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.

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.

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.

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.

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.

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.

Permanent interstitial re-irradiation with Au-198 seeds in patients with post-radiation locally recurrent uterine carcinoma.

This study sought to analyze the outcome of patients with post-treatment locally recurrent uterine carcinoma treated with Au-198 seed permanent interstitial re-irradiation (Au-198 IRI). A retrospective review of the data of 15 patients with post-treatment locally recurrent uterine carcinoma treated with Au-198 IRI between 1991 and 2009 was performed to evaluate the disease response, local control, overall survival and complication rates. All the patients had received definitive radiation therapy or surgery as the initial treatment. None were judged as being suitable candidates for surgical treatment, and were referred for Au-198 IRI. Au-198 IRI was performed for the vaginal wall in 8 patients, vaginal stump in 4 patients, vulva in 2 patients, and cervix in 1 patient. The median tumor volume was 1.3 cm(3)(range, 0.4-6.9), the median treated volume was 6.3 cm(3)(range, 1.8-11), and the median prescribed dose was 76 Gy (range, 68-90). At a median follow-up duration of 19 months (range, 4.3-146.9), 13 of 15 patients (87%) showed complete responses after Au-198 IRI, although 10 of these 13 patients (77%) developed repeat central recurrence again between 2.5 and 49.7 months after the Au-198 IRI (median, 12.5 months). The overall 2-year local control rate and 2-year overall survival rate in the 15 patients were 33% and 64%, respectively. Two (13%) of the 15 patients experienced late complications that were more severe than Grade III. As a result, Au-198 IRI is considered to be one of the salvage treatment modalities with tolerable complications for inoperable centrally recurrent uterine carcinoma.

Repeat brachytherapy for patients with residual or recurrent tumors of oral cavity.

PURPOSE: To analyze data from patients receiving repeat brachytherapy (re-BT) for the treatment of residual or recurrent tumor in the oral cavity. METHODS AND MATERIALS: Between January 2003 and December 2007, 62 patients who had undergone definitive BT as an initial treatment of oral cancer subsequently underwent re-BT for the treatment of residual or recurrent tumors at the diagnostic radiology and oncology department (Tokyo Medical and Dental University Hospital). Re-BT was performed 0.9-73 months (median, 5.7) after the initial BT. Au-198 grains were used as the re-BT source in all 62 patients, and an area of 0.8-6.3 cm(2) (median, 3.1) was permanently irradiated with 60-110 Gy (median, 83) according to the system of Paterson-Parker. RESULTS: The 2-year local control and overall survival rate was 53% and 66%, respectively, and local control significantly affected overall survival. Both local control and overall survival were affected by the initial tumor characteristics and the macroscopic appearance of the residual or recurrent tumor. Grade 3 or 4 complications were seen in 5 patients. The incidence of mandibular and mucosal complications was significantly related to a biologic effective dose of α/ß of 3 Gy to the surface of the gingiva and mucosa, respectively. CONCLUSION: Re-BT using Au-198 grains for the treatment of residual or recurrent tumor after definitive BT in the oral cavity is effective and well tolerated.

Low-dose-rate interstitial brachytherapy preserves good quality of life in buccal mucosa cancer patients.

PURPOSE: To determine the results and long-term changes in radiation toxicity of stage I-II buccal mucosa cancer patients treated by low-dose-rate (LDR) brachytherapy with (198)Au grains. MATERIALS AND METHODS: A total of 133 stage I-II buccal mucosa carcinomas patients received (198)Au grain implantation brachytherapy between January 1982 and July 2005: 75 of them were treated by (198)Au grain implantation alone and 58 were treated by (198)Au implantation in combination with external irradiation. The average (198)Au-grain dose was 70 Gy in 7 days. Gross tumor areas ranged from 2.4 cm(2) to 9 cm(2), and the clinical target areas ranged from 6 cm(2) to 15 cm(2). RESULTS: The follow-up periods ranged from 3 months to 20 years (mean: 5 years 11 months and median: 5 years 1 months). Failure at the site of the primary lesion occurred in 17 patients. Post-treatment mucosal ulceration developed in 15 patients, and all were cured within 25 months by conservative treatment. Osteoradionecrosis was diagnosed in 8 patients, but only one patient required surgical treatment. No severe complications or aggravation of complications developed more than 10 years after treatment. CONCLUSIONS: The results of low-dose-rate (LDR)-brachytherapy (BT) alone and LDR-BT in combination with external irradiation at a total dose of 25 Gy were acceptable from the standpoint of cure rate and QOL.

Brachytherapy with permanent gold grain seeds for squamous cell carcinoma of the lip.

PURPOSE: To describe the use of radioactive gold grain implantation for squamous cell carcinoma of the lip. METHODS: Retrospective review of 51 patients treated with permanent gold ((198)Au) grain implant brachytherapy. The seed arrangement delivered a dose of 5500 cGy at 0.5 cm from a single plane. Primary endpoints were local recurrence and cosmetic outcome. RESULTS: Median follow-up was 27 months. Median age was 69 years. The majority (90%) were T1 lesions. None of the patients had evidence of regional lymph node or distant metastasis. Twelve patients had recurrent disease with prior surgery and five patients had previous head and neck radiation. Local control was achieved in 49 patients. Good cosmesis was achieved in 48 patients. Two-year actuarial estimates for local failure-free survival, disease-free survival and overall survival were 97.9%, 94.1% and 87.9%, respectively; no deaths were attributable to lip cancer. CONCLUSIONS: Gold grain interstitial low-dose rate brachytherapy provides excellent local control and cosmesis in patients with squamous cell carcinoma of the lip. This technique provides an excellent option for patients that are elder or live remotely. It is particularly useful for lesions that are small, in previously radiated areas, or treated with prior surgery.

Migration of intraprostatic fiducial markers and its influence on the matching quality in external beam radiation therapy for prostate cancer.

PURPOSE: To assess the influence of fiducial marker (FM) migration on the matching quality in external beam radiation therapy (EBRT) for prostate cancer. MATERIALS AND METHODS: The position of FMs were identified using on-board kV imaging (OBI) and their 3-D position established using an in-house reconstruction algorithm for 31 patients with prostate adenocarcinoma. To carry out the match, the positions were overlaid on the digitally reconstructed radiographs (DRR) generated from the planning CT. The distance between each FM was calculated for seven treatments throughout the EBRT course. Four radiotherapy technologists were asked to independently perform and rate the match from OBI to DRR which was then correlated to the extent of FM migration. RESULTS: All the matches were rated by at least three radiotherapy technologists as "very easy" ("easy" subgroup) for 24 patients (77%), while the other seven patients had their match rated less than "very easy" and considered the "not easy" subgroup. The average daily FM migration was 0.93+/-0.34 mm for the "easy" subgroup vs. 1.82+/-0.75 mm for the latter. An average migration >2 mm was seen in five/seven patients in the "not easy" subgroup as compared to none in the "easy" subgroup. There was a trend towards less FM migration and better matching if the planning CT was done later than the day of the FM implant (p=0.093). CONCLUSIONS: FM migration >2 mm predicts for a more difficult matching process; PTV margins might have to be adjusted or the planning CT repeated.

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.

Quality of life of oral cancer patients after low-dose-rate interstitial brachytherapy.

PURPOSE: To assess the quality of life (QOL) of oral cancer patients treated with low-dose-rate interstitial brachytherapy (LDR-BT) alone. METHODS AND MATERIALS: Between June 2005 and July 2006, a total of 56 patients with oral cancer were enrolled in this prospective study. QOL was assessed by means of the core questionnaire and head and neck questionnaire module of the European Organization for Research and Treatment of Cancer (EORTC Quality of Life Questionnaire-Core 30 [QLQ-C30] and QLQ Head and Neck 35 [H&N35]). The questionnaires were distributed to the patients before the start of treatment and 3 months, 6 months, and 12 months after the start of LDR-BT. RESULTS: It was possible to analyze the results for 20 of the initial 56 patients because they did not experience metastasis or recurrence during this study. No functions or symptoms asked about in the QLQ-C30 deteriorated during the first year. The emotional function score steadily and significantly increased. No symptoms in the QLQ-H&N35 significantly deteriorated. The scores for pain, trouble with social eating, and weight loss on the QLQ-H&N35 steadily and significantly decreased. Age, gender, and LDR-BT source had no effect on the change in QOL during the first year, but T-stage significantly affected the change in global health status, tumor site affected the changes in swallowing, sensory problems, sticky saliva, and complications affected the changes in pain, swallowing, and mouth opening. CONCLUSIONS: QOL of oral cancer patients treated with LDR-BT is high. However, tumor stage, tumor site, and complications affected the changes in a few functions and symptoms during the first year.

The "Golden Age" of prostate brachytherapy: a cautionary tale.

PURPOSE: To investigate the earliest attempts to use man-made isotopes for prostate brachytherapy. METHODS AND MATERIALS: Two radiogold brachytherapy programs were analyzed, using literature review and interviews of participants. RESULTS: Although (198)Au has been discredited as a source for permanent prostate brachytherapy, the major flaw in the reviewed programs was the misapplication of the isotope. CONCLUSIONS: Safe and effective implant programs are grounded in the sound application of brachytherapy principles. New brachytherapy procedures should arise from the collaboration of radiation oncologists, surgeons, physicists, radiobiologists, and radiation safety specialists.

Stereotactic radiosurgery versus gold grain implantation in salvaging local failures of nasopharyngeal carcinoma.

BACKGROUND: Limited local failure of nasopharyngeal carcinoma (NPC) can often be salvaged by reirradiation using different techniques. Both gold grain implantation (GGI) and stereotactic radiosurgery (SRS) have been used as salvage treatment of NPC but the relative efficacy of these two treatments is not known. METHODS AND MATERIALS: A total of 74 patients with local NPC failure were included in this retrospective analysis. Of these patients, 37 underwent SRS (median dose, 12.5 Gy) and 37 split-palatal GGI at a dose of 60 Gy. The two groups were individually matched for prognostic factors, except for tumor volume. The median follow-up was 42 months. RESULTS: Local control was better in the GGI group. The 3-year local failure-free rate was 77.9% for the GGI group compared with 68.3% for the SRS group. However, the difference was not statistically significant (p = 0.098). In the subgroup with a tumor volume of

Production of radioactive particles for endovascular therapeutic interventions.

Recanalization is a common phenomenon that decreases the efficacy of embolization procedures. It can be inhibited by beta-radiation. Two novel ways of producing radioactive particles are described, by neutron beam irradiation of gold-containing microspheres, or by using the 32P binding capacity of zirconium-containing microspheres. Particles were tested in vivo, to assess their ability to deliver radioactivity locally, using canine renal artery, porcine rete mirabile, and rabbit ear embolization models. Both radioactive microspheres (198Au and 32P) showed no detectable activity outside the target territory. 32P microspheres demonstrated typical radiation changes in a porcine rete mirabile arteriovenous malformation model.

Fiducial markers implanted during prostate brachytherapy for guiding conformal external beam radiation therapy.

Prostate movement imposes limits on safe dose-escalation with external beam radiation therapy. If the precise daily location of the prostate is known, dose escalation becomes more feasible. We have developed an approach to dose escalation using a combination of prostate brachytherapy followed by external beam radiation therapy in which fiducial markers are placed along with (125)I seeds during transperineal interstitial permanent prostate brachytherapy. These markers serve to verify daily prostate location during the subsequent external beam radiotherapy. Prior to implementing this approach, preliminary studies were performed to test visibility of the markers. Three different (125)I seed models, as well as gold and silver marker seeds were placed within tissue-equivalent phantoms. Images were obtained with conventional x-rays (75-85 kV) and 6 MV photons from a linear accelerator. All (125)I seed models were clearly visible on conventional x-rays but none were seen with 6 MV photons. The gold markers were visible with both energies. The silver markers were visible with conventional x-rays and 6 MV x-rays, but not as clearly as the gold seeds at 6 MV. Subsequently, conventional x-rays, CT scans, and 6 MV port films were obtained in 29 patients in whom fiducial gold marker seeds were implanted into the prostate during (125)I prostate brachytherapy. To address the possibility of "seed migration" within the prostate, CT scans were repeated 5 weeks apart in 14 patients and relative positions of the gold seeds were evaluated. The repeated CT scans showed no change in intraprostatic gold marker location, suggesting minimal migration. The gold seeds were visible with conventional x-rays, CT, and 6 MV port films in all patients. During the course of external beam radiation therapy, the gold markers were visible on routine 6 MV port films and were seen in different locations from film to film suggesting prostate motion. Mean daily displacement was 4-5 mm in the anterior-posterior, and 4-5 mm in superior-inferior dimensions. Left-right displacement appeared less, averaging 2-3 mm. We conclude that implantation of gold marker seeds during prostate brachytherapy represents an easily implemented and practical means of prostate localization during subsequent image-guided external beam radiotherapy. With such markers, conformality of the external beam component can be confidently improved without expensive new equipment.