In silico dosimetry of low-dose rate brachytherapy using radioactive nanoparticles.

PURPOSE: Nanoparticles (NPs) with radioactive atoms incorporated within the structure of the NP or bound to its surface, functionalized with biomolecules are reported as an alternative to low-dose-rate seed-based brachytherapy. In this study, authors report a mathematical dosimetric study on low-dose rate brachytherapy using radioactive NPs. METHOD: Single-cell dosimetry was performed by calculating cellular S-values for spherical cell model using Au-198, Pd-103 and Sm-153 NPs. The cell survival and tumor volume versus time curves were calculated and compared to the experimental studies on radiotherapeutic efficiency of radioactive NPs published in the literature. Finally, the radiotherapeutic efficiency of Au-198, Pd-103 and Sm-153 NPs was tested for variable: administered radioactivity, tumor volume and tumor cell type. RESULT: At the cellular level Sm-153 presented the highest S-value, followed by Pd-103 and Au-198. The calculated cell survival and tumor volume curves match very well with the published experimental results. It was found that Au-198 and Sm-153 can effectively treat highly aggressive, large tumor volumes with low radioactivity. CONCLUSION: The accurate knowledge of uptake rate, washout rate of NPs, radio-sensitivity and tumor repopulation rate is important for the calculation of cell survival curves. Self-absorption of emitted radiation and dose enhancement due to AuNPs must be considered in the calculations. Selection of radionuclide for radioactive NP must consider size of tumor, repopulation rate and radiosensitivity of tumor cells. Au-198 NPs functionalized with Mangiferin are a suitable choice for treating large, radioresistant and rapidly growing tumors.

Radioactive gold nanocluster (198-AuNCs) showed inhibitory effects on cancer cells lines.

Cancer is a global epidemic disease responsible for over ten millions death worldwide. The early diagnosis and the precise treatment with reduced adverse reactions are the main goal worldwide. In this study, we produced, characterized and evaluated (in vitro) in three different cancer cell lines (protaste, breast and melanoma) a radioactive gold nanocluster (R-AuNC) (198Au25(Capt)18). The pharmacokinetics as the influence in the ABC transporter (MRP1 Efflux Transporter Protein) was also evaluated. The results showed that R-AuNC (198Au25(Capt)18) are capable to kill the cancer cells lines of protaste, breast and melanoma. The pharmacokinetics showed a fast clearance and great volume of distribution, confirming the use of R-AuNC as nanomedicine for cancer treatment. Finally, the ABC transporter assay corroborated that the R-AuNC (198Au25(Capt)18) has no risk of being pumped out of cells by this efflux transporter. The results validate the use of gold nanoparticles as therapeutic nanomedicine for cancer treatment.

Synthesis and Biodistribution Study of Biocompatible 198Au Nanoparticles by use of Arabinoxylan as Reducing and Stabilizing Agent.

Radioactive gold-198 is a useful diagnostic and therapeutic agent. Gold in the form of nanoparticles possesses even more exciting properties. This work aimed at arabinoxylan-mediated synthesis and biodistribution study of radioactive gold nanoparticles (198AuNPs). The particles were synthesized by mixing suspension of arabinoxylan with H198AuCl4 without use of any additional reducing and stabilizing agents. An aqueous suspension of arabinoxylan was added to a H198AuCl4 solution, which resulted in reduction of Au3+ to 198AuNPs. Biodistribution was studied in vitro and in rabbit. The particles having exceptional stability were readily formed. Highest radioactivity was recorded in spleen after 3 h followed by liver, heart, kidney, and lungs after i.v. administration. After 24 h, the activity was not detectable in the spleen; it accumulated in the liver. However, after oral administration, the activity mainly accumulated in the colon. In serum proteins, the distribution was α1-globulin 6.5%, α2-globulin ~ 2%, ß-globulin ~ 1%, γ-globulin 0.7%, and albumin 0.7% of the administered dose. This indicates a low protein binding implying high bioavailability of the particles. The cytotoxicity study showed that the particles were inactive against HeLa cell line and Agrobacteriumtumefaciens. Highly stable 198AuNPs reported in this work have the potential for targeting the colon. They show affinity for globulins, the property that can be used in the study of the immune system.

Isotopic core-satellites enable accurate and sensitive bioassay of adenosine triphosphate.

Adenosine triphosphate is a major vector of chemical energy in living organisms, but its detection is sometimes hindered by complicated physiological sample matrixes. In this work, we demonstrated a ratiometric bioassay for the accurate and sensitive detection of ATP by measuring the 197Au/115In signal ratio of a mass spectrometric core-satellite structure. Validation of the proposed bioassay was successfully demonstrated in cell lysates and human serum samples.

Internalization capabilities of gold-198 nanoparticles: Comparative evaluation of effects of chitosan agent on cellular uptake into MCF-7.

In this study, internalization of positively charged chitosan-coated nanoparticles (198AuNPs@chitosan) on MCF-7 cells was investigated by γ-ray spectroscopy and then statistically compared to that of 198Au and negatively charged citrate-stabilized nanoparticles (198AuNPs). Sub-50 nm 198AuNPs@chitosan had a higher internalization compared to 198Au and 198AuNPs (p < 0.05). More cellular uptake of 198AuNP@chitosan means a higher dose of radioactivity to the tumor cells which, in turn, more effective treatment of the cancer.

In vivo SPECT imaging of tumors by 198,199Au-labeled graphene oxide nanostructures.

Graphene oxide (GO) sheets functionalized by aminopropylsilyl groups (8.0 wt.%) were labeled by (198,199)Au nanoparticle radioisotopes (obtained through reduction of HAuCl4 in sodium citrate solution followed by thermal neutron irradiation) for fast in vivo targeting and SPECT imaging (high purity germanium-spectrometry) of tumors. Using instant thin layer chromatography method, the physicochemical properties of the amino-functionalized GO sheets labeled by (198,199)Au NPs ((198,199)Au@AF-GO) were found to be highly stable enough in organic phases, e.g. a human serum, to be reliably used in bioapplications. In vivo biodistribution of the (198,199)Au@AF-GO composite was investigated in rats bearing fibrosarcoma tumor after various post-injection periods of time. The (198,199)Au@AF-GO nanostructure exhibited a rapid as well as high tumor uptake (with uptake ratio of tumor to muscle of 167 after 4h intravenous injection) that resulted in an efficient tumor targeting/imaging. Meantime, the low lipophilicity of the (198,199)Au@AF-GO caused to its fast excretion (~24 h) throughout the body by the kidneys (as also confirmed by the urinary tract). Because of the short half-life of (198,199)Au radioisotopes, the (198,199)Au@AF-GO with an excellent tumor targeting/imaging and fast washing out from the body can be suggested as one of the most effective and promising nanomaterials in nanotechnology-based cancer diagnosis and therapy.

Radioactive 198Au-doped nanostructures with different shapes for in vivo analyses of their biodistribution, tumor uptake, and intratumoral distribution.

With Au nanocages as an example, we recently demonstrated that radioactive (198)Au could be incorporated into the crystal lattice of Au nanostructures for simple and reliable quantification of their in vivo biodistribution by measuring the γ radiation from (198)Au decay and for optical imaging by detecting the Cerenkov radiation. Here we extend the capability of this strategy to synthesize radioactive (198)Au nanostructures with a similar size but different shapes and then compare their biodistribution, tumor uptake, and intratumoral distribution using a murine EMT6 breast cancer model. Specifically, we investigated Au nanospheres, nanodisks, nanorods, and cubic nanocages. After PEGylation, an aqueous suspension of the radioactive Au nanostructures was injected into a tumor-bearing mouse intravenously, and their biodistribution was measured from the γ radiation while their tumor uptake was directly imaged using the Cerenkov radiation. Significantly higher tumor uptake was observed for the Au nanospheres and nanodisks relative to the Au nanorods and nanocages at 24 h postinjection. Furthermore, autoradiographic imaging was performed on thin slices of the tumor after excision to resolve the intratumoral distributions of the nanostructures. While both the Au nanospheres and nanodisks were only observed on the surfaces of the tumors, the Au nanorods and nanocages were distributed throughout the tumors.

Radioluminescent gold nanocages with controlled radioactivity for real-time in vivo imaging.

Cerenkov luminescence imaging based on light emission from the decay of radionuclides has recently drawn great interest in molecular imaging. In this paper, we report for the first time the Cerenkov luminescence phenomenon of (198)Au isotope, as well as a facile route to the preparation of radioluminescent Au nanocages without additional radiolabeling or dye conjugation. The specific radioactivity of the Au nanocages could be easily and precisely controlled by varying the concentration of H(198)AuCl(4) precursor used for the galvanic replacement reaction. The direct incorporation of (198)Au atoms into the structure of Au nanocages enabled the ability of accurate analysis and real-time imaging in vivo. Furthermore, under biological conditions the radioactive Au nanocages were shown to emit light with wavelengths in the visible and near-infrared regions, enabling luminescence imaging of the whole mice in vivo, as well as the organs ex vivo. When combined with their favorable scattering and absorption properties in the near-infrared region, the radioactive Au nanocages can serve as a new platform for multimodality imaging and will have a significant impact on both small animal and clinical imaging.

Do radioactive half-lives vary with the Earth-to-Sun distance?

Recently, Jenkins, Fischbach and collaborators have claimed evidence that radionuclide half-lives vary systematically over a ±0.1% range as a function of the oscillating distance between the Earth and the Sun, based on multi-year activity measurements. We have avoided the time-dependent instabilities to which such measurements are susceptible by directly measuring the half-life of (198)Au (t(1/2)=2.695 d) on seven occasions spread out in time to cover the complete range of Earth-Sun distances. We observe no systematic oscillations in half-life and can set an upper limit on their amplitude of ±0.02%.

Radioactive gold nanoparticles in cancer therapy: therapeutic efficacy studies of GA-198AuNP nanoconstruct in prostate tumor-bearing mice.

Biocompatibility studies and cancer therapeutic applications of nanoparticulate beta-emitting gold-198 (198Au; beta(max) = 0.96 MeV; half-life of 2.7 days) are described. Gum arabic glycoprotein (GA)-functionalized gold nanoparticles (AuNPs) possess optimum sizes (12-18 nm core diameter and 85 nm hydrodynamic diameter) to target individual tumor cells and penetrate through tumor vasculature and pores. We report the results of detailed in vivo therapeutic investigations demonstrating the high tumor affinity of GA-198AuNPs in severely compromised immunodeficient (SCID) mice bearing human prostate tumor xenografts. Intratumoral administration of a single dose of beta-emitting GA-198AuNPs (70 Gy) resulted in clinically significant tumor regression and effective control in the growth of prostate tumors over 30 days. Three weeks after administration of GA-198AuNPs, tumor volumes for the treated animals were 82% smaller as compared with tumor volume of control group. The treatment group showed only transitory weight loss in sharp contrast to the tumor-bearing control group, which underwent substantial weight loss. Pharmacokinetic studies have provided unequivocal evidence for the optimum retention of therapeutic payload of GA-198AuNPs within the tumor site throughout the treatment regimen with minimal or no leakage of radioactivity to various nontarget organs. The measurements of white and red blood cells, platelets, and lymphocytes within the treatment group resembled those of the normal SCID mice, thus providing further evidence on the therapeutic efficacy and concomitant in vivo tolerance and nontoxic features of GA-198AuNPs. FROM THE CLINICAL EDITOR: In this study, the biocompatibility and cancer therapeutic applications of glycoprotein (GA) functionalized gold nanoparticles containing b-emitting Au-198 are described in SCID mice bearing human prostate tumor xenografts. The findings of significant therapeutic efficacy, good in vivo tolerance and non-toxic features make these particles ideal candidates for future human applications.

Self-assembled monolayers of a bis(pyrazol-1-yl)pyridine-substituted thiol on Au(111).

Self-assembled monolayers (SAMs) of a bis(pyrazol-1-yl)pyridine-substituted thiol (bpp-SH) on Au (111)/mica were studied with scanning tunneling microscopy (STM), X-ray photoelectron spectroscopy (XPS), and near-edge X-ray absorption fine structure spectroscopy (NEXAFS). Using substrates precoated with perylene-3,4,9,10-tetracarboxylic acid dianhydride (PTCDA), preparation at elevated temperatures yields highly ordered layers whose structure is described by a rectangular (5 x radical3) unit cell containing one molecule. The bis(pyrazol-1-yl)pyridine (bpp) units exhibit pi-stacking along the 112 direction, and they are tilted significantly. We conclude the three imine nitrogen atoms in the bpp headgroup adopt a trans,trans arrangement.

Structural rearrangement of c(70) monolayers induced by octanethiol adsorption.

Mixed monolayers of C70 and octanethiol are prepared on Au(111) by a sequential adsorption method. A partial C70 monolayer is first formed and characterized, followed by the vapor deposition of octanethiol. This results in a well-ordered alkanethiol film where single C70 molecules and small molecular clusters are located at domain boundaries and in disordered regions. Substrate step defects have a large influence on the spatial distribution of C70; adjacent to a substrate defect, C70 binds preferentially on the upper terrace and is depleted on the lower terrace. We explain these observations as resulting from the kinetics of alkanethiol monolayer formation, and we present a simple model for the evolution of surface structure in the C70/octanethiol system.

Gamma camera scintigraphy of tumours using (195m)Pt-cisplatin.

Platinum enriched with 194Pt was irradiated for 4 days in NRG's TIRO 1 reactor, to produce (195m)Pt. Spectral analysis of the product was performed using a calibrated hyper pure germanium detector and its constituent radioisotopes were identified as (195m)Pt, 199Au and 192Ir. Using the detector's intrinsic efficiency calibration, their activities were estimated to be 1049, 133 and 5.8 MBq, respectively. The performance of the gamma camera was tested using quality control procedures recommended by the Institute of Physics and Engineering in Medicine (IPEM) and was found to be satisfactory. A torso phantom was used to determine the minimum detection limit (MDL) of (195m)Pt in a 2 cm diameter tumour using SPECT acquisitions (32 steps, 60 s per step). The MDL was found to be 8 ppm assuming an administered patient dose of 50 MBq and a total cisplatin dose of 105 mg. This work indicates that (195m)Pt-cisplatin is suitable for clinical scintigraphy and has led to the development of a clinical protocol that has been approved for a pilot study.

Ionization chamber measurements of the half-lives of 24Na, 42K, 76As and 198Au.

Samples of 24Na, 42K, 76As and 198Au were produced by irradiation in the National Institute of Standards and Technology (NIST) reactor, and examined for impurities before and after measurement. Half-life measurements were carried out in the NIST 4pigamma pressurized ionization chamber. The results are compared to presently accepted values and previous NIST measurements.

"High specific activity" radiotracers for metallo-toxicological studies: cyclotron and nuclear reactor production, radiochemical separation and "quality control": platinum, iridium, gold, copper and gallium.

Very High Specific Activity RadioNuclides, HSARN, are a powerful tool to label a wide variety of chemical elements and compounds present in the biosphere in ultra-trace amounts. Medium and high Z radionuclides, can be produced by irradiation in light-ions accelerator and sometimes nuclear reactor. If the nuclear reaction product has atomic number different from irradiated target, it is possible separating the radioactive nuclide from irradiated target, without addition of isotopic carrier. These kinds of radionuclides are named No Carrier Added, NCA, and their specific activity is very high and can reach values close to the theoretical Carrier Free one. The true specific activity must be determined by use of very sensitive radioanalytical techniques. If a low isotopic dilution factor is obtained, these radiotracers are used to label inorganic species and complexes of elements, which are presently introduced into the echo-systems by human activities. New production methods for NCA Pt, Ir, Au, Cu and Ga radiotracers are presented, with some details on radiochemistry and quality controls.

198Au-labeled hydroxymethyl phosphines as models for potential therapeutic pharmaceuticals.

The development of novel gold-198 complexes with water-soluble phosphines is reported. A series of cationic and hydrophilic 198Au complexes containing the ligands tris(hydroxymethyl)phosphine (THP, 1) 1,2-bis[bis(hydroxymethyl)phosphino]benzene (HMPB, 2), and 1,2-bis[bis(hydroxymethyl)phosphino]ethane (HMPE, 3) were prepared and evaluated as models for potential gold-199 radiopharmaceuticals. The 198Au complexes were formed in high radiochemical purity by simply mixing H198AuCl4 with the respective ligand. The complexes were shown to exhibit high in vitro stability over wide pH ranges and temperatures. However, only the 198Au(HMPB)2+ complex was found to exhibit good in vivo stability. HPLC analyses indicated that the 198Au complexes with these three phosphine ligands produced singular species with similar retention times as compared to their known macroscopic complexes.