Ashok K. Kakkar

McGill University, Montréal, Quebec, Canada

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Publications (123)573.16 Total impact

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    Anjali Sharma · Ashok Kakkar
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    ABSTRACT: To address current complex health problems, there has been an increasing demand for smart nanocarriers that could perform multiple complimentary biological tasks with high efficacy. This has provoked the design of tailor made nanocarriers, and the scientific community has made tremendous effort in meeting daunting challenges associated with synthetically articulating multiple functions into a single scaffold. Branched and hyper-branched macromolecular architectures have offered opportunities in enabling carriers with capabilities including location, delivery, imaging etc. Development of simple and versatile synthetic methodologies for these nanomaterials has been the key in diversifying macromolecule based medical therapy and treatment. This review highlights the advancement from conventional "only one function" to multifunctional nanomedicine. It is achieved by synthetic elaboration of multivalent platforms in miktoarm polymers and dendrimers by physical encapsulation, covalent linking and combinations thereof.
    Preview · Article · Sep 2015 · Molecules
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    ABSTRACT: A simple and versatile methodology, which employs a combination of ring-opening polymerization and alkyne-azide click chemistry to synthesize amphiphilic AB3 miktoarm stars, is reported. Their aqueous self-assembly behavior was studied using dynamic light scattering, fluorescence, and asymmetrical flow field-flow fractionation (AF4 ). AB3 miktoarm stars form micelles which incorporate curcumin with high efficiency, and significantly reduce the viability of glioblastoma cells in spheroids. We demonstrate that AF4 is an effective technique to determine the size distribution of self-assembled structures exposed to a biological medium. The ease, with which asymmetric AB3 miktoarm polymers are constructed, provides a platform that can be widely employed to deliver a variety of lipophilic drugs. © 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.
    No preview · Article · Aug 2015 · Macromolecular Bioscience
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    ABSTRACT: Design and synthesis of branched tetraethylene glycol (TEG) based ligands for subsequent conjugation to gold nanoshells, are reported. TEG enhances aqueous solubility of hollow gold nanoshells (HAuNSh), and the branched architecture provides stability. An examination of the supernatant of the surface displacement reaction shows that the structure of the ligand plays an important role during functionalization of HAuNSh. The binding of multivalent ligands leads to rupturing of the gold nanoshell architecture due most probably to the large dendron not compensating the replacement of small citrate capping agents. The construction of a probe with dual imaging capabilities is demonstrated by covalent linking of a dendron containing Cy5.5A dye to gold nanoshells. It leads to fluorescence quenching of Cy5.5A by the gold nanoshells, as evidenced in solution and in cellular internalization studies with J774 and bEnd.3 cells.
    Full-text · Article · Jan 2015 · Journal of Materials Chemistry B
  • Amir Sheikhi · Na Li · Theo G. M. van de Ven · Ashok Kakkar
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    ABSTRACT: Inorganic crystallization, commonly referred to as mineral scale formation, has posed tremendous challenges and is one of the leading assurance problems in water-based industries. A detailed understanding of the mechanism and influencing factors for the initiation and build-up of deposited scale is not only highly relevant for many industries but has also catalyzed academic research in developing efficient antiscalants. Macromolecules that can stop nucleation and inhibit crystallization or interact with forming crystals and modify their morphology to retard further growth have been the focus of intense scientific endeavors. There has been immense activity in developing additives which can regulate unwanted inorganic crystallization and understanding the complexity of how they work in preventing scale deposits. In this review, after a summary of the controlling parameters that define mineral scale growth, we review opportunities generated by using macromolecules as a platform for developing inhibitors for the two most common scale deposits, i.e. calcium salts and silica, with a discussion on their efficiencies in controlling nucleation and changing growing crystal morphology.
    No preview · Article · Jan 2015
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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.
    No preview · Article · Oct 2014 · ACS Macro Letters
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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.
    Full-text · Article · Sep 2014 · Macromolecular Bioscience
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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.
    Full-text · Article · Jul 2014 · Journal of Materials Chemistry B
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    Full-text · Dataset · Jan 2014
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    ABSTRACT: A versatile platform to track transport of dendrimers with fluorescent labels in the core and a desired number of drug molecules at the periphery, is reported.
    No preview · Article · Jan 2014 · RSC Advances
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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.
    Full-text · Article · Nov 2013 · Advances in Colloid and Interface Science
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    Pramod K Avti · Dusica Maysinger · Ashok Kakkar
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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.
    Full-text · Article · Aug 2013 · Molecules
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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.
    Full-text · Article · Apr 2013 · Molecular Pharmaceutics
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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.
    No preview · Article · Jan 2013
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    Pramod K. 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.
    Full-text · Article · Jan 2013 · Brazilian Journal of Pharmaceutical Science
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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.
    Full-text · Article · Jan 2013 · Contrast Media & Molecular Imaging

  • No preview · Article · May 2012 · ChemInform
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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.
    No preview · Article · Jan 2012 · New Journal of Chemistry
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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.
    Full-text · Article · Dec 2011 · Biomacromolecules
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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.
    Full-text · Article · Dec 2011 · Journal of Biomedical Optics
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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.
    No preview · Article · Nov 2011 · Chemical Communications

Publication Stats

3k Citations
573.16 Total Impact Points

Institutions

  • 1995-2015
    • McGill University
      • Department of Chemistry
      Montréal, Quebec, Canada
  • 1992-2010
    • Northwestern University
      • Department of Chemistry
      Evanston, Illinois, United States
  • 1991-2010
    • University of Cambridge
      Cambridge, England, United Kingdom
  • 1989-1999
    • University of Waterloo
      • Department of Chemistry
      Ватерлоо, Ontario, Canada
  • 1995-1996
    • Sultan Qaboos University
      • Department of Chemistry
      Masqaţ, Muḩāfaz̧at Masqaţ, Oman