Henry M. Smilowitz
University of Connecticut Health Center
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Featured researches published by Henry M. Smilowitz.
Physics in Medicine and Biology | 2004
James F. Hainfeld; Daniel N. Slatkin; Henry M. Smilowitz
Mice bearing subcutaneous EMT-6 mammary carcinomas received a single intravenous injection of 1.9 nm diameter gold particles (up to 2.7 g Au/kg body weight), which elevated concentrations of gold to 7 mg Au/g in tumours. Tumour-to-normal-tissue gold concentration ratios remained approximately 8:1 during several minutes of 250 kVp x-ray therapy. One-year survival was 86% versus 20% with x-rays alone and 0% with gold alone. The increase in tumours safely ablated was dependent on the amount of gold injected. The gold nanoparticles were apparently non-toxic to mice and were largely cleared from the body through the kidneys. This novel use of small gold nanoparticles permitted achievement of the high metal content in tumours necessary for significant high-Z radioenhancement.
Journal of Pharmacy and Pharmacology | 2008
James F. Hainfeld; F. Avraham Dilmanian; Daniel N. Slatkin; Henry M. Smilowitz
Gold is an excellent absorber of X‐rays. If tumours could be loaded with gold, this would lead to a higher dose to the cancerous tissue compared with the dose received by normal tissue during a radiotherapy treatment. Calculations indicate that this dose enhancement can be significant, even 200% or greater. In this paper, the physical and biological parameters affecting this enhancement are discussed. Gold nanoparticles have shown therapeutic efficacy in animal trials and these results are reviewed. Some 86% long‐term (>1 year) cures of EMT‐6 mouse mammary subcutaneous tumours was achieved with an intravenous injection of gold nanoparticles before irradiation with 250‐kVp photons, whereas only 20% were cured with radiation alone. The clinical potential of this approach is also discussed.
Physics in Medicine and Biology | 2010
James F. Hainfeld; F. Avraham Dilmanian; Zhong Zhong; Daniel N. Slatkin; John Kalef-Ezra; Henry M. Smilowitz
The purpose of this study is to test the hypothesis that gold nanoparticle (AuNP, nanogold)-enhanced radiation therapy (nanogold radiation therapy, NRT) is efficacious when treating the radiation resistant and highly aggressive mouse head and neck squamous cell carcinoma model, SCCVII, and to identify parameters influencing the efficacy of NRT. Subcutaneous (sc) SCCVII leg tumors in mice were irradiated with x-rays at the Brookhaven National Laboratory (BNL) National Synchrotron Light Source (NSLS) with and without prior intravenous (iv) administration of AuNPs. Variables studied included radiation dose, beam energy, temporal fractionation and hyperthermia. AuNP-mediated NRT was shown to be effective for the sc SCCVII model. AuNPs were more effective at 42 Gy than at 30 Gy (both at 68 keV median beam energy) compared to controls without gold. Similarly, at 157 keV median beam energy, 50.6 Gy NRT was more effective than 44 Gy NRT. At the same radiation dose ( approximately 42 Gy), 68 keV was more effective than 157 keV. Hyperthermia and radiation therapy (RT) were synergistic and AuNPs enhanced this synergy, thereby further reducing TCD50 s (tumor control dose 50%) and increasing long-term survivals. It is concluded that gold nanoparticles enhance the radiation therapy of a radioresistant mouse squamous cell carcinoma. The data show that radiation dose, energy and hyperthermia influence efficacy and better define the potential utility of gold nanoparticles for cancer x-ray therapy.
Nanomedicine: Nanotechnology, Biology and Medicine | 2013
James F. Hainfeld; Henry M. Smilowitz; Michael J O’Connor; Farrokh Avraham Dilmanian; Daniel N. Slatkin
AIM To test intravenously injected gold nanoparticles for x-ray imaging and radiotherapy enhancement of large, imminently lethal, intracerebral malignant gliomas. MATERIALS & METHODS Gold nanoparticles approximately 11 nm in size were injected intravenously and brains imaged using microcomputed tomography. A total of 15 h after an intravenous dose of 4 g Au/kg was administered, brains were irradiated with 30 Gy 100 kVp x-rays. RESULTS Gold uptake gave a 19:1 tumor to normal brain ratio with 1.5% w/w gold in tumor, calculated to increase local radiation dose by approximately 300%. Mice receiving gold and radiation (30 Gy) demonstrated 50% long term (>1 year) tumor-free survival, whereas all mice receiving radiation only died. CONCLUSION Intravenously injected gold nanoparticles cross the blood-tumor barrier, but are largely blocked by the normal blood-brain barrier, enabling high-resolution computed tomography tumor imaging. Gold radiation enhancement significantly improved long-term survival compared with radiotherapy alone. This approach holds promise to improve therapy of human brain tumors and other cancers.
British Journal of Radiology | 2011
James F. Hainfeld; M J O’Connor; F A Dilmanian; Daniel N. Slatkin; Douglas J. Adams; Henry M. Smilowitz
OBJECTIVES Gold nanoparticles are of interest as potential in vivo diagnostic and therapeutic agents, as X-ray contrast agents, drug delivery vehicles and radiation enhancers. The aim of this study was to quantitatively determine their targeting and microlocalisation in mouse tumour models after intravenous injection by using micro-CT. METHODS Gold nanoparticles (15 nm) were coated with polyethylene glycol and covalently coupled to anti-Her2 antibodies (Herceptin). In vitro, conjugates incubated with Her2+ (BT-474) and Her2- (MCF7) human breast cancer cells showed specific targeted binding with a Her2+ to Her2- gold ratio of 39.4±2.7:1. Nude mice, simultaneously bearing subcutaneous Her2+ and Her2- human breast tumours in opposite thighs were prepared. Gold nanoparticles alone, conjugated to Herceptin or to a non-specific antibody were compared. After intravenous injection of the gold nanoparticles, gold concentrations were determined by atomic absorption spectroscopy. Microlocalisation of gold was carried out by calibrated micro-CT, giving both the radiodensities and gold concentrations in tumour and non-tumour tissue. RESULTS All gold nanoparticle constructs showed accumulation, predominantly at tumour peripheries. However, the Herceptin-gold nanoparticles showed the best specific uptake in their periphery (15.8±1.7% injected dose per gram), 1.6-fold higher than Her2- tumours and 22-fold higher than surrounding muscle. Imaging readily enabled detection of small, 1.5 mm-thick tumours. CONCLUSION In this pre-clinical study, antibody-targeted 15 nm gold nanoparticles showed preferential uptake in cognate tumours, but even untargeted gold nanoparticles enhanced the visibility of tumour peripheries and enabled detection of millimetre-sized tumours. Micro-CT enabled quantification within various regions of a tumour.
International Symposium on Optical Science and Technology | 2001
Jean A. Laissue; Hans Blattmann; Marco Di Michiel; Daniel N. Slatkin; Nadia Lyubimova; Raphael Guzman; Werner Zimmermann; Stephan Birrer; Tim Bley; Patrick Kircher; Regina Stettler; Rosmarie Fatzer; A. Jaggy; Henry M. Smilowitz; Elke Brauer; Alberto Bravin; Géraldine Le Duc; Christian Nemoz; M. Renier; W Thomlinson; Jiri Stepanek; Hans-Peter Wagner
The cerebellum of the weanling piglet (Yorkshire) was used as a surrogate for the radiosensitive human infant cerebellum in a Swiss-led program of experimental microbeam radiation therapy (MRT) at the ESRF. Five weanlings in a 47 day old litter of seven, and eight weanlings in a 40 day old litter of eleven were irradiated in November, 1999 and June, 2000, respectively. A 1.5 cm-wide x 1.5 xm-high array of equally space approximately equals 20-30 micrometers wide, upright microbeams spaced at 210 micrometers intervals was propagated horizontally, left to right, through the cerebella of the prone, anesthetized piglets. Skin-entrance intra-microbeam peak adsorbed doses were uniform, either 150, 300, 425, or 600 gray (Gy). Peak and inter-microbeam (valley) absorbed doses in the cerebellum were computed with the PSI version of the Monte Carlo code GEANT and benchmarked using Gafchromic and radiochromic film microdosimetry. For approximately equals 66 weeks [first litter; until euthanasia], or approximately equals 57 weeks [second litter; until July 30, 2001] after irradiation, the littermates were developmentally, behaviorally, neurologically and radiologically normal as observed and tested by experienced farmers and veterinary scientists unaware of which piglets were irradiated or sham-irradiated. Morever, MRT implemented at the ESRF with a similar array of microbeams and a uniform skin-entrance peak dose of 625 Gy, followed by immunoprophylaxis, was shown to be palliative or curative in young adult rats bearing intracerebral gliosarcomas. These observations give further credence to MRTs potential as an adjunct therapy for brain tumors in infancy, when seamless therapeutic irradiation of the brain is hazardous.
Nanomedicine: Nanotechnology, Biology and Medicine | 2014
James F. Hainfeld; Lynn Lin; Daniel N. Slatkin; F. Avraham Dilmanian; Timothy M. Vadas; Henry M. Smilowitz
UNLABELLED Gold nanoparticles can absorb near infrared light, resulting in heating and ablation of tumors. Gold nanoparticles have also been used for enhancing the X-ray dose to tumors. The combination of hyperthermia and radiotherapy is synergistic, importantly allowing a reduction in X-ray dose with improved therapeutic results. Here we intratumorally infused small 15 nm gold nanoparticles engineered to be transformed from infrared-transparent to infrared-absorptive by the tumor, then heated by infrared followed by X-ray treatment. Synergy was studied using a very radioresistant subcutaneous squamous cell carcinoma (SCCVII) in mice. It was found that the dose required to control 50% of the tumors, normally 55 Gy, could be reduced to <15 Gy (a factor of >3.7). Gold nanoparticles therefore provide a method to combine hyperthermia and radiotherapy to drastically reduce the X-ray radiation needed, thus sparing normal tissue, reducing side effects, and making radiotherapy more effective. FROM THE CLINICAL EDITOR Gold nanoparticles are known to enhance the efficacy of X-ray in tumor irradiation resulting in tumor heating and ablation. They also absorb near infrared light. This dual property was studied using a very radioresistant subcutaneous squamous cell carcinoma in mice, demonstrating that the dose required to control 50% of the tumors could be reduced by a factor of > 3.7, paving the way to potential future clinical applications.
Cell | 1980
Henry M. Smilowitz
Abstract We show in this paper that the monovalent ionophores have a differential effect on the intracellular transport of two glycoproteins of skeletal muscle—an integral membrane protein (the acetylcholine receptor, ACHR) and a secretory protein (the acetylcholinesterase, ACHE). Both of these glycoproteins are found in the Golgi following their synthesis. Yet in the presence of very low concentrations of the monovalent ionophores, nigericin and monensin, ACHR continues to appear and accumulate at a-bungarotoxin-accessible sites at a nearly normal rate and is degraded at a normal rate, while ACHE secretion is substantially inhibited. Under these conditions, ACHE can be visualized associated with intracellular membranous structures that are probably deformed Golgi. These ACHE-enriched membranes have a distinctly different density profile from most of the ACHR-containing membranes of the myotube. Since it has been shown that the monovalent ionophores block the flow of membranes out of the Golgi, our data suggest that there are at least two kinds of mechanisms by which glycoproteins exit from the Golgi—one which is inhibited by the monovalent ionophores and one which is unaffected. We believe our data provide strong evidence that a secretory glycoprotein and an integral membrane glycoprotein are transported through the cell by distinct mechanisms.
PLOS ONE | 2014
James F. Hainfeld; Michael J. O'Connor; Ping Lin; Luping Qian; Daniel N. Slatkin; Henry M. Smilowitz
Gold nanoparticles (AuNPs) absorb light and can be used to heat and ablate tumors. The “tissue window” at ∼800 nm (near infrared, NIR) is optimal for best tissue penetration of light. Previously, large, 50–150 nm, gold nanoshells and nanorods that absorb well in the NIR have been used. Small AuNPs that may penetrate tumors better unfortunately barely absorb at 800 nm. We show that small AuNPs conjugated to anti-tumor antibodies are taken up by tumor cells that catalytically aggregate them (by enzyme degradation of antibodies and pH effects), shifting their absorption into the NIR region, thus amplifying their photonic absorption. The AuNPs are NIR transparent until they accumulate in tumor cells, thus reducing background heating in blood and non-targeted cells, increasing specificity, in contrast to constructs that are always NIR-absorptive. Treatment of human squamous cell carcinoma A431 which overexpresses epidermal growth factor receptor (EGFr) in subcutaneous murine xenografts with anti-EGFr antibodies conjugated to 15 nm AuNPs and NIR resulted in complete tumor ablation in most cases with virtually no normal tissue damage. The use of targeted small AuNPs therefore provides a potent new method of selective NIR tumor therapy.
Life Sciences | 1991
Henry M. Smilowitz; Lili Armli; Dong Xu; Paul M. Epstein
Using O-phosphotyrosine as a substrate, human platelets were shown to contain a highly active phosphotyrosine phosphatase (PTPase) activity. This activity was potently inhibited by vanadate, molybdate, and HgCl2. About 80% of the PTPase activity was particulate. When Triton-solubilized PTPase activity from whole platelets was applied to a DEAE Sephacel column about 40% came through unbound. The activity that bound was eluted by a NaCl gradient as a broad, heterogeneous peak. The possibility is raised for the existence of multiple forms of phosphotyrosine phosphatases in human platelets. That one or more of these forms may be regulated by activators of platelet aggregation and secretion, such as thrombin and collagen, is discussed.