Jayeeta Bhaumik

Biosynthesis of silver nanoparticles: Elucidation of prospective mechanism and therapeutic potential.

The synthesis of silver nanoparticles (AgNPs) was accomplished using Syzygium cumini fruit extract at room temperature. Various techniques were used to characterize the newly synthesized silver nanoparticles and their size was determined to be 10-15nm. Important findings of this study were the identification of biomolecules responsible for the synthesis of silver nanoparticles and elucidate the mechanism of biosynthesis. Flavonoids present in S. cumini were mainly responsible for the reduction and the stabilization of nanoparticles. The antioxidant properties of AgNPs were evaluated using various assays. The nanoparticles were also found to destroy Dalton lymphoma cell lines under in vitro condition. Silver nanoparticles (100μg/mL) decreased the viability of Dalton lymphoma (DL) cell lines up to 50%. The studies describing the biosynthesis of silver nanoparticles by fruit extract followed by the investigation of synthesis mechanism and anti-cancer activities may be useful for nanobiotechnology research opening a new arena in this field.

Imidazole metalloporphyrins as photosensitizers for photodynamic therapy: Role of molecular charge, central metal and hydroxyl radical production

The in vitro photodynamic therapy activity of four imidazole-substituted metalloporphyrins has been studied using human (HeLa) and mouse (CT26) cancer cell lines: an anionic Zn porphyrin and a homologous series of three cationic Zn, Pd or InCl porphyrins. A dramatic difference in phototoxicity was found: Pd cationic>InCl cationic>Zn cationic>Zn anionic. HeLa cells were more susceptible than CT26 cells. Induction of apoptosis was demonstrated using a fluorescent caspase assay. The anionic Zn porphyrin localized in lysosomes while the cationic Zn porphyrin localized in lysosomes and mitochondria, as assessed by fluorescence microscopy. Studies using fluorescent probes suggested that the cationic Pd porphyrin produced more hydroxyl radicals as the reactive oxygen species. Thus, the cationic Pd porphyrin has high potential as a photosensitizer and gives insights into characteristics for improved molecular designs.

Targeted nanoagents for the detection of cancers

Nanotechnology has enabled a renaissance in the diagnosis of cancers. This is due, in part to the ability to develop agents bearing multiple functionalities, including those utilized for targeting, imaging, and therapy, allowing for the tailoring of the properties of the nanomaterials. Whereas many nanomaterials exhibit localization to diseased tissues via intrinsic targeting, the addition of targeting ligands, such as antibodies, peptides, aptamers, and small molecules, facilitates far more sensitive cancer detection. As such, this review focuses upon some of the most poignant examples of the utility of affinity ligand targeted nanoagents in the detection of cancer.

Quantum dot/antibody conjugates for in vivo cytometric imaging in mice

Significance One of the key questions in biology is understanding how cells move, interact, and evolve in living organisms. Tremendous efforts have been made to answer these questions in vitro, which have yielded a molecular-level understanding of cellular events. However, an increasing number of studies indicate that cellular activities need to be understood in the context of their natural environments. Single-cell labeling methods in use currently involve immunohistochemistry, genetic manipulation, or irradiation of mice, none of which reflect the native microenvironments. Here, we report quantum dot immunoconstructs that can be used for intravital imaging of single cells in unmanipulated mice and multiplexed in vivo cytometric analysis of rare cell populations. Multiplexed, phenotypic, intravital cytometric imaging requires novel fluorophore conjugates that have an appropriate size for long circulation and diffusion and show virtually no nonspecific binding to cells/serum while binding to cells of interest with high specificity. In addition, these conjugates must be stable and maintain a high quantum yield in the in vivo environments. Here, we show that this can be achieved using compact (∼15 nm in hydrodynamic diameter) and biocompatible quantum dot (QD) -Ab conjugates. We developed these conjugates by coupling whole mAbs to QDs coated with norbornene-displaying polyimidazole ligands using tetrazine–norbornene cycloaddition. Our QD immunoconstructs were used for in vivo single-cell labeling in bone marrow. The intravital imaging studies using a chronic calvarial bone window showed that our QD-Ab conjugates diffuse into the entire bone marrow and efficiently label single cells belonging to rare populations of hematopoietic stem and progenitor cells (Sca1+c-Kit+ cells). This in vivo cytometric technique may be useful in a wide range of structural and functional imaging to study the interactions between cells and between a cell and its environment in intact and diseased tissues.

Applications of phototheranostic nanoagents in photodynamic therapy

Nanotherapeutics has an increasing role in the treatment of diseases such as cancer. In photodynamic therapy (PDT) a therapeutically inactive photosensitizer compound is selectively activated by light to produce molecules capable of killing diseased cells and pathogens. A phototheranostic agent can be defined as a single nanoentity with the capabilities for targeted delivery, optical imaging and photodynamic treatment of a disease. Malignant cells, tissue and microbial etiologic agents can be effectively targeted by PDT. Photodynamic therapy is noninvasive, or minimally invasive, and has few side effects as damage to healthy tissue is minimized and the killing effect is localized. Various forms of cancer, acne and other diseases may be treated. The in vivo efficacy of photosensitizers is further improved by attaching them to nanostructures capable of targeting the diseased site. Such photosensitizer-functionalized nanostructures, or nanotherapeutics, allow site-specific delivery of imaging and therapeutic agents for improved phototheranostic performance. This review explores the potential applications of phototheranostic nanostructures in diagnosis and therapy.

Arginine dependence of tumor cells: targeting a chink in cancer's armor.

Arginine, one among the 20 most common natural amino acids, has a pivotal role in cellular physiology as it is being involved in numerous cellular metabolic and signaling pathways. Dependence on arginine is diverse for both tumor and normal cells. Because of decreased expression of argininosuccinate synthetase and/or ornithine transcarbamoylase, several types of tumor are auxotrophic for arginine. Deprivation of arginine exploits a significant vulnerability of these tumor cells and leads to their rapid demise. Hence, enzyme-mediated arginine depletion is a potential strategy for the selective destruction of tumor cells. Arginase, arginine deiminase and arginine decarboxylase are potential enzymes that may be used for arginine deprivation therapy. These arginine catabolizing enzymes not only reduce tumor growth but also make them susceptible to concomitantly administered anti-cancer therapeutics. Most of these enzymes are currently under clinical investigations and if successful will potentially be advanced as anti-cancer modalities.

High-yielding syntheses of hydrophilic conjugatable chlorins and bacteriochlorins

Next-generation photodynamic therapy agents based upon the conjugation of multiple photosensitizers to a targeting backbone will allow for more efficacious light-based therapies. To this end, we have developed glucose-modified chlorins and bacteriochlorins featuring a reactive carboxylic acid linker for conjugation to targeting moieties. The photosensitizers were synthesized in relatively high yields from meso-tetra(p-aminophenyl)porphyrin, and resulted in neutral, hydrophilic chromophores with superb absorption profiles in the far-red and near-infrared portions of the electromagnetic spectrum. In addition, conjugation of these photosensitizers to a model nanoscaffold (crosslinked dextran-coated nanoparticles) demonstrated that the inclusion of hydrophilic sugar moieties increased the number of dyes that can be loaded while maintaining suspension stability. The described compounds are expected to be particularly useful in the synthesis of a number of targeted nanotherapeutic systems.

Lipase-catalyzed green synthesis of enantiopure atenolol

A new green route is proposed for the synthesis of enantiopure atenolol (a β1-blocker). An enzymatic kinetic resolution approach was used to synthesize the enantiopure intermediates (R)- and (S)-2-(4-(3-chloro-2-hydroxypropoxy)phenyl)acetamide from the corresponding racemic alcohol. Of the commercially available lipases screened, Candida antarctica lipase-A (CLEA) showed maximum enantioselectivity in the transesterification of the racemic alcohol using vinyl acetate as the acyl donor. The reactions afforded the (S)-alcohol along with the (R)-acetate, with 48.9% conversion (E = 210, eeP = 96.9% and eeS = 91.1%). Various reaction parameters were optimized in order to achieve maximum enantioselectivity. N-alkylation of the (S)-alcohol with isopropylamine afforded the (S)-atenolol, and the (R)-acetate was chemically hydrolyzed to the corresponding alcohol and further converted to the (R)-atenolol via N-alkylation of the (R)-alcohol with isopropylamine. The use of ionic liquids, to solve the solubility related problems of the drug intermediates, made this process greener and more efficient compared to the previously reported methods.

Synthesis and photophysical properties of sulfonamidophenyl porphyrins as models for activatable photosensitizers.

The ability to localize agents to specific anatomic sites remains an important aspect in designing more efficient therapeutics. Light-activated therapies, in particular, allow for the focal ablation of target tissues and cells. In order to increase the specificity of these agents, stimuli-activated systems have been developed, which are nonphototoxic in the absence of activation. To this end, we propose a novel paradigm for excited state quenching and activation based upon the direct conjugation of quenching moieties to the porphyrinic macrocycle. Model compounds, based upon meso-(p-aminophenyl)porphyrins were synthesized bearing 1 to 4 sulfonamide-linked 2,4-dinitrobenzene. The singlet oxygen and fluorescence quantum yields of these compounds were obtained and compared, as well as the kinetics of activation with relevant activating agents. In addition, methods were developed to further modify the porphyrin in order to modulate the polarity and effect conjugation to biomolecules or nanoparticulate scaffolds. These systems may prove useful in the treatment of a number of disease states, such as cancer and bacterial infection.

Regioselective β-pyrrolic electrophilic substitution of hydrodipyrrin–dialkylboron complexes facilitates access to synthetic models for chlorophyll f

Substituents in ring A of chlorophylls can exert profound effects on spectral properties. A de novo route to synthetic chlorins employs a tetrahydrodipyrrin reactant containing pyrrole and pyrroline rings. Complexation of the tetrahydrodipyrrin with a dialkylboron motif caused electrophilic substitution (bromination, formylation) to proceed predominantly at the β7- rather than α-position of the pyrrole ring, whereas an analogous dihydrodipyrrin underwent substitution equally at the 7- and 8-positions. The fully unsaturated dipyrrin–difluoroboron complex is known to undergo electrophilic substitution at the 8-position. The 7-position of the hydrodipyrrin ultimately gives rise to substituents at the chlorin 2-position (ring A), which heretofore has been little accessed. The position of substitution was confirmed by four single-crystal X-ray structures. Two isomeric formylchlorins were prepared by Pd-mediated carbonylation of the corresponding bromochlorins. Access to a 2-formylchlorin relied on bromination of the tetrahydrodipyrrin–dibutylboron complex, whereas a 3-formylchlorin was prepared by installation of the bromo group in the earliest precursor, pyrrole-2-carboxaldehyde. The two formylchlorins differ in absorption spectral properties: the Qy absorption maximum is 654 or 664 nm for the 2- or 3-formylchlorin, respectively. The synthetic formylchlorins provide initial models for understanding the strong red absorption of native 2- or 3-formylchlorophylls (f and d).