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Huang H.S.,Nanoprobes, Inc. | Hainfeld J.F.,Nanoprobes, Inc.
International Journal of Nanomedicine | Year: 2013

Magnetic nanoparticles heated by an alternating magnetic field could be used to treat cancers, either alone or in combination with radiotherapy or chemotherapy. However, direct intratumoral injections suffer from tumor incongruence and invasiveness, typically leaving undertreated regions, which lead to cancer regrowth. Intravenous injection more faithfully loads tumors, but, so far, it has been difficult achieving the necessary concentration in tumors before systemic toxicity occurs. Here, we describe use of a magnetic nanoparticle that, with a well-tolerated intravenous dose, achieved a tumor concentration of 1.9mg Fe/g tumor in a subcutaneous squamous cell carcinoma mouse model, with a tumor to non-tumor ratio > 16. With an applied field of 38 kA/m at 980 kHz, tumors could be heated to 60°C in 2 minutes, durably ablating them with millimeter (mm) precision, leaving surrounding tissue intact. © 2013 Huang and Hainfeld, publisher and licensee Dove Medical Press Ltd.


Patent
Nanoprobes, Inc. | Date: 2010-11-24

Described herein are a class of metal oligomers and polymers that contain both metals and organic groups. Said oligomers and polymers have utility in many applications including biomedical imaging, radiation therapy, drug delivery, and in vitro analytical techniques, such as fluorescence and phosphorescence.


Grant
Agency: Department of Health and Human Services | Branch: National Institutes of Health | Program: SBIR | Phase: Phase I | Award Amount: 252.46K | Year: 2015

DESCRIPTION provided by applicant Novel transition metal complex cluster based probes for correlative light and electron microscopy CLEM and universally adoptable robust protocols for labeling whole tissue mounts will be developed The new probes and protocols will enable simultaneous localization of two or more antigens labeled using a single step labeling procedure Following fluorescence imaging the fluorescently labeled targets with analogs of ruthenium II poly pyridine will be made andquot visibleandquot in the electron microscope by catalyzed deposition of electron dense silver that provides higher contrast and well defined punctuate signal as compared to the photo polymerized andapos diaminobenzidine DAB that results in defuse signal and requires osmium tetroxide OsO The proposed probes have following advantages i higher quantum yields QY than gold probes and comparable QYs to the semiconductor andquot quantum dotsandquot QDs ii smaller hydrodynamic radii less toxicity and better stability in biological buffers than QDs iii long half lives and large Stokes shifts for time resolved imaging iv punctate signal and better signal to noise ratios in the EM following silver deposition as compared to photoconvertible fluorescent proteins and ReAsH reagents that use DAB OsO v possible imaging with some of the andquot super resolutionandquot techniques and vi correlative multiplexing when used with genetically encoded photo convertible and EM tags In Phase I the proposed probes will be used to accurately locate gap junctions at andquot mixed synapsesandquot conjoined electrical and chemical synaptic components and facilitate the unambiguous identification of one or two constituent synaptic proteins found at mixed synapses and determination of the membrane andquot sidednessandquot with correlative light and electron microscopy CLEM Localization of mixed synapses and specific synaptic proteins is problematic because cell membranes and their constituent proteins are below the limit of resolution of light microscopic imaging techniques CLEM will be carried out in collaboration with Dr Eduardo Rosa Molinar Biological Imaging Group University of Puerto Rico Rio Piedras Dr Rosa Molinar has been working on elucidating the spinal motor circuitry controlling the adult male Gambusiaandapos s extremely rapid ms coital behavior Gambusiaandapos s circuitry which is an ideal test system for performing CLEM with the new probes In the longer term we plan to develop reagents and protocols for correlative andquot super resolutionandquot microscopy and serial section electron tomography Serial Block Face dual beam SEM and tilt series TEM PUBLIC HEALTH RELEVANCE This project will provide researchers in cell molecular and structural biology with simple universal reagents for correlative light and electron microscopy to study cellular life processes and disease processes at macromolecular resolution providing structural information at the molecular level


Grant
Agency: Department of Health and Human Services | Branch: National Institutes of Health | Program: SBIR | Phase: Phase I | Award Amount: 224.54K | Year: 2015

DESCRIPTION provided by applicant We have discovered a novel method to eliminate specimen charging during scanning electron microscopic examination of tissue specimens using a metallographic staining technique that imparts bulk conductivity to embedded tissue This allows increased beam exposure and dwell time and when used in conjunction with backscatter electron detection and gold nanoparticle labeling potentially affords increased resolution from current limits of around nm to as little as nm The reagent comprises a novel combination of heavy metal staining and targeted enzyme mediated metal deposition enzyme metallography or EnzMet These reagents and procedure will be investigated step by step in order to establish a mechanism for the formation of conductivity establish which reagents are required and simplify and optimize the reagents and procedure for use with other stains and labels Systematic omission of processing steps will be used to identify the critical reactions systematic omission of reagents will then be used to determine which reagents are essential Controlled variation in reaction conditions time temperature buffers and concentrations will then be conducted for each reagent in order to infer its mechanism and mode of action Once optimized the new staining methodology will be combined with gold labeling using progressively smaller gold nanoparticle probes from to nm in size These studies will be used to determine a minimum gold nanoparticle size that may be visualized within large volume samples using FIB SEM and b extent of penetration of probes into samples up to m or more in all dimensions and cutoff sizes for gold nanoparticle conjugates that allow complete penetration In addition multiple labeling will be pursued using different sized gold nanoparticle labels to differentiate pre and post synaptic proteins Connexin and Connexin respectively in the spinal cord of the Western Mosquitofish Gambusia affinis while simultaneously contouring and segmenting neuronal boundaries using the optimized conductive metallographic staining PUBLIC HEALTH RELEVANCE A new specimen preparation method and reagents will be developed that may improve the resolution of the electron microscopic analysis of large volume specimens such as entire neuronal circuits by serial section methods such as Serial Block Face scanning electron microscopy SBFSEM and Focussed Ion Beam scanning electron microscopy FIB SEM from its current limits of around nm to as little as nm This will be co developed with small gold probes that will enable the macromolecular localization of functional components such as proteins with structures such as gap junctions that are too small to be resolved by current methods This will provide a breakthrough in understanding the structure function and distribution of components of systems such as neuronal networks Deliverables will include research tools to bring a new level of resolution to large scale projects such as the BRAIN initiative to map the structure function connectivity and plasticity of neural circuits but will also be applicable to many larger organs and systems in general This poses great challenges to conventional microscopic methods because integrative neuroscience requires information on both the distribution of targets within entire neural circuits and the precise localization of specific functional components of synapses and gap junctions at nanometer scale resolution Our approach is intended to provide an enabling technology that will stimulate the development of other complementary tools for brain mapping and large scale microscopic investigation such as novel correlative instrumentation and probes data acquisition and analysis and imaging technologies


Grant
Agency: Department of Health and Human Services | Branch: | Program: SBIR | Phase: Phase II | Award Amount: 791.25K | Year: 2011

DESCRIPTION (provided by applicant): This proposal is based on a recent discovery that tumors can bioconvert non-absorbing small metal nanoparticles into intense infrared (IR) absorbers. In preliminary tests, non-IR absorbing 15 nm gold nanoparticles wereimmunotargeted to human tumors in mice which then became highly IR absorbing. The amplification factor in IR absorption can be a factor of 20 or more, which is not accessible by use of other much larger nanoparticles (~130 nm) that are designed to initially absorb IR. This factor greatly enhances the tumor- to-non-tumor distinction. The small size also enhances tumor uptake. Treatment with IR led to rapid and complete tumor ablation in 1 cm tumors, whereas the tumors were not controlled in irradiated mice without the gold. This new IR bioamplification process will be studied and optimized to treat squamous cell carcinomas, which comprise 90% of head and neck cancers. Epidermal growth factor receptors (EGFr) are overexpressed by these tumors and covalent anti-EGFr antibody-gold conjugates will be used for targeting human A431 tumors in mice. A microscopic study will document tumor and normal tissue responses. In Phase II, this novel therapy will be optimized with respect to gold size and targeting ligand. TheIR hyperthermia therapy will then be combined with radiotherapy, since we have recently shown that hyperthermia and x-rays are highly synergistic in treating squamous cell carcinomas. The new combination therapy should better avoid damage to salivary glands and surrounding normal tissue, which is one of the serious side effects of current therapies. In order to demonstrate safety and safety limits, an acute, subacute, and long-term toxicity study will be conducted. Work will culminate in a product for FDA approval of clinical trials. If successful, this new approach could improve the treatment of head and neck as well as other cancers. PUBLIC HEALTH RELEVANCE: A novel cancer treatment using nanotechnology has recently been developed that is very promising inpreliminary animal studies. It also may be used for sensitive early detection of tumors and enable image guided interventions. If successful, it could improve detection and treatment of head and neck tumors as well as other cancers.


Grant
Agency: Department of Health and Human Services | Branch: National Institutes of Health | Program: STTR | Phase: Phase I | Award Amount: 225.00K | Year: 2016

DESCRIPTION provided by applicant We propose new probes for correlative super resolution fluorescence and electron microscopy that use biorthogonal reactions Click SNAP and HALO tags to label targets in living cells To minimize quenching of the fluorophores by the gold particles the small Undecagold gold atoms gold cluster label will be used this has minimal absorption at wavelengths above nm and therefore minimal overlap with emission of longer wavelength fluorophores Undecagold will be conjugated to ATTO N and SiR siliconized rhodamine longer wavelength fluorophores which are optimized for super resolution imaging and to Click and HALO tag ligands for bioorthogonal reactivity in living cells as well as for general labeling use We hypothesize that this probe configuration will provide much brighter fluorescence signals and will enable live cell and super resolution imaging which often photon are limiting These probes will combine high resolution dense and potentially quantitative labeling with a much smaller probe size than antibodies thus facilitating cellular delivery diffusion and targeting in living cells Preparations will be optimized to provide retenton of native fluorescence by quantum yield with average of or more fluorophores per gold label and Undecagold targeting group retention of native Click and HALO reactivity will be demonstrated by conjugation to test proteins bearing the conjugate tags followed chromatographic separation spectroscopic characterization and in vitro blot and light microscopy labeling The new probes will then be validated in correlative super resolution fluorescence and EM labeling experiments SIM STED and EM studies to a localize G protein coupled receptors GPCRs e g smoothened and b visualize the structure of the ciliary pocket by correlative fluorescence and electron microscopy Fluorescence brightness and quantum yield will be compared with those of combined fluorescent and gold immunoprobes fluorescence SIM and STED signals will be correlated with EM localization of targets PUBLIC HEALTH RELEVANCE A new class of combined fluorescent and gold labeling reagents will be developed that will enable labeling for both super resolution fluorescence microscopy and electron microscopy in a single labeling procedure furthermore these new probes will use biorthogonal reactions for labeling and thus may be used in living cells These will be the first combined fluorescent and gold labeling reagents Synthetic strategies and choice of labeling components will be optimized to minimize fluorescence quenching and deliver brighter fluorescent signals using smaller probes capable of high density labeling and fast tissue penetration Deliverables will include research tools to leverage the power of correlated electron microscopy to provide a morphological context and macromolecular localization for super resolution fluorescence microscopy to bring a new level of resolution to the study of biological processes at high resolution in both prepared specimens and in living cells In addition to the specific application proposed for validation our approach is intended to provide an enabling technology that will stimulate the development of complementary tools for other large scale projects such as the BRAIN initiative to map the structure function connectivity and plasticity of neural circuits Such systems pose great challenges for conventional microscopic methods because information is required on both the distribution of targets within entire systems and the precise localization of specific functional components at nanometer scale resolution


Grant
Agency: Department of Health and Human Services | Branch: National Institutes of Health | Program: SBIR | Phase: Phase I | Award Amount: 245.98K | Year: 2016

DESCRIPTION provided by applicant Every year more than people in the U S are diagnosed with primary brain tumors with deaths The five year survival rate is Primary brain tumors also account for of the cancers in children More effective treatments of malignant brain tumors are desperately needed We have pioneered the use of gold nanoparticles AuNPs to enhance radiotherapy In previous work we showed that Nanogold enhanced radiosurgery of a very aggressive orthotopic glioma in mice resulted in long term survival andgt days compared to with radiosurgery alone The AuNPs were IV administered Concerns about translation to humans of this very promising result include a the high cost of gold actually less than many antibody therapies b slow body clearance and c effectiveness of the Enhanced Permeability andamp Retention EPR effect for delivery in humans Upon further analysis we now propose a novel procedure to overcome not just these objections but the true barriers to effective glioma therapy After urgent surgery to remove the primary brain tumor and relieve dangerous intracranial pressure recurrence invariably develops Surgery typically does not remove the entire tumor especially difficult since tumor cells migrate even up to cm A number of studies have shown escaping tumor cells migrate in the peritumor edema often along white matter tracts Our hypothesis is that AuNPs can be designed to also move and distribute in this peritumor edema When infused in the primary tumor site they will because of their smaller size andquot catch upandquot to and engulf migrating tumor cells A gold concentration will be administered that will lead to enhancing radiotherapy by a factor of boosting Gy to Gy Normal brain would be spared since the X ray generated electrons from the gold only travel several microns thus tightly confining the boosted radiation dose To test this F tumor cells will be transduced with red fluorescent protein and luciferase and tumors orthotopically grown in rats The small AuNPs will be visualized with silver enhancement and the coincidence of AuNPs and tumor cells will be studied histologically Edema will be stained with anti albumin FITC Acceptable toxicity will be sought Radiotherapy will test efficacy Another advantage of this approach is that radiation resistant cancer stem cell as well as dormant and drug resistant tumor cells will be killed since the target of the increased radiation is the tumor cellsandapos DNA itself rather than any particular metabolic pathway This approach overcomes concerns of cost of an IV injection of gold a much smaller amount needed locally Loading other organs and whole body retention will be minimal and the gold no longer has to pass through a leaky endothelium it is administered directly to the edema in which the tumor cells reside Importantly it addresses the main reason why all current GBM therapies fail ineffective treatment of residual and migrant cells This approach represents a major paradigm shift for radiotherapy since a larger brain volume to cover the escaped cells will be irradiated a procedure now forbidden due to whole brain radiation constraints but now made possible via the very specific gold boost PUBLIC HEALTH RELEVANCE A new method is proposed using gold nanoparticles to kill brain tumor cells that currently evade surgery radiotherapy and chemotherapy This could significantly improve outcomes from one of the most dangerous and difficult to treat cancers


Grant
Agency: Department of Health and Human Services | Branch: | Program: SBIR | Phase: Phase I | Award Amount: 159.65K | Year: 2014

DESCRIPTION (provided by applicant): Gold nanoparticles are the label of choice for electron microscopy (EM) since they offer a choice of sizes that provide quantitative, high-resolution identification of targets. Recently, high-resolution EM methods including cryoEM and electron tomography have benefitted from significant advances in instrumentation and a series of breakthroughs in specimen processing and preparative equipment that have made these methods widely accessible. However, conventional colloidalgold labels do not allow the full realization of the potential in these methods, because they require extensive stabilization with large macromolecules that limit penetration and antigen access, and also because their mechanism of conjugation, through adsorption to targeting antibodies or proteins, does not allow direct labeling of specific reactive sites within macromolecular complexes at sufficiently high resolution. Nanoprobes has developed 1.4 nm (Nanogold) and 0.8 nm (Undecagold) gold nanoparticle


Grant
Agency: Department of Health and Human Services | Branch: | Program: SBIR | Phase: Phase I | Award Amount: 228.90K | Year: 2012

DESCRIPTION (provided by applicant): Recent advances in microCT machines have made it possible to image with a resolution of lt 10 m. Scans take ~6 to 20 minutes to acquire, and current iodine contrast agents due to their short half life are not generallysuitable. We recently commercialized gold X-ray contrast agent, AuroVist , but they are more expensive than iodine agents. We now propose to develop heavy metal nanoparticle contrast agents based on tungsten and bismuth that are lot cheaper than our gold-based contrast agents and more absorptive than iodine. The new agents can be functionalized with reactive groups for covalent cross-linking to targeting molecules and will enable in vivo visualization of organ function, angiogenesis, repair, tumor formation, metastasis, studies of response to drugs and other therapies or conditions, such as ischemia or radiation, and basic biological studies of animals including development, infection, immune response, cardiac studies, tissue injury and healing. The iodinated contrast agents cause contrast induced reactions (CIRs) in many patients, including those with allergies, asthma, kidney diseases and diabetes. For patients with compromised kidneys the CIRs can have serious consequences. The CIRs are attributed to the high viscosity and osmolality of the iodine agents. The proposed novel surface modifications to the heavy metal agents will improve their viscosities. The smaller tungsten and bismuth nanoparticles with lt 5.5 nm hydrodynamic diameter can hold gt250 metal atoms per particles as compared to 3 or 6 iodine atoms; they will have much lower osmolality and produce higher contrast, and help alleviate problems related to contrast induced nephropathy. Finally, because the K-edges of tungsten (69.52 keV) and bismuth (90.5 keV) are well separated from iodine (33.12 keV), simultaneous double contrasting ( K-edge imaging with iodine and tungsten/or bismuth) will be possible with dual-energy (dual-beam/dual-detector) CT. PUBLIC HEALTH RELEVANCE: The proposed novel non-toxic tungsten and bismuth contrast agents for in vivo microCT X-ray imaging have higher attenuation coefficients than iodine agents and will reduce X-ray dose to millions of patents, and when used with iodine agents will enable simultaneousimaging of two targets with dual-energy CT.


Patent
Nanoprobes, Inc. | Date: 2011-03-25

The present disclosure relates to the product, process, and use of 5 nm Nickel-Nitrilotriacetic acid (Ni-NTA) gold nanoparticles. Applications include diagnostic tests, imaging, therapies, detection technologies, gold conjugation to other molecules, and novel material constructs.

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