Metal Complexes of Curcumin for Cellular Imaging, Targeting, and Photoinduced Anticancer Activity

CONSPECTUS: Curcumin is a polyphenolic species. As an active ingredient of turmeric, it is well-known for its traditional medicinal properties. The therapeutic values include antioxidant, anti-inflammatory, antiseptic, and anticancer activity with the last being primarily due to inhibition of the transcription factor NF-kappa B besides affecting several biological pathways to arrest tumor growth and its progression. Curcumin with all these positive qualities has only remained a potential candidate for cancer treatment over the years without seeing any proper usage because of its hydrolytic instability involving the diketo moiety in a cellular medium and its poor bioavailability. The situation has changed considerably in recent years with the observation that curcumin in monoanionic form could be stabilized on binding to a metal ion. The reports from our group and other groups have shown that curcumin in the metal-bound form retains its therapeutic potential. This has opened up new avenues to develop curcumin-based metal complexes as anticancer agents. Zinc(II) complexes of curcumin are shown to be stable in a cellular medium. They display moderate cytotoxicity against prostate cancer and neuroblastoma cell lines. A similar stabilization and cytotoxic effect is reported for (arene)ruthenium(II) complexes of curcumin against a variety of cell lines. The half-sandwich 1,3,5-triaza-7-phosphatricyclo-3.3.1.1]decane (RAPTA)-type ruthenium(II) complexes of curcumin are shown to be promising cytotoxic agents with low micromolar concentrations for a series of cancer cell lines. In a different approach, cobalt(III) complexes of curcumin are used for its cellular delivery in hypoxic tumor cells using intracellular agents that reduce the metal and release curcumin as a cytotoxin. Utilizing the photophysical and photochemical properties of the curcumin dye, we have designed and synthesized photoactive curcumin metal complexes that are used for cellular imaging by fluorescence microscopy and damaging the cancer cells on photoactivation in visible light while being minimally toxic in darkness. In this Account, we have made an attempt to review the current status of the chemistry of metal curcumin complexes and present results from our recent studies on curcumin complexes showing remarkable in vitro photocytotoxicity. The undesirable dark toxicity of the complexes can be reduced with suitable choice of the metal and the ancillary ligands in a ternary structure. The complexes can be directed to specific subcellular organelles. Selectivity by targeting cancer cells over normal cells can be achieved with suitable ligand design. We expect that this methodology is likely to provide an impetus toward developing curcumin-based photochemotherapeutics for anticancer treatment and cure.

Particle field imaging using digital in-line holography

Digital holography is the direct recording of holograms using a CCD camera and is an alternative to the use of a film or a plate. In this communication in-line digital holographic microscopy has been explored for its application in particle imaging in 3D. Holograms of particles of about 10 mu m size have been digitally reconstructed. Digital focusing was done to image the particles in different planes along the depth of focus. Digital holographic particle imaging results were compared with conventional optical microscope imaging. A methodology for dynamic analysis of microparticles in 3D using in-line digital holography has been proposed.

Defect-selective photothermal imaging: a sensitive tool for damage mapping in optical coatings

A defect-selective photothermal imaging system for the diagnostics of optical coatings is demonstrated. The instrument has been optimized for pump and probe parameters, detector performance, and signal processing algorithm. The imager is capable of mapping purely optical or thermal defects efficiently in coatings of low damage threshold and low absorbance. Detailed mapping of minor inhomogeneities at low pump power has been achieved through the simultaneous action of a low-noise fiber optic photothermal beam defection sensor and a common-mode-rejection demodulation (CMRD) technique. The linearity and sensitivity of the sensor have been examined theoretically and experimentally, and the signal to noise ratio improvement factor is found to be about 110 compared to a conventional bicell photodiode. The scanner is so designed that mapping of static or shock sensitive samples is possible. In the case of a sample with absolute absorptance of 3.8 x 10(-4), a change in absorptance of about 0.005 x 10(-4) has been detected without ambiguity, ensuring a contrast parameter of 760. This is about 1085% improvement over the conventional approach containing a bicell photodiode, at the same pump power. The merits of the system have been demonstrated by mapping two intentionally created damage sites in a MgF2 coating on fused silica at different excitation powers. Amplitude and phase maps were recorded for thermally thin and thick cases, and the results are compared to demonstrate a case which, in conventional imaging, would lead to a deceptive conclusion regarding the type and location of the damage. Also, a residual damage profile created by long term irradiation with high pump power density has been depicted.

Oxovanadium(IV)-based near-IR PDT agents: design to biological evaluation

An oxovanadium(IV) complex of dipyridophenazine, as a potent metal-based PDT agent, shows efficient DNA photocleavage activity at near-IR region and high photocytotoxicity in both UV-A and visible light in HeLa cells.

Imaging in turbid media using quasi-ballistic photons

We study by means of experiments and Monte Carlo simulations, the scattering of light in random media, to determine the distance up to which photons travel along almost undeviated paths within a scattering medium, and are therefore capable of casting a shadow of an opaque inclusion embedded within the medium. Such photons are isolated by polarisation discrimination wherein the plane of linear polarisation of the input light is continuously rotated and the polarisation preserving component of the emerging light is extracted by means of a Fourier transform. This technique is a software implementation of lock-in detection. We find that images may be recovered to a depth far in excess of that predicted by the diffusion theory of photon propagation. To understand our experimental results, we perform Monte Carlo simulations to model the random walk behaviour of the multiply scattered photons. We present a. new definition of a diffusing photon in terms of the memory of its initial direction of propagation, which we then quantify in terms of an angular correlation function. This redefinition yields the penetration depth of the polarisation preserving photons. Based on these results, we have formulated a model to understand shadow formation in a turbid medium, the predictions of which are in good agreement with our experimental results.

Micro-Raman imaging of Te precipitates in CdZnTe (Zn similar to 4%) crystals

Micro-Raman imaging of the distribution of Te precipitates in CdZnTe crystals in different phases is reported. For the normal phase of Te precipitates, the Raman modes appear centered around 121(A1), 141(E)/TO(CdTe) cm−1 and a weak mode around 92(E) cm−1 in CdZnTe indicating the presence of trigonal lattice of Te. Under high pressure phase, the volume of Te precipitates collapses, giving more bond energy resulting in the blueshift of the corresponding Raman bands. Also, the spatial distribution of the area ratio of 121 to 141 cm−1 Raman modes is used to quantify Te precipitates. Further, near-infrared microscopy images support these results.

Diversity: Cultural and biological

Early human populations utilized a wide range of biological resources in a tremendous diversity of environments. As a result, they possessed high levels of cultural diversity dependent on and supportive of high levels of biological diversity. This pattern changed drastically with technological innovations enabling certain human groups to break down territorial barriers and to usurp resources of other groups. The dominant groups have gone on to exhaust a whole range of resources, depleting both biological and cultural diversity. Traditions of resource conservation can, however, re-emerge when the dominant cultures spread over the entire area and the innovations diffuse to other human groups. This could change once again as genetically engineered organisms become an economically viable proposition with the accruing advantages concentrated in the hands of a few human groups: a further drastic reduction in biological and cultural diversity may ensue.

Chemical Modification Studies of Gelonin - Involvement of Arginine Residues in Biological-Activity

Gelonin inhibits protein synthesis by inactivating the eukaryotic 60 S ribosomal subunit by an unknown mechanism. The protein was purified in high yield by a new method using Cibacron blue F3GA-Sepharose. Chemical modification studies reveal that arginine residues are essential for biological activity.

Novel ultrahigh resolution silverless photothermal imaging in obliquely deposited amorphous Se-Ge films

A new photothermal imaging process which utilizes no silver has been demonstrated in obliquely deposited Se-Ge films. Band-gap irradiation of Se-Ge films has been found to give rise to phases of the type SeOx, GeO, and Se as borne by x-ray initiated Auger electron spectroscopy and x-ray photoelectron spectroscopy. Annealing of SeOx leads to the formation of SeO2. The large (several orders of magnitude) difference in vapor pressures of SeO2 and Se-Ge films results in differential evaporation of the films when annealed around 200 °C, thereby leading to imaging. Such a large contrast in evaporation rates between the exposed and unexposed regions has great potential applications in high resolution image storage and phase holography. Applied Physics Letters is copyrighted by The American Institute of Physics.

A comparative study of side-band Fresnel holograms recorded with self-imaging and general objects

This paper deals with new results obtained in regard to the reconstruction properties of side-band Fresnel holograms (SBFH) of self-imaging type objects (for example, gratings) as compared with those of general objects. The major finding is that a distribution I2, which appears on the real-image plane along with the conventional real-image I1, remains a 2Z distribution (where 2Z is the axial distance between the object and its self-imaging plane) under a variety of situations, while its nature and focusing properties differ from one situation to another. It is demonstrated that the two distributions I1 and I2 can be used in the development of a novel technique for image subtraction.

Generation of optimum random pinhole arrays for multiple imaging

Through an analysis using the transfer function of a pinhole camera, the multiple imaging characteristics of photographic diffusers described by Grover and Tremblay [Appl. Opt.21,4500(1982)] is studied. It is found that only one pinhole diameter satisfies the optimum imaging condition for best contrast transfer at any desired spatial frequency. A simple method of generating random pinhole arrays with a controlled pinhole diameter is described. These pinhole arrays are later used to generate high frequency sinusoidal gratings from a coarse grid. The contrast in the final gratings is found to be reasonably high.

Flux balance analysis of biological systems: applications and challenges

Systems level modelling and simulations of biological processes are proving to be invaluable in obtaining a quantitative and dynamic perspective of various aspects of cellular function. In particular, constraint-based analyses of metabolic networks have gained considerable popularity for simulating cellular metabolism, of which flux balance analysis (FBA), is most widely used. Unlike mechanistic simulations that depend on accurate kinetic data, which are scarcely available, FBA is based on the principle of conservation of mass in a network, which utilizes the stoichiometric matrix and a biologically relevant objective function to identify optimal reaction flux distributions. FBA has been used to analyse genome-scale reconstructions of several organisms; it has also been used to analyse the effect of perturbations, such as gene deletions or drug inhibitions in silico. This article reviews the usefulness of FBA as a tool for gaining biological insights, advances in methodology enabling integration of regulatory information and thermodynamic constraints, and finally addresses the challenges that lie ahead. Various use scenarios and biological insights obtained from FBA, and applications in fields such metabolic engineering and drug target identification, are also discussed. Genome-scale constraint-based models have an immense potential for building and testing hypotheses, as well as to guide experimentation.

Synthesis and biological evaluation of novel 1-(4-methoxyphenethyl)-1H-benzimidazole-5-carboxylic acid derivatives and their precursors as antileukemic agents

We report here the synthesis and preliminary evaluation of novel 1-(4-methoxyphenethyl)-1H-benzimidazole-5-carboxylic acid derivatives 6(a–k) and their precursors 5(a–k) as potential chemotherapeutic agents. In each case, the structures of the compounds were determined by FTIR, 1H NMR and mass spectroscopy. Among the synthesized molecules, methyl 1-(4-methoxyphenethyl)-2-(4-fluoro-3-nitrophenyl)-1H-benzimidazole-5-carboxylate (5a) induced maximum cell death in leukemic cells with an IC50 value of 3 μM. Using FACS analysis we show that the compound 5a induces S/G2 cell cycle arrest, which was further supported by the observed down regulation of CDK2, Cyclin B1 and PCNA. The observed downregulation of proapoptotic proteins, upregulation of antiapoptotic proteins, cleavage of PARP and elevated levels of DNA strand breaks indicated the activation of apoptosis by 5a. These results suggest that 5a could be a potent anti-leukemic agent.

The Frontiers of India's Biological Diversity

India has a long and rich history of tropical science. But here, as elsewhere in the tropical world, there are surprises to be discovered. One thinks immediately of the description, in December 2004, of a new species of macaque from India - the Arunachal macaque Macaca munzala. I use the word description deliberately, because this species was long known to the local people, and the species name rightly reflects this knowledge. Mun zala means "deep-forest monkey" in the language of the Dirang Monpa people of Tawang and West Kameng Districts of Arunachal Pradesh, where this species lives. The new macaque was discovered by science during field trips to these areas by Indian scientists from the Nature Conservation Foundation in Mysore, the National Institute of Advanced Studies in Bangalore, the Wildlife Conservation Society in New York, and the International Snow Leopard Trust. In this habitat, the largely Buddhist local community abstains from killing wildlife for food or sport, although the monkey has been reportedly shot for crop raiding. This species, one of the world's highest-living primate species, lives at altitudes between 1,600 and 3,500m, and is thus a veritable yeti.