[Show abstract][Hide abstract] 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.
[Show abstract][Hide abstract] 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.
[Show abstract][Hide abstract] 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.
[Show abstract][Hide abstract] 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.
[Show abstract][Hide abstract] 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.
[Show abstract][Hide abstract] 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; · 6.17 Impact Factor
[Show abstract][Hide abstract] 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.
[Show abstract][Hide abstract] 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. · 2.97 Impact Factor
[Show abstract][Hide abstract] 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.
[Show abstract][Hide abstract] 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. · 2.88 Impact Factor
[Show abstract][Hide abstract] 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
[Show abstract][Hide abstract] 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
[Show abstract][Hide abstract] 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 4.24.4 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 chainchain 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
[Show abstract][Hide abstract] 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
[Show abstract][Hide abstract] 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.
[Show abstract][Hide abstract] ABSTRACT: We report here the design, synthesis, and properties, of multifunctional niacin nanoconjugates based on dendritic, miktoarm and linear backbone nanocarriers, using "click" chemistry. The conjugates were in this instance used to deliver the therapeutic agent niacin to lipid droplets. The desired combination of niacin, a lipophilic fluorescent dye (BODIPY), and polyethylene glycol (PEG), was achieved by covalently linking the desired agents to the selected carrier. The nanocarriers containing niacin and BODIPY were found almost exclusively within cytoplasmic lipid droplets in the cells used in this study (living hepatocytes and microglia), whereas the trifunctional carrier containing niacin, BODIPY and PEG was partially localized within these organelles but also elsewhere in the cytoplasmic compartment. Spectrofluorometric analyses, confocal microscopy and fluorescence cell sorting revealed different rates and extent of multifunctional conjugate(s) internalization in the two cell types. Even micromolar concentrations of the internalized multifunctional conjugates did not cause significant cell death or mitochondrial functional impairment, suggesting that they are suitable candidate nanostructures for lipid droplet imaging and for targeting drugs to these cellular organelles. These studies provide an efficient and easy way to synthesize multifunctional nanocarriers by click chemistry, applicable to the synthesis of related multifunctional nanostructures and to their use in the targeting of cellular organelles, including lipid droplets.
[Show abstract][Hide abstract] ABSTRACT: We report a nanocarrier based on A(2)B type miktoarm polymers (A=polyethylene glycol (PEG); B=polycaprolactone (PCL)) for nimodipine (NIM), a hydrophobic drug with very poor aqueous solubility that is commonly prescribed for the prevention and treatment of delayed ischemic neurological disorders. The A(2)B star polymers were constructed on a core with orthogonal functionalities that facilitated the performance of "click" chemistry followed by ring-opening polymerization. These star polymers assemble into spherical micelles into which NIM can be easily loaded by the co-solvent evaporation method. The micelles obtained from the star polymer PEG775(2)-PCL5800 showed NIM encapsulation efficiency of up to 78 wt% at a feed weight ratio of 5.0%. The loading efficiency of the micelles was dependent on the length of the PCL arm in the A(2)B miktoarm polymers. Aqueous solubility of NIM was increased by approximately 200 fold via micellar encapsulation. The in vitro release of NIM from the micelles was found to occur at a much slower rate than from its solution. Lipopolysaccharide induced nitric oxide production in N9 microglia cells was reduced in the presence of micelle-encapsulated NIM, as well as in the presence of micelles alone. The treatment of microglia with micelle-encapsulated NIM reduced the release of TNF-alpha, a pro-inflammatory cytokine. These results suggest that NIM-loaded miktoarm micelles could be useful in the treatment of neuroinflammation.
[Show abstract][Hide abstract] ABSTRACT: Silver nanoparticles continue to evoke great current interest due to their tremendous potential in designing smart materials for a wide variety of applications. Much emphasis has been placed lately in developing methodologies that could modulate the size and shape of these metal particles. Dendrimers that are monodisperse in nature with a regular and highly branched three-dimensional architecture, provide a useful platform to accomplish this goal. These hyperbranched macromolecules have been widely explored as templates in the construction of silver metal nanoparticles, and this review aims to provide a detailed overview of dendrimer-assisted synthesis of silver nanoparticles.
Advances in colloid and interface science 10/2010; 160(1-2):76-87. · 5.68 Impact Factor