indicating that mitochondrial apoptotic pathways are involved. This study represents the first steps towards understanding the mode of action of this promising class of new osmium-based chemotherapeutics.

Cigarette smoke mediates DNA damage, lipid peroxidation, and modification and misfolding of proteins, thereby inducing severe cellular damage. The ubiquitin proteasome system serves as the major disposal system for modified and misfolded proteins and is thus essential for proper cellular function. Its role in cigarette smoke-induced cell damage, however, is largely unknown. We hypothesized that the ubiquitin-proteasome system is involved in the degradation of cigarette smoke-damaged proteins and that cigarette smoke exposure impairs the proteasome itself. Here, we show that treatment of human alveolar epithelial cells with cigarette smoke extract (CSE) induced time- and dose-dependent cell death, a rise in intracellular reactive oxygen species, and increased levels of carbonylated and polyubiquitinated proteins. While high doses of CSE severely impaired all three proteasomal activities, low CSE concentrations significantly inhibited only the trypsin-like activity of the proteasome in alveolar and bronchial epithelial cells. Moreover, acute exposure of mice to cigarette smoke significantly impaired the trypsin-like activity by 25% in the lungs. Reduced proteasome activity was not due to transcriptional regulation of the proteasome. Notably, cigarette smoke exposure induced accumulation of polyubiquitinated proteins in the soluble and insoluble protein fraction of the lung. We show for the first time that acute exposure to cigarette smoke directly impairs proteasome activity in the lungs of mice and in human epithelial cells at low doses without affecting proteasome expression. Our results indicate that defective proteasomal protein quality control may exacerbate the detrimental effects of cigarette smoke in the lung.

Background: Chronic obstructive pulmonary disease (COPD) is associated with an abnormal inflammatory response of the lungs to cigarette smoke (CS). The products of CS oxidatively modify proteins thereby inducing severe oxidative cellular damage. The ubiquitin proteasome system serves as the major disposal system for oxidatively modified proteins and is thus essential for proper cellular function. However, its role in CS-induced cell damage is currently unknown. We hypothesized that CS exposure impairs the function of the proteasome resulting in accumulation of oxidatively modified proteins, and exacerbation of cellular stress. Methods and Results: Treatment of human lung epithelial cells with CSE resulted in time and dose-dependent decrease of survival and increase of intracellular reactive oxygen species. The increased levels of oxidative stress correlated with accumulation of oxidatively modified proteins. CSE exposure also induced accumulation of polyubiquitinated proteins. Notably, treatment with CSE significantly impaired all three proteasomal activities at high doses. The trypsin-like activity was also inhibited at nontoxic CSE doses. Expression of the proteasome was unaffected. To confirm these observations in vivo, mice were exposed for 3 days to CS. Importantly, the trypsin-like activity of the proteasome was significantly reduced in lungs of smoked mice. We also observed increased levels of polyubiquitinated proteins in tissue extracts of smoked lungs compared controls. Conclusion: Our data clearly indicate that acute cigarette smoke exposure impairs proteasome function in the lung. Reduced proteasomal protein degradation might thus contribute to the detrimental cellular effects of cigarette smoke exposure in COPD.

This first in vivo antitumour activity for an organometallic osmium arene complex, [Os(eta(6)-p-cym)(4-(2-pyridylazo)-N,N-dimethylaniline)I]PF(6), is reported. The complex delays the growth of HCT116 human colon cancer xenografts in mice, with negligible toxicity. Its activity appears to involve redox mechanisms and its potency towards A2780 ovarian and A549 lung cancer cells is increased significantly in combination with L-buthionine-sulfoximine.

The side-on end-on dinitrogen complex [PhP(CH(2)SiMe(2)NPh)(2)Ta](μ-H)(2)(μ-η(2):η(1)-N(2)) reacts with CS(2) with complete cleavage of both C=S double bonds and the formation of [PhP(CH(2)SiMe(2)NPh)(2)Ta](μ-S)(2)(μ-CH(2)), which has two bridging sulfides and a bridging methylene unit. Further reaction with H(2) produces CH(4) and the disulfide complex.

The cytotoxicity, hydrophobicity (log P), cellular uptake, aqueous reactivity, and extent of DNA adduct formation in the A2780 ovarian carcinoma cells for four osmium(II) arene complexes [(eta(6)-arene)Os(4-methyl-picolinate)Cl] that differ only in their arene ligands as benzene (1), p-cymene (2), biphenyl (3), or tetrahydroanthracene (4) are reported. There is a correlation between hydrophobicity (log P), cellular uptake, nucleus uptake, and cytotoxicity of the complexes, following the order 3 approximately 4 > 2 > 1, suggesting that the arene plays an important role in the biological activity of these types of compounds. Cell distribution studies using fractionation showed that all four compounds distribute similarly within cells. DNA binding of osmium did not correlate with cytotoxicity, indicating that the nature of the DNA lesion may also be crucial to activity. TEM images of ovarian cells treated with 3 revealed morphological changes associated with apoptosis with possible involvement of mitochondria.

We show that the binding mode adopted by picolinamide derivatives in organometallic Os(II) and Ru(II) half-sandwich complexes can lead to contrasting cancer cell cytotoxicity. N-Phenyl picolinamide derivatives (XY) in Os(II) (1, 3-5, 7, 9) and Ru(II) (2, 6, 8, 10) complexes [(eta(6)-arene)(Os/Ru)(XY)Cl](n+), where arene = p-cymene (1-8, 10) or biphenyl (9), can act as N,N- or N,O-donors. Electron-withdrawing substituents on the phenyl ring resulted in N,N-coordination and electron-donating substituents in N,O-coordination. Dynamic interconversion between N,O and N,N configurations can occur in solution and is time- and temperature- (irreversible) as well as pH-dependent (reversible). The neutral N,N-coordinated compounds (1-5 and 9) hydrolyzed rapidly (t(1/2)or= min), exhibited significant (32-70%) and rapid binding to guanine, but no binding to adenine. The N,N-coordinated compounds 1, 3, 4, and 9 exhibited significant activity against colon, ovarian, and cisplatin-resistant ovarian human cancer cell lines (3419). In contrast, N,O-coordinated complexes 7 and 8 hydrolyzed slowly, did not bind to guanine or adenine, and were nontoxic.

This review illustrates notable recent progress in the field of medicinal bioinorganic chemistry as many new approaches to the design of innovative metal-based anticancer drugs are emerging. Current research addressing the problems associated with platinum drugs has focused on other metal-based therapeutics that have different modes of action and on prodrug and targeting strategies in an effort to diminish the side-effects of cisplatin chemotherapy.

Chlorido osmium(II) arene [(eta(6)-biphenyl)Os(II)(X-pico)Cl] complexes containing X = Br (1), OH (2), and Me (3) as ortho, or X = Cl (4), CO(2)H (5), and Me (6) as para substituents on the picolinate (pico) ring have been synthesized and characterized. The X-ray crystal structures of 1 and 6 show typical "piano-stool" geometry with intermolecular pi-pi stacking of the biphenyl outer rings of 6. At 288 K the hydrolysis rates follow the order 264351 with half-lives ranging from minutes to 4.4 h illustrating the influence of both electronic and steric effects of the substituents. The pK(a) values of the aqua adducts 3A, 4A, 5A, and 6A were all in the range of 6.3-6.6. The para-substituted pico complexes 4-6 readily formed adducts with both 9-ethyl guanine (9EtG) and 9-ethyl adenine (9EtA), but these were less favored for the ortho-substituted complexes 1 and 3 showing little reaction with 9EtG and 9EtA, respectively. Density-functional theory calculations confirmed the observed preferences for nucleobase binding for complex 1. In cytotoxicity assays with A2780, cisplatin-resistant A2780cis human ovarian, A549 human lung, and HCT116 colon cancer cells, only complexes 4 (p-Cl) and 6 (p-Me) exhibited significant activity (IC(50) values25 microM). Both of these complexes were as active as cisplatin in A2780 (ovarian) and HCT116 (colon) cell lines, and even overcome cisplatin resistance in the A2780cis (ovarian) cell line. The inactivity of 5 is attributed to the negative charge on its para carboxylate substituent. These data illustrate how the chemical reactivity and cancer cell cytotoxicity of osmium arene complexes can be controlled and "fine-tuned" by the use of steric and electronic effects of substituents on a chelating ligand to give osmium(II) arene complexes which are as active as cisplatin but have a different mechanism of action.

Our studies of half-sandwich osmium(II) arene complexes of the type [(η6-arene)Os(XY)Z] show that hydrolysis of the Os–Z (Z = Cl) bond and degree of formation of biologically inactive hydroxo-bridged dimers can be controlled by the choice of the chelated ligand XY. The chemistry and cancer-cell cytotoxicity of complexes containing N,N-, N,O-, or O,O-chelating ligands are compared and contrasted. The wide kinetic timescales of the reactions of these osmium complexes are notable and promising for the design of novel anti-cancer agents.