Ashok K. Kakkar

McGill University, Montréal, Quebec, Canada

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Publications (86)308.28 Total impact

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    ABSTRACT: Simple and highly versatile click chemistry based synthetic strategy to develop an ABC type miktoarm star ligand that is conjugated to gold nanoshells (GNS), is reported. The surface functionalized multifunctional GNS contain lipoic acid (LA) as a model therapeutic, poly(ethylene glycol) (PEG350) as solubilizing and stealth agent, and tetraethylene glycol (TEG) with a terminally conjugated thiol moiety. These GNS have an average size of 40 nm, shell thickness of 6 nm, a well-defined crystal structure lattice (111), and a surface absorption plasmon band in the near infrared (NIR) region. Miktoarm star and GNS functionalized with this ligand are non-cytotoxic for up to 5 µg/mL concentrations, and human umbilical vein endothelial cells internalize more than 85% of these GNS at 5µg/mL. Our results establish that biocompatible miktoarm star ligand provides a useful platform to synthetically articulate the introduction of multiple functions onto GNS, and enhance their scope by combining their inherent imaging capabilities with efficient delivery and accumulation of active therapeutic agents.
    Journal of Material Chemistry B. 07/2014;
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    ABSTRACT: A versatile methodology to develop an inherently fluorescent and thus traceable multifunctional nanodelivery platform based on miktoarm polymers is reported. Miktoarm stars containing covalently linked tetraiodofluorescein dye, polyethylene glycol, and polycaprolactone self-assemble into micelles, and integrate multiple functions including fluorescent tags for imaging, a hydrophobic core for drug incorporation, and a hydrophilic corona for micelle stabilization. Curcumin, a pleiotropic but very poorly water-soluble drug, is loaded into these micelles with an efficiency of 25-60 wt%. It leads to a 25 000-fold increase in its aqueous solubility, and a sustained release over a period of 7 d. These micelles are rapidly internalized into murine J774A.1 macrophages, and accumulated into discrete cellular compartments, whereas the free and physically encapsulated dye is diffused in the cytoplasm. Curcumin-loaded micelles reduce lipopolysaccharide-induced nitric oxide release. The studies establish miktoarm star based nanocarriers as highly efficient in tracking their fate and expanding the scope of pharmacological agents with limited utility in experimental medicine.
    Macromolecular Bioscience 06/2014; · 3.74 Impact Factor
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    ABSTRACT: We report a versatile approach in which two highly efficient chemical reactions, multicomponent A3 coupling and alkyne?azide click chemistry, are combined to construct dendrimer-based tools for applications in biology. Using a convergent approach, dendrons with desired architecture and an alkyne at the focal point are first assembled and then stitched together via multicomponent A3 coupling reaction. The desired functional groups, including a stealth agent, imaging dye, and drug molecules, could be easily covalently linked to the surfaces of these hyperbranched macromolecules using alkyne?azide click chemistry. These A3-click dendrimers are noncytotoxic at concentrations as high as 1 ?M and in fact reduce the toxicity of the drug. The dye-coated dendrimers specifically target and localize in lipid droplets. This unison methodology represents an attractive chemical strategy in exploiting the untapped potential of A3 coupling and facilitating the development of nanodevices for imaging and drug delivery.
    ACS Macro Letters 01/2014; · 5.24 Impact Factor
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    ABSTRACT: These studies explore the relationship between the inhibitory actions of low generation dendrimers in stimulated microglia and dendrimer-enzyme interactions using in-silico molecular modelling. Low generation (G0 and G1) dendrimers with acetylene and hydroxyl terminal groups were tested for their anti-inflammatory effect in microglia stimulated by lipopolysaccharides (LPS), and the results compared with those from the established anti-inflammatory agents, ibuprofen and celecoxib. We hypothesized that hydroxyl terminal groups of G0 and G1 dendrimers could bind favourably to the active sites of the inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) enzymes due to their small size and favourable electro-chemical properties. The enzymatic activity of iNOS and COX-2 was determined in the presence of low generation dendrimers using biochemical assays and their values related to dendrimer docking confirmations from in-silico molecular modeling. We found that results from the molecular modeling studies correlated well with the in vitro biological data, suggesting that indeed, hydroxyl terminal groups of low generation dendrimers enable multivalent macromolecular interactions, resulting in the inhibition of both iNOS and COX-2 enzymes.
    Molecular Pharmaceutics 04/2013; · 4.57 Impact Factor
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    Pramod Avti, Ashok kakkar
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    ABSTRACT: Dendrimers constitute an intriguing class of macromolecules which find applications in a variety of areas including biology. These hyperbranched macromolecules with tailored backbone and surface groups have been extensively investigated as nanocarriers for gene and drug delivery, by molecular encapsulation or covalent conjugation. Dendrimers have provided an excellent platform to develop multivalent and multifunctional nanoconjugates incorporating a variety of functional groups including drugs which are known to be anti-inflammatory agents. Recently, dendrimers have been shown to possess anti-inflammatory properties themselves. This unexpected and intriguing discovery has provided an additional impetus in designing novel active pharmaceutical agents. In this review, we highlight some of the recent developments in the field of dendrimers as nanoscale anti-inflammatory agents.
    Brazilian Journal of Pharmaceutical Science 01/2013; 49(Special Issue):57-65. · 0.37 Impact Factor
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    ABSTRACT: The development of molecular probes and novel imaging modalities, allowing better resolution and specificity, is associated with an increased potential for molecular imaging of atherosclerotic plaques especially in basic and pre-clinical research applications. In that context, a photoacoustic molecular probe based on gold nanoshells targeting VCAM-1 in mice (immunonanoshells) was designed. The molecular probe was validated in vitro and in vivo, showing no noticeable acute toxic effects. We performed the conjugation of gold nanoshells displaying near-infrared absorption properties with VCAM-1 antibody molecules and PEG to increase their biocompatibility. The resulting immunonanoshells obtained under different conditions of conjugation were then assessed for specificity and sensitivity. Photoacoustic tomography was performed to determine the ability to distinguish gold nanoshells from blood both in phantoms and in vivo. Ex vivo optical projection tomography of hearts and aortas from atherosclerotic and control mice confirmed the selective accumulation of the immunonanoshells in atherosclerotic-prone regions in mice, thus validating the utility of the probe in vivo in small animals for pre-clinical research. These immunonanoshells represent an adequate mean to target atherosclerotic plaques in small animals, leading to new tools to follow the effect of therapies on the progression or regression of the disease. Copyright © 2012 John Wiley & Sons, Ltd.
    Contrast Media & Molecular Imaging 01/2013; 8(1):27-39. · 2.87 Impact Factor
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    ABSTRACT: Imaging for diagnostics or for evaluating the efficacy of a particular drug constitutes a key challenge, and a topical area of research in nanomedicine. There has been a tremendous effort devoted to the evaluation of a variety of contrast agents, and gold nanomaterials due to their inherent and geometrically induced optical properties, have offered significant potential for in vivo imaging. The gold based nanostructures that are most commonly employed for biological imaging include nano-spheres, -rods, -shells, -cages and -stars. This feature article provides an overview of the current state of research in utilizing these gold nano-architectures in imaging, with particular emphasis on modalities such as two-photon luminescence, computed tomography, optical coherence tomography, near infrared and photoacoustic imaging.
    J. Mater. Chem. B. 01/2013; 1(1):9-25.
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    ABSTRACT: The need to target, deliver and subsequently evaluate the efficacy of therapeutics in the treatment of a disease has provided added impetus in developing novel and highly efficient contrast agents. Superparamagnetic iron oxide nanoparticles (SPIONs) have offered tremendous potential in designing advanced magnetic resonance imaging (MRI) diagnostic agents, due to their unique physicochemical properties. There has been tremendous effort devoted in the recent past in developing synthetic methodologies through which their size, hydrodynamic radii, chemical composition and morphologies could be tailored at the nanoscale. This enables one to fine tune their magnetic behavior, and thus their MRI response. While novel synthetic strategies are being assembled for directing SPIONs to the diseased site as well as imparting them stealth and biocompatibility, it is also essential to evaluate their biological toxicological profiles. This review highlights recent advances that have been made in the synthesis of SPIONs, subsequent functionalization with desired entities, and a discussion on their use as MRI contrast agents in cardiovascular research.
    Advances in Colloid and Interface Science 01/2013; · 8.64 Impact Factor
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    ABSTRACT: The alkyne-azide cycloaddition, popularly known as the "click" reaction, has been extensively exploited in molecule/macromolecule build-up, and has offered tremendous potential in the design of nanomaterials for applications in a diverse range of disciplines, including biology. Some advantageous characteristics of this coupling include high efficiency, and adaptability to the environment in which the desired covalent linking of the alkyne and azide terminated moieties needs to be carried out. The efficient delivery of active pharmaceutical agents to specific organelles, employing nanocarriers developed through the use of "click" chemistry, constitutes a continuing topical area of research. In this review, we highlight important contributions click chemistry has made in the design of macromolecule-based nanomaterials for therapeutic intervention in mitochondria and lipid droplets.
    Molecules 01/2013; 18(8):9531-49. · 2.43 Impact Factor
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    ABSTRACT: Hyperbranched and monodisperse macromolecules of nanodimensions, commonly referred to as dendrimers, have offered significant potential in addressing key issues in biology. In addition, their monodisperse nature and a generally described globular architecture with high surface group density, make them very coveted candidates as antimicrobial agents. Here, we provide an overview of what has been accomplished in exploring the potential of dendrimers as bactericides, as well as an analysis of the factors influencing their biocidal activity.
    New Journal of Chemistry 01/2012; 36(2):199-204. · 3.16 Impact Factor
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    ABSTRACT: Impairments of mitochondrial functions have been associated with failure of cellular functions in different tissues, leading to various pathologies. We report here a mitochondria-targeted nanodelivery system for coenzyme Q10 (CoQ10) that can reach mitochondria and deliver CoQ10 in adequate quantities. Multifunctional nanocarriers based on ABC miktoarm polymers (A = poly(ethylene glycol (PEG), B = polycaprolactone (PCL), and C = triphenylphosphonium bromide (TPPBr)) were synthesized using a combination of click chemistry with ring-opening polymerization, self-assembled into nanosized micelles, and were employed for CoQ10 loading. Drug loading capacity (60 wt %), micelle size (25-60 nm), and stability were determined using a variety of techniques. The micelles had a small critical association concentration and were colloidally stable in solution for more than 3 months. The extraordinarily high CoQ10 loading capacity in the micelles is attributed to good compatibility between CoQ10 and PCL, as indicated by the low Flory-Huggins interaction parameter. Confocal microscopy studies of the fluorescently labeled polymer analog together with the mitochondria-specific vital dye label indicated that the carrier did indeed reach mitochondria. The high CoQ10 loading efficiency allowed testing of micelles within a broad concentration range and provided evidence for CoQ10 effectiveness in two different experimental paradigms: oxidative stress and inflammation. Combined results from chemical, analytical, and biological experiments suggest that the new miktoarm-based carrier provides a suitable means of CoQ10 delivery to mitochondria without loss of drug effectiveness. The versatility of the click chemistry used to prepare this new mitochondria-targeting nanocarrier offers a widely applicable, simple, and easily reproducible procedure to deliver drugs to mitochondria or other intracellular organelles.
    Biomacromolecules 12/2011; 13(1):239-52. · 5.37 Impact Factor
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    ABSTRACT: In this paper, we present a dual-modality imaging system combining three-dimensional (3D) continuous-wave transillumination fluorescence tomography with 3D ultrasound (US) imaging. We validated the system with two phantoms, one containing fluorescent inclusions (Cy5.5) at different depths, and another varying-thickness semicylindrical phantom. Using raster scanning, the combined fluorescence/US system was used to collect the boundary fluorescent emission in the X-Y plane, as well as recovered the 3D surface and position of the inclusions from US signals. US images were segmented to provide soft priors for the fluorescence image reconstruction. Phantom results demonstrated that with priors derived from the US images, the fluorescent reconstruction quality was significantly improved. As further evaluation, we show pilot in vivo results using an Apo-E mouse to assess the feasibility and performance of this system in animal studies. Limitations and potential to be used in artherosclerosis studies are then discussed.
    Journal of Biomedical Optics 12/2011; 16(12):126010. · 2.75 Impact Factor
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    ABSTRACT: A simple and versatile dendrimer based platform to deliver therapeutic agents at temperatures within the physiological range, is reported. Lipoic acid conjugated at the periphery of the thermosensitive dendrimer formulations undergoes slow and sustained release at 37-42 °C, and rescues the cells from oxidative stress and a pro-inflammatory endotoxic agent.
    Chemical Communications 11/2011; 47(44):12146-8. · 6.38 Impact Factor
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    ABSTRACT: The delivery of biologically active agents to the desired site in the body and intracellular organelles is still a big challenge despite efforts made for more than five decades. With the elaboration of synthetic methodologies to branched and hyperbranched macromolecules such as miktoarm stars and dendrimers, the focus has shifted to nanocarriers able to release and direct drug molecules to a desired location in a controlled manner. We present here recent developments in the field of targeted drug delivery with a focus on two specific macromolecular nanocarriers, dendrimers and miktoarm stars, and provide examples of these nanocarriers tested in different biological systems. A particular attraction of miktoarm stars is their versatility in achieving superior drug loading within their self-assembled structures. Advantages of dendrimers over linear polymers are that the former provide a platform for development of multivalent and multifunctional nanoconjugates, in addition to their ability to accommodate a large number of molecules inside, or at their surfaces.
    Chemical Communications 06/2011; 47(34):9572-87. · 6.38 Impact Factor
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    ABSTRACT: Geometric modelling techniques are used to map the potential energies of packing for self-assembled alkyl- and phenyl-backboned monolayers across a range of intermolecular separations. Natural packing distances of 4.2–4.4 Å produce less stable, more isotropic monolayers because of repulsive interchain contacts. Optimizations at unnatural surface densities found thin films of lower energy and higher symmetry existed at increased chain–chain separations. Head-group bonding is therefore identified as a force for controlling monolayer order. Analysis of the natural monolayer structures on a silicon dioxide surface determined the favourable head-group structures, and allowed the topochemical polymerization of p-bis(butadiynyl)benzene monolayers to be rationalized.Key words: self-assembled monolayers, molecular modelling studies, repeating symmetry units, thin-film order, topochemical polymerization.
    Canadian Journal of Chemistry 02/2011; 81(11):1228-1240. · 0.96 Impact Factor
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    ABSTRACT: Reactions of (η5-1-CH3-C9H6)Rh(η2-C2H4)2 with PCy3 (Cy = cyclohexyl) and 1,2-bis(dicyclohexylphos - phino)ethane (dcpe = Cy2PCH2CH2PCy2) gave complexes (η5-1-CH3-C9H6)Rh(η2-C2H4)(PCy3) (1) and (η5-1-CH3-C9H6)Rh(dcpe) (2), respectively, in high yields. Complexes 1 and 2 were characterized by x-ray diffraction studies and by multinuclear NMR spectroscopy. Variable temperature 31P{1H} NMR spectra allowed for evaluation of energy barriers associated with indenyl ring rotation. While 1 and 2 displayed similar degrees of slip-fold distortion with respect to bonding of the indenyl ligand to the RhL2 fragment, a lower energy barrier to ring rotation was calculated for the mixed ethylene-phosphine complex 1. Yellow crystals of 1 are orthorhombic, Pbca with 16 molecules per unit cell of dimensions a = 11.341(3), b = 32.915(10), and c = 29.413(9) Å. Yellow crystals of 2 are triclinic, P1 with two molecules per unit cell dimensions a = 9.327(3), b = 10.117(3), c = 18.934(6) Å, α = 104.28(2)°, β = 101.34(2)°, and γ = 92.99(2)°.Key words: indenyl, rhodium, phosphines, ring-slippage.
    Canadian Journal of Chemistry 02/2011; 77(2):205-215. · 0.96 Impact Factor
  • Tatiana Vassilieff, Ashok Kakkar
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    ABSTRACT: We report on the synthesis and detailed characterization of dendrimers that evolve symmetrically from a linear core of 2-butyne-1,4-diol with 3,5-dihydroxybenzyl alcohol based dendron arms. The divergent layer-by-layer build-up of the dumbbell-shaped dendrimers is based on simple acid–base hydrolytic chemistry of bis(dimethylamino)dimethylsilane with OH-terminated molecules. The self-assembly of these dendrimers in THF and water is significantly influenced by their generation number, the backbone structure, and the solvent.Key words: dendrimers, divergent synthesis, macromolecules, self-assembly
    Canadian Journal of Chemistry 02/2011; 86(6):540-547. · 0.96 Impact Factor
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    ABSTRACT: The synthesis of a series of permethylindenyl (Ind*) rhodium(III) complexes, [(η5-C9Me7)RhCl(μ-Cl)]2, [(η5-C9Me7)RhLCl2] (L = PMe3, PMe2Ph, PPh3), and [(η5-C9Me7)Rh(PMe3)2Cl]+Cl−, is reported. The structure of [(η5-C9Me7)RhCl(μ-Cl)]2, (4) was determined, confirming the dimeric nature of the compound. Ruby red crystals of 4 are monoclinic, space group C2/c, with four molecules per unit cell of dimensions a = 18.598(5), b = 10.520(3), c = 17.376(3) Å and β = 115.10(2)°. The indenyl rings exhibit minimal distortion from perfect η5 coordination to the Rh centres. A single crystal X-ray structure determination of [(η5-C9Me7)Rh(PMe2Ph)Cl2] (6) indicates a more distorted η5-coordination of the indenyl ligand, with the auxiliary ligand having the greatest trans influence, namely, the PMe2Ph group, being trans to the indenyl ring junction C—C bond. Yellow prismatic crystals of 6 are orthorhombic, space group P212121, with four molecules per unit cell of dimensions a = 8.819(1), b = 15.303(3), c = 17.296(3) Å. Keywords: rhodium, indenyl, permethylindenyl, heptamethylindenyl, phosphine complex. X-ray structure.
    Canadian Journal of Chemistry 02/2011; 73(7):981-988. · 0.96 Impact Factor
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    ABSTRACT: Bi- and trifunctional dendrimer and miktoarm nanocarriers, containing a combination of covalently linked model drug (α-lipoic acid), fluorescent dye (BODIPY), and poly(ethylene glycol) (PEG), are synthesized using a core with orthogonal functional groups, on which Huisgen alkyne?azide ?click? reactions are performed in sequence. These carriers are internalized into the cells where they reduce H2O2 induced reactive oxygen species formation. In addition, miktoarm nanocarriers conjugated with α-lipoic acid enhance intracellular glutathione (GSH) concentrations.
    Macromolecules 01/2011; 44(3):521-529. · 5.93 Impact Factor

Publication Stats

318 Citations
308.28 Total Impact Points

Institutions

  • 1995–2014
    • McGill University
      • Department of Chemistry
      Montréal, Quebec, Canada
  • 1994
    • Beloit College
      Beloit, Wisconsin, United States
  • 1993
    • Northwestern University
      • Department of Chemistry
      Evanston, Illinois, United States
  • 1991–1992
    • University of Cambridge
      • Department of Chemistry
      Cambridge, England, United Kingdom