Inhibition of HIV Fusion with Multivalent Gold Nanoparticles

Bowman, Mary Catherine; Ballard, T. Eric; Ackerson, Christopher J.; Feldheim, Daniel L.; Margolis, David M.; Melander, Christian

doi:10.1021/ja710321g

Cited by 345 publications

(309 citation statements)

References 13 publications

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“…The SNA-NC structure is highly tailorable, and the gold core can serve as a scaffold for multicomponent functionalization, not just with siRNAs, but with targeting antibodies or peptides, and small molecule drugs as well (22). As such, these SNA conjugates are part of the growing arsenal of nanomaterials that are showing promise as alternatives to conventional molecular formats for the development of novel and effective therapies for a wide variety of diseases (22,(37)(38)(39)(40).…”

Section: Discussionmentioning

confidence: 99%

Topical delivery of siRNA-based spherical nucleic acid nanoparticle conjugates for gene regulation

Zheng

Giljohann

Chen

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

368

288

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Topical application of nucleic acids offers many potential therapeutic advantages for suppressing genes in the skin, and potentially for systemic gene delivery. However, the epidermal barrier typically precludes entry of gene-suppressing therapy unless the barrier is disrupted. We now show that spherical nucleic acid nanoparticle conjugates (SNA-NCs), gold cores surrounded by a dense shell of highly oriented, covalently immobilized siRNA, freely penetrate almost 100% of keratinocytes in vitro, mouse skin, and human epidermis within hours after application. Significantly, these structures can be delivered in a commercial moisturizer or phosphate-buffered saline, and do not require barrier disruption or transfection agents, such as liposomes, peptides, or viruses. SNANCs targeting epidermal growth factor receptor (EGFR), an important gene for epidermal homeostasis, are >100-fold more potent and suppress longer than siRNA delivered with commercial lipid agents in cultured keratinocytes. Topical delivery of 1.5 uM EGFR siRNA (50 nM SNA-NCs) for 3 wk to hairless mouse skin almost completely abolishes EGFR expression, suppresses downstream ERK phosphorylation, and reduces epidermal thickness by almost 40%. Similarly, EGFR mRNA in human skin equivalents is reduced by 52% after 60 h of treatment with 25 nM EGFR SNA-NCs. Treated skin shows no clinical or histological evidence of toxicity. No cytokine activation in mouse blood or tissue samples is observed, and after 3 wk of topical skin treatment, the SNA structures are virtually undetectable in internal organs. SNA conjugates may be promising agents for personalized, topically delivered gene therapy of cutaneous tumors, skin inflammation, and dominant negative genetic skin disorders.T he recent development of small molecule inhibitors and antibodies that target components of signaling pathways has revolutionized the treatment of cancers, inflammatory diseases, and genetic disorders, including those that largely manifest in skin (1-3). These protein-based therapeutics, however, are costly, have limited targeting ability, and, when delivered through traditional intravenous or gastrointestinal routes, can lead to systemic toxicity (4, 5). Topical delivery is particularly attractive for the therapy of skin disorders. However, proteins larger than a few hundred daltons cannot easily enter the skin, and high concentrations of proteins must be applied for a cutaneous effect (6). An alternative to protein-based pathway inhibition involves the blocking and/or degradation of precursor mRNA before translation into protein. Gene silencing leads to down-regulation of protein expression and functions with greater specificity than inhibitors of protein function (7). In fact, targeted gene suppression by antisense DNA and siRNA has shown promising preclinical results, and/or is currently in clinical trials for a variety of diseases, including many forms of cancer (e.g., melanoma, neuroblastoma, and pancreatic adenocarcinoma), genetic disorders, and macular degeneration (8). For gene su...

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Section: Discussionmentioning

confidence: 99%

Topical delivery of siRNA-based spherical nucleic acid nanoparticle conjugates for gene regulation

Zheng

Giljohann

Chen

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

368

288

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“…Bowman and co-workers [180] have documented the first application of small-molecule coated gold nanoparticles as effective inhibitors of virus fusion. The gold nanoparticles employed as a platform (2.0 nm diameter) transformed a weakly binding and biologically inactive small molecule into a multivalent conjugate that effectively inhibited HIV-1 fusion to human T-cells.…”

Section: Antimicrobial and Antibacterial Agentsmentioning

confidence: 99%

“…The gold nanoparticles employed as a platform (2.0 nm diameter) transformed a weakly binding and biologically inactive small molecule into a multivalent conjugate that effectively inhibited HIV-1 fusion to human T-cells. Of significance is the similarity of this class of gold particles to proteins and dendrimers in terms of their atomical precision and mono-disperse nanosize [180] . The mercapto benzoic acid-coated gold nanoparticles were conjugated to SDC-1721, a derivative of TAK-779, which is a known CCR5 antagonist.…”

Section: Antimicrobial and Antibacterial Agentsmentioning

confidence: 99%

“…This molecule was thus instituted to demonstrate the feasibility of conjugating a low affinity, biologically inactive small molecule to a gold nanoparticle for the design of biologically active multivalent gold nanoparticle therapeutics. The mechanism of inhibition of viral replication was specific for viral entry [180] . A significant contribution was thus made by this study in demonstrating the first application of small molecule coated gold nanoparticles as effective inhibitors of HIV fusion.…”

Section: Antimicrobial and Antibacterial Agentsmentioning

confidence: 99%

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Plasmonic Nanoparticles and Their Conjugates: Preparation, Optical Properties and Antimicrobial Activity

Capek¹,

Internationals²

2015

JNMS

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To manipulate the size of noble metal particles on a nanometer scale are priority subjects in the field of nanotechnology. So far various approaches have been developed to synthesize noble metal nanoparticles in controlled sizes and dimensions. Among them the colloidal systems become broadly used. These systems can be made up of several very different reactants and solvents: a continuous medium water or alkane, surfactant and precursor(s). In some systems the formation of (sub) nanoparticles is based on the supersaturation of solution by reactants. The existence of the microenvironments gives them a particular ability to modulate the chemical reactivity of the reactants due to their compartmentalization in different microenvironments. The size and shape of noble metal nanoparticles follow the feed composition of reactants in the precursor solution, the reaction conditions and concentration and type of reactants. Surface modification and functionalization is expected to increase the stability of nanoparticles and organize them to the assembly of higher order array conjugates. Various soft and hard templates can be applied to produce noble metal nanoparticles in different shaped nanoreactors. Monodisperse gold nano crystals can grow inside soft templates and the cavities of hard templates by the reduction of metal ions trapped in the cavities. The interesting optical properties of noble metal nanoparticles and their (bio)conjugates results from the strong absorption in the visible spectrum region, so called the surface plasmon absorption. Some noble metal nanoparticles have been studied for their antimicrobial potential and have proven to be antibacterial and antiviral agents.

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“…Feldheim, Margolis, and Melander show that binding a weak inhibitor of HIV fusion to gold nanoparticles results in strong inhibition via multivalency. 14 The increased affinity that results from binding a CCR5 agonist to 2 nm gold nanoparticles is sufficient to overcome the need for a previously required quarternary ammonium group, which gave the agonist poor pharmacological properties. Dai and Lippard studied single-walled carbon nanotubes coupled via a Pt(VI) complex to a folic acid ligand.…”

mentioning

confidence: 99%

Chemistry at the Nano−Bio Interface

2009

J. Am. Chem. Soc.

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The interface of biology and inorganic materials represents one of the fastest growing and most promising areas of nanotechnology. The fifth issue of JACS Select contains 22 Communications and Articles from 2008 and early 2009 that illustrate the breadth and creative energy of this young field.Although the use of colloidal particles of metals and semiconductors as pigments dates back many centuries, and although the recipe for stable 6 nm diameter particles of gold ("Ruby gold") was famously devised by Faraday in 1857, 1 the unique properties of nanomaterials and their promise for applications in biochemistry, cell biology, and medicine have only recently been appreciated. Prior to the 1990s, the principal role of inorganic colloids in biological research was as high-contrast stains for electron microscopy. 2 A paradigm shift occurred in 1996, when Mirkin, Alivisatos, and co-workers coupled metal nanoparticles to DNA. 3 Their experiments demonstrated not only that DNA could be used for the organization of nanostructures, as had been suggested in earlier experiments by Seeman, 4 but also that nanoparticles were highly sensitive spectroscopic reporters for the base-pairing of DNA. Advances in the synthesis of crystalline, size-selected, and epitaxially capped semiconductor quantum dots early in the 1990s 5 set the stage for their conjugation to antibodies that could target them to specific biological molecules in cells. 6 These experiments demonstrated that brightly luminescent quantum dots were effective for intracellular imaging and were potentially competitive in that role with fluorescent molecules and proteins. Almost simultaneously, techniques were devised for controlling the size and understanding the magnetic behavior of transition metal oxide and magnetic alloy nanoparticles. By the end of the 1990s, bioconjugated magnetic nanoparticles were used for sophisticated imaging experiments 7 as well as for the targeted destruction of cancer cells. 8 Carbon nanotubes were discovered in the early 1990s, and versatile techniques were also developed for growing semiconductor nanowires. 9,10 Nanotubes and nanowires, because of their extreme aspect ratio and sensitivity to charge-transfer interactions, proved to be very sensitive platforms for the detection of biomolecules. 11 Research in the current decade has led to a much more sophisticated set of tools for controlling the size, shape, dispersity, and surface chemistry of nanoparticles. The complexity of nanoparticle structures s as nanoshells, prisms, Janus particles, derivatized nanotubes, core-shell particles, and striped nanowires, to name a few s offers new tools to tailor particles to specific problems in ultratrace detection, imaging, drug delivery, DNA/RNA delivery, and therapy. Sophisticated schemes for signal amplification, enhanced bioaffinity through multivalency, and cooperative binding highlight the synergy of nanoparticles as platforms for biological molecular recognition. The deliberate design of nanoparticles for biological applications, for exa...

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Inhibition of HIV Fusion with Multivalent Gold Nanoparticles

Cited by 345 publications

References 13 publications

Topical delivery of siRNA-based spherical nucleic acid nanoparticle conjugates for gene regulation

Topical delivery of siRNA-based spherical nucleic acid nanoparticle conjugates for gene regulation

Plasmonic Nanoparticles and Their Conjugates: Preparation, Optical Properties and Antimicrobial Activity

Chemistry at the Nano−Bio Interface

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