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1.
Int J Cancer ; 139(12): 2838-2849, 2016 Dec 15.
Article in English | MEDLINE | ID: mdl-27543754

ABSTRACT

Glioblastoma (GBM) is one of the most pernicious forms of cancer and currently chances of survival from this malady are extremely low. We have used the noninvasive strategy of intranasal (IN) delivery of a glioblastoma-directed adduct of curcumin (CC), CC-CD68Ab, into the brain of mouse GBM GL261-implanted mice to study the effect of CC on tumor remission and on the phenotype of the tumor-associated microglial cells (TAMs). The treatment caused tumor remission in 50% of GL261-implanted GBM mice. A similar rescue rate was also achieved through intraperitoneal infusion of a lipid-encapsulated formulation of CC, Curcumin Phytosome, into the GL261-implanted GBM mice. Most strikingly, both forms of CC elicited a dramatic change in the tumor-associated Iba1+ TAMs, suppressing the tumor-promoting Arginase1high , iNOSlow M2-type TAM population while inducing the Arginase1low , iNOShigh M1-type tumoricidal microglia. Concomitantly, we observed a marked induction and activation of microglial NF-kB and STAT1, which are known to function in coordination to cause induction of iNOS. Therefore, our novel findings indicate that appropriately delivered CC can directly kill GBM cells and also repolarize the TAMs to the tumoricidal M1 state.


Subject(s)
Antineoplastic Agents/pharmacology , Curcumin/pharmacology , Glioblastoma/pathology , Microglia/drug effects , Microglia/pathology , Animals , Antigens, CD/metabolism , Antigens, Differentiation, Myelomonocytic/metabolism , Antineoplastic Agents/administration & dosage , Arginase/metabolism , Biomarkers , Calcium-Binding Proteins , Cell Line, Tumor , Curcumin/administration & dosage , DNA-Binding Proteins/metabolism , Disease Models, Animal , Glioblastoma/drug therapy , Glioblastoma/metabolism , Glioblastoma/mortality , Humans , Immunophenotyping , Inhibitory Concentration 50 , Male , Mice , Microfilament Proteins , Microglia/metabolism , NF-kappa B/metabolism , Nitric Oxide Synthase Type II/metabolism , STAT1 Transcription Factor/metabolism , Xenograft Model Antitumor Assays
2.
Nanoscale ; 7(27): 11667-77, 2015 Jul 21.
Article in English | MEDLINE | ID: mdl-26098759

ABSTRACT

Strong inter-nanocrystal electronic coupling is a prerequisite for delocalization of exciton wave functions and high conductivity. We report 170 meV electronic coupling energy of short chain poly(ethylene glycol) thiolate-coated ultrasmall (<2.5 nm in diameter) CdSe semiconductor nanocrystals (SNCs) in solution. Cryo-transmission electron microscopy analysis showed the formation of a pearl-necklace assembly of nanocrystals in solution with regular inter-nanocrystal spacing. The electronic coupling was studied as a function of CdSe nanocrystal size where the smallest nanocrystals exhibited the largest coupling energy. The electronic coupling in spin-cast thin-film (<200 nm in thickness) of poly(ethylene glycol) thiolate-coated CdSe SNCs was studied as a function of annealing temperature, where an unprecedentedly large, ∼400 meV coupling energy was observed for 1.6 nm diameter SNCs, which were coated with a thin layer of poly(ethylene glycol) thiolates. Small-angle X-ray scattering measurements showed that CdSe SNCs maintained an order array inside the films. The strong electronic coupling of SNCs in a self-organized film could facilitate the large-scale production of highly efficient electronic materials for advanced optoelectronic device application.

3.
Langmuir ; 30(26): 7851-8, 2014 Jul 08.
Article in English | MEDLINE | ID: mdl-24926916

ABSTRACT

Here we report an unprecedentedly large and controllable decrease in the optical band gap (up to 107 nm, 610 meV) of molecule-like ultrasmall CdSe nanocrystals (diameters ranging from 1.6 to 2.0 nm) by passivating their surfaces with conjugated ligands (phenyldithiocarbamates, PDTCs) containing a series of electron-donating and -withdrawing functional groups through a ligand-exchange reaction on dodecylamine (DDA)-coated nanocrystals. This band-edge absorption shift is due to the delocalization of the strongly confined excitonic hole from nanocrystals to the ligand molecular orbitals and not from nanocrystal growth or dielectric constant effects. (1)H NMR analysis confirmed that the nanocrystal surface contained a mixed ligation of DDA and PDTC. The effects of the nanocrystal size on the extent of exciton delocalization were also studied and found to be smaller for larger nanocrystals. Modulating the energy level of ligand-passivated ultrasmall nanocrystals and controlling the electronic interaction at the nanocrystal-passivating ligand interface are very important to the fabrication of solid-state devices.

4.
Int J Cancer ; 135(3): 710-9, 2014 Aug 01.
Article in English | MEDLINE | ID: mdl-24142484

ABSTRACT

Current therapies for glioblastoma are largely palliative, involving surgical resection followed by chemotherapy and radiation therapy, which yield serious side effects and very rarely produce complete recovery. Curcumin, a food component, blocked brain tumor formation but failed to eliminate established brain tumors in vivo, probably because of its poor bioavailability. In the glioblastoma GL261 cells, it suppressed the tumor-promoting proteins NF-κB, P-Akt1, vascular endothelial growth factor, cyclin D1 and BClXL and triggered cell death. Expression of exogenous p50 and p65 subunits of NF-κB conferred partial protection on transfected GL261 cells against curcumin insult, indicating that NF-κB played a key role in protecting glioblastoma cells. To enhance delivery, we coupled curcumin to the glioblastoma-specific CD68 antibody in a releasable form. This resulted in a 120-fold increase in its efficacy to eliminate GL261 cells. A very similar dose response was also obtained with human glioblastoma lines T98G and U87MG. GL261-implanted mice receiving intratumor infusions of the curcumin-CD68 adduct followed by tail-vein injections of solubilized curcumin displayed a fourfold to fivefold reduction in brain tumor load, survived longer, and about 10% of them lived beyond 100 days. Hematoxylin-eosin staining of brain sections revealed a small scar tissue mass in the rescued mice, indicating adduct-mediated elimination of glioblastoma tumor. The tumor cells were strongly CD68+ and some cells in the tumor periphery were strongly positive for microglial Iba1, but weakly positive for CD68. This strategy of antibody targeting of curcumin to tumor comes with the promise of yielding a highly effective therapy for glioblastoma brain tumors.


Subject(s)
Antibodies, Neoplasm/immunology , Antigens, CD/immunology , Antigens, Differentiation, Myelomonocytic/immunology , Antineoplastic Agents/therapeutic use , Brain Neoplasms/drug therapy , Curcumin/therapeutic use , Drug Synergism , Glioblastoma/drug therapy , Animals , Antigens, CD/chemistry , Antigens, Differentiation, Myelomonocytic/chemistry , Brain Neoplasms/immunology , Glioblastoma/immunology , Humans , Immunoenzyme Techniques , Male , Mice , Mice, Inbred C57BL , NF-kappa B/metabolism , Signal Transduction , Tumor Cells, Cultured
5.
Langmuir ; 29(20): 6187-93, 2013 May 21.
Article in English | MEDLINE | ID: mdl-23621327

ABSTRACT

Advancing our understanding of the photophysical and electrochemical properties of semiconductor nanoclusters with a molecule-like HOMO-LUMO energy level will help lead to their application in photovoltaic devices and photocatalysts. Here we describe an approach to the synthesis and isolation of molecule-like CdSe nanoclusters, which displayed sharp transitions at 347 nm (3.57 eV) and 362 nm (3.43 eV) in the optical spectrum with a lower energy band extinction coefficient of ~121,000 M(-1) cm(-1). Mass spectrometry showed a single nanocluster molecular weight of 8502. From this mass and various spectroscopic analyses, the nanoclusters are determined to be of the single molecular composition Cd34Se20(SPh)28, which is a new nonstiochiometric nanocluster. Their reversible electrochemical band gap determined in Bu4NPF6/CH3CN was found to be 4.0 V. There was a 0.57 eV Coulombic interaction energy of the electron-hole pair involved. The scan rate dependent electrochemistry suggested diffusion-limited transport of nanoclusters to the electrode. The nanocluster diffusion coefficient (D = 5.4 × 10 (-4) cm(2)/s) in acetonitrile solution was determined from cyclic voltammetry, which suggested Cd34Se20(SPh)28 acts as a multielectron donor or acceptor. We also present a working model of the energy level structure of the newly discovered nanocluster based on its photophysical and redox properties.


Subject(s)
Cadmium Compounds/chemistry , Nanostructures/chemistry , Selenium Compounds/chemistry , Cadmium Compounds/chemical synthesis , Electrochemical Techniques , Oxidation-Reduction , Photochemical Processes , Selenium Compounds/chemical synthesis , Temperature
6.
Anticancer Agents Med Chem ; 13(10): 1531-9, 2013 Dec.
Article in English | MEDLINE | ID: mdl-23387971

ABSTRACT

Curcumin, which is derived from the plant Curcuma longa, has received considerable attention as a possible anti-cancer agent. In cell culture, curcumin is capable of inducing apoptosis in cancer cells at concentrations that do not affect normal cells. One draw-back holding curcumin back from being an effective anti-cancer agent in humans is that it is almost completely insoluble in water and therefore has poor absorption and subsequently poor bioavailability. Here we have generated a number of curcumin derivatives (tetrahydro-curcumin, curcumin mono-carboxylic acid, curcumin mono-galactose, curcumin mono-alkyne and dendrimer-curcumin conjugate) to test whether any of them display both cytotoxicity and water solubility. Of those tested only dendrimer-curcumin conjugate exhibited both water solubility and cytotoxicity against SKBr3 and BT549 breast cancer cells. When compared to curcumin dissolved in DMSO, dendrimer-curcumin conjugate dissolved in water was significantly more effective in inducing cytotoxicity, as measured by the MTT assay and effectively induced cellular apoptosis measured by caspase-3 activation. Since dendrimer-curcumin conjugate is water soluble and capable of inducing potent cytotoxic effects on breast cancer cell lines, it may prove to be an effective anti-cancer therapy to be used in humans.


Subject(s)
Antineoplastic Agents, Phytogenic/pharmacology , Curcumin/analogs & derivatives , Curcumin/pharmacology , Cytotoxins/pharmacology , Dendrimers/chemistry , Alkynes/chemistry , Antineoplastic Agents, Phytogenic/chemical synthesis , Apoptosis/drug effects , Carboxylic Acids/chemistry , Caspase 3/metabolism , Cell Line, Tumor , Cell Survival/drug effects , Curcumin/chemical synthesis , Cytotoxins/chemical synthesis , Dose-Response Relationship, Drug , Enzyme Activation/drug effects , Female , Galactose/chemistry , Humans , Hydrogenation , Hydrophobic and Hydrophilic Interactions , Molecular Structure , Solubility , Structure-Activity Relationship , Water
7.
Int J Cancer ; 131(4): E569-78, 2012 Aug 15.
Article in English | MEDLINE | ID: mdl-21989768

ABSTRACT

In vitro studies have shown that curcumin, a polyphenol from the culinary component turmeric, has strong anticancer properties. However, there is no consensus on its therapeutic effect in human. Our earlier experiments involving implanted murine melanoma B16F10 cells in the neck or brain of syngeneic C57BL6 mice showed that tail vein injection of curcumin blocks formation of lesions and tumor in these mice. However, such treatment was ineffective in eliminating established tumors that already occupied ≤10% of brain volume. Possible reasons include low solubility and rapid metabolism of curcumin in vivo. To increase its efficacy, we have linked curcumin through a cleavable arm to an antibody (Ab) against the melanoma surface antigen Muc18. The antibody-coupled curcumin was 230-fold more effective in eliminating B16F10 cells in vitro, and in vivo, it rapidly decimated established, B16F10-evoked brain tumors, enabling the rescued mice to live normally far beyond 90 days from implantation of cancer cells. In contrast, mice treated with Muc18 Ab alone died of brain tumor within a month. In B16F10 cells, curcumin-Ab (adduct) treatment caused a dramatic inhibition of NF-kB: a transcription factor that is constitutively activated in cancer cells. Furthermore, overexpression of NF-kB in the B16F10 cells blocked adduct-evoked stimulation of caspase-3/7 activity. Thus, by suppressing NF-kB, the curcumin adduct inhibits other downstream tumor-promoting proteins, thereby eliminating the B16F10 cells. Our study submits a novel yet generally applicable strategy of converting curcumin into a potent anticancer agent and provides a mechanistic framework for its action.


Subject(s)
Antibodies, Neoplasm/immunology , Brain Neoplasms/drug therapy , Curcumin/therapeutic use , Immunoconjugates/therapeutic use , Melanoma, Experimental/pathology , Animals , Brain Neoplasms/immunology , Brain Neoplasms/secondary , Male , Mice , Mice, Inbred C57BL
8.
Methods Mol Biol ; 751: 29-42, 2011.
Article in English | MEDLINE | ID: mdl-21674323

ABSTRACT

We present here a general methodology for significantly increasing the number of dye/drug molecules that can be attached per protein molecule. As a demonstration of this approach, poly(acrylic acid) (PAA)-based near-infrared fluorescence (NIRF) dye- and glucose-incorporated novel copolymers were synthesized, which were further employed for bioconjugation to avidin and bovine serum albumin (BSA). In this method, azide-terminated poly(tert-butyl acrylate) was synthesized via atom transfer radical polymerization (ATRP). Subsequent deprotection was performed to yield poly(acrylic acid) (PAA) possessing a reactive chain-end. A one-pot sequential amidation of the PAA with the amine derivatives of a near-infrared fluorescent dye (ADS832WS) and glucose produced NIRF dye-incorporated water-soluble copolymers. End-group modifications were performed to produce alkyne/biotin-terminated copolymers, which were further employed to generate dye-incorporated polymer-protein hybrids via the biotin-avidin interaction with avidin or by "click" bioconjugation with azide-modified BSA.


Subject(s)
Fluorescent Dyes/chemistry , Polymers/chemistry , Proteins/chemistry , Alkynes/chemistry , Amines/chemistry , Animals , Avidin/chemistry , Biotin/chemistry , Cattle , Chromatography, Gel , Electrophoresis, Polyacrylamide Gel , Glucosamine/chemistry , Polyglutamic Acid/chemistry , Serum Albumin, Bovine/chemistry
9.
ACS Chem Neurosci ; 2(12): 694-9, 2011 Dec 21.
Article in English | MEDLINE | ID: mdl-22860163

ABSTRACT

The synthesis of a water/plasma soluble, noncytotoxic, "clicked" sugar-derivative of curcumin with amplified bioefficacy in modulating amyloid-ß and tau peptide aggregation is presented. Curcumin inhibits amyloid-ß and tau peptide aggregation at micromolar concentrations; the sugar-curcumin conjugate inhibits Aß and tau peptide aggregation at concentrations as low as 8 nM and 0.1 nM, respectively. In comparison to curcumin, this conveniently synthesized Alzheimer's drug candidate is a more powerful antioxidant.


Subject(s)
Amyloid beta-Peptides/metabolism , Curcumin/chemical synthesis , Curcumin/metabolism , Galactose/chemical synthesis , Galactose/metabolism , tau Proteins/metabolism , Alzheimer Disease/drug therapy , Alzheimer Disease/metabolism , Animals , Antioxidants/administration & dosage , Antioxidants/chemical synthesis , Antioxidants/metabolism , Cells, Cultured , Curcumin/administration & dosage , Galactose/administration & dosage , Hippocampus/drug effects , Hippocampus/metabolism , Humans , Mice
10.
Langmuir ; 26(4): 2688-93, 2010 Feb 16.
Article in English | MEDLINE | ID: mdl-20141209

ABSTRACT

The azide-alkyne cycloaddition "click" reaction was used to covalently bond high loadings of polymers and monosaccharides to the surface of an ordered mesoporous silica. The functionalization process was followed using thermogravimetry, gas adsorption, small-angle X-ray scattering, and infrared spectroscopy. Large-pore SBA-15 silica with cylindrical mesopores of diameter approximately 15 nm was synthesized using triisopropylbenzene as a micelle expander. The surface of the silica was modified with aminopropyl groups that were converted to propargyl-bearing groups through a reaction with 4-pentynoyl chloride. Thus prepared "clickable" pores were reacted with azide-functionalized poly(methyl methacrylate) (PMMA) and oligo(ethylene glycol) as well as protected and deprotected D-galactose. The new "grafting to" procedure allowed us to introduce uniform polymer films of thickness up to about 2 nm without any appreciable pore blocking, even for the polymer loading as high as 25 wt %. Uniform layers of monosaccharides with loadings up to 20 wt % were also obtained with remarkable grafting efficiency. No change in the periodic structure of the silica support was observed throughout the grafting process. These results demonstrate that the "click" reaction is a powerful approach to ordered mesoporous silicas with accessible pores functionalized with high loadings of various macromolecules and biomolecules.


Subject(s)
Ethylene Glycol/chemistry , Monosaccharides/chemistry , Polymethyl Methacrylate/chemistry , Silicon Dioxide/chemistry , Membranes, Artificial , Porosity , Surface Properties
11.
Bioconjug Chem ; 20(8): 1595-601, 2009 Aug 19.
Article in English | MEDLINE | ID: mdl-19588920

ABSTRACT

Azide-terminated poly(tert-butyl acrylate) was synthesized via atom transfer radical polymerization (ATRP). Subsequent deprotection was performed to yield poly(acrylic acid) (PAA) possessing a reactive chain-end. A one-pot sequential amidation of the PAA with the amine derivatives of a near-infrared fluorescent dye (ADS832WS) and glucose produced NIRF dye-incorporated water-soluble copolymers. End-group modifications were performed to produce alkyne/biotin-terminated copolymers which were further employed to generate dye-incorporated polymer-protein hybrids via the biotin-avidin interaction with avidin or "click" bioconjugation with azide-modified BSA. We have overcome two fundamental limitations in the synthesis of bioconjugates: (a) the basic restriction in the diversity of copolymers which can be synthesized for producing bioconjugates, (b) the limitation in the number of dyes/drug molecules that can be attached per protein molecule. The copolymers possessed enhanced optical properties compared to the dye due to increased solubility in water. Potential utility of these copolymers and conjugates in multiwell plate based assays, cell surface imaging and in vivo animal imaging were explored.


Subject(s)
Acrylic Resins/chemistry , Avidin/chemistry , Azides/chemistry , Fluorescent Dyes/chemistry , Glucose/chemistry , Serum Albumin, Bovine/chemistry , Acrylic Resins/chemical synthesis , Animals , Biotin/chemistry , Female , Fluorescent Dyes/chemical synthesis , Mice , Molecular Structure , Retinal Pigment Epithelium/chemistry , Retinal Pigment Epithelium/cytology , Solubility
12.
Org Lett ; 9(26): 5461-4, 2007 Dec 20.
Article in English | MEDLINE | ID: mdl-18020348

ABSTRACT

Curcumin, the primary active ingredient in the spice turmeric, was converted to reactive monofunctional derivatives (carboxylic acid/azide/alkyne). The derivatives were employed to produce a 3 + 2 azide-alkyne "clicked" curcumin dimer and a poly(amidoamine) (PAMAM) dendrimer-curcumin conjugate. The monofunctional curcumin derivatives retain biological activity and are efficient for labeling and dissolving amyloid fibrils. The curcumin dimer selectively destroys human neurotumor cells. The synthetic methodology developed affords a general strategy for attaching curcumin to various macromolecular scaffolds.


Subject(s)
Curcumin/chemistry , Polyamines/chemistry , Dendrimers , Dimerization , Humans , Magnetic Resonance Spectroscopy
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