Phytosynthesis of gold-198 nanoparticles for a potential therapeutic radio-photothermal agent.

We produced spherical gold-198 nanoparticles with an average size of 41 nm, good stability, and high radiochemical purity for a promising single agent of radio-photothermal therapy using Curcuma longa rhizome extract as a reducing and capping agent. The combination of in vitro treatment using gold-198 nanoparticles and irradiation of 980 nm wavelength lasers with a power output of 2 W/cm2 induced hyperthermia temperature and exhibited enhancement of the percentage dead on MDA-MB-123 cancer cells compared to gold-198 nanoparticles alone.

A tetrahydroacridine derivative and its conjugate with gold nanoparticles: promising agents for the treatment of Alzheimer's disease.

A new tetrahydroacridine derivative (CHDA) with acetylcholinesterase inhibitory properties was synthesized. Using a range of physicochemical techniques, it was shown that the compound strongly adsorbs onto the surface of planar macroscopic or nanoparticulate gold, forming a nearly full monolayer. The adsorbed CHDA molecules reveal well-defined electrochemical behavior, being irreversibly oxidized to electroactive species. The CHDA also exhibits strong fluorescence, which is effectively quenched after adsorption onto gold via a static quenching mechanism. Both CHDA and its conjugate reveal considerable inhibitory properties against acetylcholinesterase activity, which is promising from the perspective of therapeutic application in the treatment of Alzheimer's disease. Moreover, both agents appear to be non-toxic as demonstrated using in vitro studies. On the other hand, conjugation of CHDA with nanoradiogold particles (Au-198) offers new potential diagnostic perspectives in medical imaging.

Preparation of Surface-Supported Polylactide Spherical-Cap Particles.

Biodegradable polymer particles are of considerable importance due to their multiple applications in medical diagnostics and therapy. Spherical-cap particles have been prepared in a very general and simple method by melting a thin polymer film supported on a solid substrate that is in contact with a hydrophilic solvent. The melted polymer forms droplets which transform into solid particles attached to the surface after cooling down the sample. This approach has been demonstrated for polylactide adlayers on glass, which, when melted in glycerol, produce an array of polymer particles supported on the surface. The size of the particles depends on the experimental conditions and ranges from tens of nanometers to several micrometers. The particles can be employed to incorporate guest species, for example, drug molecules or inorganic nanoparticles. This has been confirmed herein through entrapment of an anticancer drug (doxorubicin) and radiogold (Au-198) nanoparticles. The resulting structures have been examined using a number of complementary physicochemical techniques including scanning and transmission electron microscopy, atomic force and optical microscopy as well as Raman and fluorescence spectroscopy.

Treatment outcomes of real-time intraoral sonography-guided implantation technique of 198Au grain brachytherapy for T1 and T2 tongue cancer.

It is often challenging to determine the accurate size and shape of oral lesions through computed tomography (CT) or magnetic resonance imaging (MRI) when they are very small or obscured by metallic artifacts, such as dental prostheses. Intraoral ultrasonography (IUS) has been shown to be beneficial in obtaining precise information about total tumor extension, as well as the exact location and guiding the insertion of catheters during interstitial brachytherapy. We evaluated the role of IUS in assessing the clinical outcomes of interstitial brachytherapy with 198Au grains in tongue cancer through a retrospective medical chart review. The data from 45 patients with T1 (n = 21) and T2 (n = 24) tongue cancer, who were mainly treated with 198Au grain implants between January 2005 and April 2019, were included in this study. 198Au grain implantations were carried out, and positioning of the implants was confirmed by IUS, to ensure that 198Au grains were appropriately placed for the deep border of the tongue lesion. The five-year local control rates of T1 and T2 tongue cancers were 95.2% and 95.5%, respectively. We propose that the use of IUS to identify the extent of lesions and the position of implanted grains is effective when performing brachytherapy with 198Au grains.

Dose characteristics of Au-198 eye brachytherapy applicator: A Monte Carlo study.

PURPOSE: The use of ocular plaques is a promising treatment option for eye melanoma brachytherapy. Although several studies have been done on various ocular plaques, little is known about the dose characterization of 198Au plaque. MATERIALS AND METHOD: The full mathematical model of the eye phantom, tumor, 106Ru/106Rh CCA, and 198Au plaque were simulated using the Monte Carlo MCNPX code. The dose distribution was measured in the plaque's central axis direction, and a dose profile was also measured at a distance of 2.5 mm from the plaque surface. RESULTS: The findings showed that 198Au plaque has superior dosimetric characteristics than CCA plaque for tumors with a thickness of greater than 3.5 mm, while CCA plaque is better for tumors with a thickness of less than 3.5 mm. The dose to the sclera and choroid is higher in the case of CCA plaque, while the dose to the organs at risk (lens and optic nerve) is greater in the case of 198Au applicator. In the case of 198Au plaque, however, the dose to sensitive organs was within their permissible dose range. CONCLUSION: In the treatment of medium and large tumors, 198Au plaque is more successful than CCA plaque. It can produce a much more homogeneous lateral dose profile in the target. In the treatment of dome-shaped tumors, 198Au plaque may be more successful than CCA plaque. As a result, the tumor's shape influences the plaque type selection.

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.

Labeling and tracking cells with gold nanoparticles.

Gold nanoparticles (AuNPs) have garnered much attention as contrast agents for computerized tomography (CT) because of their facile synthesis and surface functionalization, in addition to their significant X-ray attenuation and minimal cytotoxicity. Cell labeling using AuNPs and tracking of the labeled cells using CT has become a time-efficient and cost-effective method. Actively targeted AuNPs can enhance CT contrast and sensitivity, and further reduce the radiation dosage needed during CT imaging. In this review, we summarize the state-of-the-art use of AuNPs in CT for cell tracking, including the precautionary steps necessary for their use and the difficulty in translating the process into clinical use.

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.

Design of the spacer for brachytherapy using 198Au grain for carcinoma of the tongue as a tool of perioperative oral management.

PATIENTS: Seventy-one and 73 years-old males visited a perioperative oral care support center to receive perioperative oral management during tongue cancer (T1N0M0) treatment. To improve their quality of life (QOL) during brachytherapy while preventing radiation-related complications including osteoradionecrosis due to 198Au grain brachytherapy, spacers for their maxilla and mandible were designed with consideration of wearing condition at an isolation ward. The spacer was created with unilateral design and with consideration of the tongue mobility during day and night. Then, the spacer was thickened on the plaster model, demonstrating the cancer lesion in the tongue in order to secure the distances from the mandibular body, maxilla and sublingual gland to the radiation sources embedded in the tongue. DISCUSSION: Tongue impression made the spacers as small as possible by thickening just around the cancer lesions so that the patients could wear them comfortably, while keeping adequate distance between the radiation sources and peripheral normal tissues. Breakable hard materials were avoided so that the patients were able to utilize the spacers safely without accidentally swallowing a broken fragment. Additionally, considering the upward movement of the tongue in a sleeping posture, the upper spacers were also prepared to protect the maxillae. Computer simulation revealed that the design of our spacers had enough effect on a reduction in radiation to prevent osteoradionecrosis in the maxilla as well as mandibular body. CONCLUSIONS: This report demonstrated the importance of the spacers created with consideration of patients' wearing condition to improve their QOL during brachytherapy.

Reirradiation Using Permanent Interstitial Brachytherapy: A Potentially Durable Technique for Salvaging Recurrent Pelvic Malignancies.

PURPOSE: To present a time-to-failure (TTF) analysis for all patients treated with permanent interstitial brachytherapy (PIB) at our institution, with additional analyses to correlate successful reirradiation and to identify the frequency of severe grade 3 to 4 toxicity. METHODS AND MATERIALS: Forty-two previously irradiated patients received curative or palliative intent PIB for a recurrent pelvic malignancy between January 2009 and August 2016. Minimum follow-up was 6 months after the PIB procedure. All patients had a biopsy-proven recurrence and were treated using PIB alone (n=32) or in combination with a short course of additional radiation therapy (n=10). Competing risk analyses were performed to assess the risk of failures in the presence of death without failure. Exploratory analyses were performed for factors related to failure using competing risk analyses and the Gray statistic. RESULTS: A total of 61 PIB implants were performed among 42 patients with a median follow-up of 16.3 months. Fifty-two implants were performed as the first salvage reirradiation to a solitary recurrence (8 patients had more than 1 lesion); the success rate for initial reirradiation using PIB was 73% (38 cases out of 52), and the median TTF was not reached. Nine patients underwent a second repeat PIB to the same recurrence as a form of salvage; 3 (33%) remain without evidence of recurrence. The median TTF after second salvage was 7.7 months. Even with the limited sample size, prolonged TTF was marginally associated with definitive intent (P=.07) and the extent of disease at the time of PIB (P=.08). Grade 3+ toxicities were seen in 8 patients (16.7%). CONCLUSIONS: Permanent interstitial brachytherapy is a feasible and potentially durable treatment modality that can be used to curatively salvage selected recurrent pelvic malignancies in a previously irradiated field.

Mangiferin functionalized radioactive gold nanoparticles (MGF-198AuNPs) in prostate tumor therapy: green nanotechnology for production, in vivo tumor retention and evaluation of therapeutic efficacy.

We report here an innovative feature of green nanotechnology-focused work showing that mangiferin-a glucose functionalized xanthonoid, found in abundance in mango peels-serves dual roles of chemical reduction and in situ encapsulation, to produce gold nanoparticles with optimum in vivo stability and tumor specific characteristics. The interaction of mangiferin with a Au-198 gold precursor affords MGF-198AuNPs as the beta emissions of Au-198 provide unique advantages for tumor therapy while gamma rays are used for the quantitative estimation of gold within the tumors and various organs. The laminin receptor specificity of mangiferin affords specific accumulation of therapeutic payloads of this new therapeutic agent within prostate tumors (PC-3) of human prostate tumor origin induced in mice which overexpress this receptor subtype. Detailed in vivo therapeutic efficacy studies, through the intratumoral delivery of MGF-198AuNPs, show the retention of over 80% of the injected dose (ID) in prostate tumors up to 24 h. By three weeks post treatment, tumor volumes of the treated group of animals showed an over 5 fold reduction as compared to the control saline group. New opportunities for green nanotechnology and a new paradigm of using mangiferin as a tumor targeting agent in oncology for the application of MGF-198AuNPs in the treatment of cancer are discussed.

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.

[Use of gold radionuclide markers implanted into the prostate for image-guided radiotherapy in prostate cancer: side effects caused by the marker implantation]. / A prosztatába ültetett aranymarkerek alkalmazásának bevezetése prosztatarákos betegek képvezérelt sugárkezeléséhez. A beültetés okozta mellékhatások ismertetése.

The purpose of the study was to introduce the use of the gold radiopaque markers implanted into the prostate for image-guided radiotherapy of prostate cancer patients and to present the side effects caused by the marker implantation. Between November 2011 and November 2013, three radiopaque, gold-plated markers (Best Medical International, Springfield, VA, USA, 1.0 mm x 3.0 mm) were implanted transperineally into the prostate of 60 patients under transrectal ultrasound guidance. Local anaesthesia was performed in all patients. A week after the procedure the patients filled in a questionnaire regarding the pain, dysuria, urinary frequency, nycturia, rectal bleeding, haematuria, haematospermia or fever symptoms caused by the implantation. The pain caused by the intervention was scored on a 1-10 scale, where 1 was a very weak and 10 was an unbearable pain. Ten days after the implantation a treatment planning CT was performed and subsequently patients started intensity-modulated radiation therapy (IMRT) within one week. During the treatments markers were used for daily verification and correction of patient's setup. No patients experienced fever or infection. Based on the questionnaires nobody experienced dysuria or rectal bleeding after implantation. Among the 60 patients studied, five (8 %) had haematospermia, nine (15 %) haematuria, which lasted in average of 3.4 and 1.8 days, respectively. The average pain score on 1-10 scale was 4.2 (range: 0-9). After the marker implantation 18 patients (30%) reported less, 10 patients (17%) more, and 27 patients (45%) equal amount of pain compared to biopsy. Five patients, who had a biopsy performed under general anaesthesia, did not answer this question. None of the patients needed analgesics after implantation. The gold marker implantation implemented for image-guided radiotherapy was well tolerated under a local anaesthesia. The complications were limited, rate and frequency of perioperative pain was comparable to the pain caused by biopsy. After implantation, the patients did not require analgesics. The method can be performed safely in clinical practice.

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.

Size dependent translocation and fetal accumulation of gold nanoparticles from maternal blood in the rat.

BACKGROUND: There is evidence that nanoparticles (NP) cross epithelial and endothelial body barriers. We hypothesized that gold (Au) NP, once in the blood circulation of pregnant rats, will cross the placental barrier during pregnancy size-dependently and accumulate in the fetal organism by 1. transcellular transport across the hemochorial placenta, 2. transcellular transport across amniotic membranes 3. transport through ~20 nm wide transtrophoblastic channels in a size dependent manner. The three AuNP sizes used to test this hypothesis are either well below, or of similar size or well above the diameters of the transtrophoblastic channels. METHODS: We intravenously injected monodisperse, negatively charged, radio-labelled 1.4 nm, 18 nm and 80 nm ¹98AuNP at a mass dose of 5, 3 and 27 µg/rat, respectively, into pregnant rats on day 18 of gestation and in non-pregnant control rats and studied the biodistribution in a quantitative manner based on the radio-analysis of the stably labelled ¹98AuNP after 24 hours. RESULTS: We observed significant biokinetic differences between pregnant and non-pregnant rats. AuNP fractions in the uterus of pregnant rats were at least one order of magnitude higher for each particle size roughly proportional to the enlarged size and weight of the pregnant uterus. All three sizes of ¹98AuNP were found in the placentas and amniotic fluids with 1.4 nm AuNP fractions being two orders of magnitude higher than those of the larger AuNP on a mass base. In the fetuses, only fractions of 0.0006 (30 ng) and 0.00004 (0.1 ng) of 1.4 nm and 18 nm AuNP, respectively, were detected, but no 80 nm AuNP (<0.000004 (<0.1 ng)). These data show that no AuNP entered the fetuses from amniotic fluids within 24 hours but indicate that AuNP translocation occurs across the placental tissues either through transtrophoblastic channels and/or via transcellular processes. CONCLUSION: Our data suggest that the translocation of AuNP from maternal blood into the fetus is NP-size dependent which is due to mechanisms involving (1) transport through transtrophoblastic channels - also present in the human placenta - and/or (2) endocytotic and diffusive processes across the placental barrier.

198Au grain implantation for early tongue cancer in patients of advanced age or poor performance status.

Brachytherapy using (198)Au grains is minimally invasive and the only curative treatment for early tongue cancer in patients of advanced age or poor performance status available in our institution. From March 1993 to February 2008, (198)Au grains were used to treat a group of 96 Stage I-II tongue cancer patients who could not undergo surgery or brachytherapy using (192)Ir pins because of an advanced age (≥75 years) or poor performance status (≥2). The patients were followed for 3.9 ± 3.3 years, and the cause-specific survival and local control rates were determined. Survival analyses were performed using the Kaplan-Meier method, and univariate and multivariate analyses were performed using the Cox proportional hazard model. The results were compared with those for a group of 193 early tongue-cancer patients who underwent treatment using iridium pins. The 5-year cause-specific survival and local control rates of the (198)Au grains group were 71% and 68%, respectively, both of which were 16% lower than the corresponding rates for the (192)Ir pins group. Our study demonstrated that as the last curative treatment available, (198)Au grain implantation could be used to achieve moderate treatment results for early tongue cancer in patients of advanced age or poor performance status.