Intra-tracheal administration increases gallium availability in lung: implications for antibacterial chemotherapy.

The emergence of pan-resistant strains in nosocomial settings underscores the urgent need of novel therapies targeting vital bacterial functions. Bacterial iron metabolism is a fascinating target for new antimicrobials. Iron mimetic metal Ga(III) has been repurposed as an antimicrobial drug, in pre-clinical studies and recent clinical studies have raised the possibility of using Ga(III) for the treatment of P. aeruginosa pulmonary infection. Ga(III) has been approved by FDA for the treatment of cancer, autoimmune and bone resorption disorders. However, some critical issues affect the therapeutic schedule of Ga(III), principally the intra-venous (i.v.) administration, and the nephrotoxicity caused by prolonged administration. Ga(III) aerosolization could represent a viable alternative for treatment of lung infections, since delivery of antimicrobial agents to the airways maximizes drug concentration at the site of infection, improves the therapeutic efficacy, and alleviates systemic toxic effects. We demonstrate the advantage of inhaled vs i.v. administered Ga(III), in terms of bio-distribution and lung acute toxicity, by using a rat model. In vivo results support the use of Ga(III) for inhalation since intra-tracheal Ga(III) delivery improved its persistence in the lung, while the i.v. administration caused rapid clearance and did not allow to attain a significant Ga(III) concentration in this organ. Moreover, local and systemic acute toxicity following intra-tracheal administration was not observed, since no significant signs of inflammation were found. At this stage of evidence, the direct administration of Ga(III) to the lung appears feasible and safe, boosting the development of Ga(III)-based drugs for inhalation therapy.

Dermal absorption of gallium antimonide in vitro and pro-inflammatory effects on human dermal fibroblasts.

Gallium antimonide (GaSb) is a group III-V compound semiconductor with a comparatively narrow band gap energy (0.73 eV at 300 K) that allows efficient operation in the near-infrared region. This property may be useful in developing new biomedical instruments such as epidermal optoelectronic devices. The present study investigated the absorption of GaSb in pig skin in vitro for 24 h using Franz cells. A donor solution was prepared by soaking GaSb thin films in synthetic sweat. The results showed that both gallium and antimony penetrated the skin, and permeation and resorption occurred for gallium. Histopathological findings showed no inflammatory responses in pig skin exposed to GaSb for 24 h. Cytotoxicity was significantly elevated after 3 and 7 days, and pro-inflammatory cytokines and IL-8 levels were low after 1 and 3 days but elevated 7 days following the direct culturing of human dermal fibroblasts (HDF) on GaSb thin films. These results demonstrate that the short-term cytotoxicity and pro-inflammatory effect of GaSb on HDF were relatively low.

The toxicology of gallium oxide in comparison with gallium arsenide and indium oxide.

Gallium arsenide (GaAs) and indium oxide (In2O3) are used in electronic industries at high and increasing tonnages since decades. Gallium oxide (Ga2O3) is an emerging wide-bandgap transparent conductive oxide with as yet little industrial use. Since GaAs has received critical attention due to the arsenic ion, it seemed reasonable to compare its toxicology with the respective endpoints of Ga2O3 and In2O3 toxicology in order to find out if and to what extent arsenic contributes. In addition, the toxicology of Ga2O3 has not yet been adequately reviewed, Therefore, this review provides the first evaluation of all available toxicity data on Ga2O3. The acute toxicity of all three compounds is rather low. Subchronic inhalation studies in rats and mice revealed persistent pulmonary alveolar proteinosis (PAP) and/or alveolar histiocytic infiltrates down to the lowest tested concentration in rats and mice, i.e. 0.16 mg Ga2O3/m3. These are also the predominant effects after GaAs and In2O3 exposure at similarly low levels, i.e. 0.1 mg/m3 each. Subchronic Ga2O3 exposure caused a minimal microcytic anemia with erythrocytosis in rats (at 6.4 mg/m3 and greater) and mice (at 32 and 64 mg/m3), a decrease in epididymal sperm motility and concentration as well as testicular degeneration at 64 mg/m3. At comparable concentrations the hematological effects and male fertility of GaAs were much stronger. The stronger effects of GaAs are due to its better solubility and presumed higher bioavailability. The database for In2O3 is too small and subchronic testing was at very low levels to allow conclusive judgements if blood/blood forming or degrading and male fertility organs/tissues would also be targets.

Lambda sign on a gallium scan: not always sarcoidosis.

Sarcoidosis is a systemic disease of unknown origin. We describe a case of sputum smear-and culture-negative tuberculosis that was diagnosed with histological examination of a surgical lung biopsy, as other entities such as sarcoidosis could not be excluded after extended investigation. Even a typical lambda sign on gallium scintigraphy proved to be misleading.

Effects of chronic immobilization stress on biokinetics and dosimetry of 67Ga in a murine model.

The aim of this work is to determine the effect of chronic immobilization stress on kinetics and dosimetry of 67Ga in a mouse model. A control group (CG) and a stress group (SG), each with 15 mice, were included in the study, and the latter group was subjected to a chronic immobilization stress model 2 h daily for 14 consecutive days. At day 13, 67Ga-citrate was administered intraperitoneally (11.24 ± 0.44 MBq) to each mouse. Then, sets of three mice were obtained sequentially at 24, 36, 48, 60 and 72 h, in which the radionuclide activity was measured with an activity counter. The 67Ga biokinetic data showed a fast blood clearance in the SG, with a mean residence time of 0.06 h. The calculated mean radiation absorbed doses were: liver (2.45 × 10-03 Gy), heart (3.17 × 10-04 Gy) and kidney (1.88 × 10-04 Gy) in the SG. The results show that stress reduced weight gain by approximately 13% and also increased adrenal gland weight by 26%. On the other hand, chronic stress accelerates 67Ga clearance after 24 h compared to normal conditions. It is concluded that murine organisms under chronic immobilization stress have higher gallium-67 clearance rates, decreasing the cumulated activity and absorbed dose in all organs.

Preparation, radiolabeling with 99mTc and 67Ga and biodistribution studies of albumin nanoparticles covered with polymers. / Preparación, radiomarcaje con 99mTc y 67Ga y estudios de biodistribución de nanopartículas de albúmina con recubrimientos poliméricos.

OBJECTIVE: To optimize radiolabeling with 99mTc and 67Ga of albumin nanoparticles coated with 4 differents synthetic polymers and to evaluate their stability in vivo and in vitro, as well as their biodistribution in vivo after intravenous administration. MATERIAL AND METHODS: The nanoparticles were prepared using albumin and NOTA-modified albumin by the desolvation method and coated with 4 different polymers; HPMC, GMN2, GPM2 and GTM2. They were purified, lyophilized and characterized. Radiolabelling with 99mTc was perfomed with 74 MBq of 99mTc sodium pertechnetate, previously reduced with and acid solution of tin chloride at different concentrations (0.003, 0.005, 0.007, 0.01, 0.05 and 0.1mg/ml) and at different times (5, 10, 15, 30 and 60minutes) and temperatures (room temperature, 40°C and 60°C). Radiolabelling with 67Ga was perfomed by incubation of the nanoparticles with 37 MBq of 67Gallium chloride (obtained from commercial gallium-67 citrate) at different times (10 and 30minutes) and temperatures (room temperature, 30°C and 60°C), and posterior purification with microconcentrators. The radiochemical purity was evaluated by TLC. Stability studies of radiolabeled nanoparticles in physiological serum and blood plasma were perfomed. Biodistribution studies of nanoparticles coated with GPM2 polymer were carried out in Wistar rats after intravenous administration of the nanoparticles. Control animals were carried out with 99mTc sodium pertechnetate and 67Ga chloride. To do so, the animals were killed and activity in organs was measured in a gamma counter. RESULTS: 99mTc labeling was carried out optimally with a tin concentration of 0.007mg/ ml for the GPM2 nanoparticles and 0.005mg / ml for the rest of the formulations, with a radiolabelling time of 10minutes at room temperature. In the case of 67Ga the label was optimized at 30° C temperature and 30minutes of incubation. In both cases the radiochemical purity obtained was greater than 97%. The nanoparticles showed high stability in vitro after 48hours of labeling (70% nanoparticles labeled with 99mTc and 90% those labeled with 67Ga). Biodistribution studies of nanoparticles 99mTc -GPM2 and 67Ga -NOTA-GPM2 showed a high accumulation of activity in the liver at 2 and 24hours after intravenous administration. CONCLUSION: The labeling procedure with 99mTc and 67Ga of albumin and albumin modified with NOTA nanoparticles allows obtaining nanoparticles with high labeling yields and adequate in vitro stability, allowing their use for in vivo studies.

Accuracy of Oral 67Gallium Citrate Scintigraphy in assessment of inflammatory activity of Crohn's disease.

AIM: The main goal in Crohn´s disease (CD) is a sustained suppression of inflammatory activity associated with mucosa healing in endoscopic evaluation. During clinical routine, there are small numbers of good markers to monitor inflammatory activity under treatment. We postulated that Oral 67Gallium Citrate Scintigraphy is able to mark inflammatory disease in mucosa and deep inflammation in CD, when used in oral form. OBJECTIVE: Measure the accuracy of Oral 67Gallium Citrate Scintigraphy in intestinal inflammatory activity of Crohn´s disease. PATIENTS AND METHODS: In a prospective consecutive cross-sectional study from January 2018 to June 2019, the ileocolonic region of 32 patients with CD were studied by dividing into four regions of interest (ROI) from the ileum to the rectum. A total of 128 intestinal segments were analyzed in cluster data. Accuracy values of Oral 67Gallium Scintigraphy and colonoscopy tests were evaluated with the histological reference test. Values of the respective receiver operating characteristic (ROC) curves were obtained  and compared. The reliability between the tests was evaluated by Kappa statistical with the segment-level analyses using variance adjustments. All statistical analyses were performed with a test significance level of 0.05. RESULTS: The study population included 32 patients with CD (10 men, 22 women; average age 39 years). Disease time was five years on average. Anti-TNFs treatment was found in 71%. The most found phenotype of the Montreal classification was L3. Differences in ROC curves for colonoscopy (0.94) and Oral 67Ga Scintigraphy (0.96) did not show significant value (p = 0.32). The sensitivity of scintigraphy to detect intestinal inflammatory activity in CD was 64%, specificity of 96% and accuracy of 84%. A high agreement was found between oral scintigraphy and histological measurements with kappa = 0.64. CONCLUSIONS: Oral 67Ga Scintigraphy had similar accuracy and agreement compared to colonoscopy in the identification of inflammatory activity in Crohn´s Disease. This new approach may be useful and less invasive for long term follow-ups.

Gallium nanoparticles along with low-dose gamma radiation modulate TGF-ß/MMP-9 expression in hepatocellular carcinogenesis in rats.

Combining chemotherapy with radiotherapy potentiates the outcome of cancer treatment for the more comprehensive attack. In the current study, we continued to assess the therapeutic efficaciousness of the newly synthesized gallium nanoparticles (GaNPs) combined with low level of gamma radiation (IR), on the incidence of diethylnitrosamine (DEN)-induced hepatocellular carcinoma (HCC) in rats. Oral administration of GaNPs (1 mg/Kg b.wt.) 5 times per week for 6 weeks combined with IR to rats treated with DEN (20 mg/Kg b.wt. 5 times per week for 6 weeks) significantly reduced serum levels of alpha-fetoprotein (AFP), aspartate transferase (AST), alanine transferase (ALT), and gamma-glutamyltransferase (GGT). In addition, the immunoblotting results of matrix metalloproteinase-9 (MM-9) showed a marked downregulation of protein expression along with a significant decrease in the hepatic level of transforming growth factor ß (TGF-ß). Furthermore, GaNPs and/or low dose of radiation significantly elevated the level of caspase-3 gene transcript accompanied with evoked DNA fragmentation in rats treated with DEN. The ameliorative effect of GaNPs and IR well appreciated with the histopathological alteration finding in DEN groups. It can be concluded that the combination of GaNPs and/or IR can serve as a good therapeutic agent for the treatment of HCC, which ought to attract more studies.

Flexible, multifunctional neural probe with liquid metal enabled, ultra-large tunable stiffness for deep-brain chemical sensing and agent delivery.

Flexible neural probes have been pursued previously to minimize the mechanical mismatch between soft neural tissues and implants and thereby improve long-term performance. However, difficulties with insertion of such probes deep into the brain severely restricts their utility. We describe a solution to this problem using gallium (Ga) in probe construction, taking advantage of the solid-to-liquid phase change of the metal at body temperature and probe shape deformation to provide temperature-dependent control of stiffness over 5 orders of magnitude. Probes in the stiff state were successfully inserted 2 cm-deep into agarose gel "brain phantoms" and into rat brains under cooled conditions where, upon Ga melting, they became ultra soft, flexible, and stretchable in all directions. The current 30 µm-thick probes incorporated multilayer, deformable microfluidic channels for chemical agent delivery, electrical interconnects through Ga wires, and high-performance electrochemical glutamate sensing. These PDMS-based microprobes of ultra-large tunable stiffness (ULTS) should serve as an attractive platform for multifunctional chronic neural implants.

Targeting iron metabolism in high-grade glioma with 68Ga-citrate PET/MR.

Noninvasive tools that target tumor cells could improve the management of glioma. Cancer generally has a high demand for Fe(III), an essential nutrient for a variety of biochemical processes. We tested whether 68Ga-citrate, an Fe(III) biomimetic that binds to apo-transferrin in blood, detects glioma in preclinical models and patients using hybrid PET/MRI. Mouse PET/CT studies showed that 68Ga-citrate accumulates in subcutaneous U87MG xenografts in a transferrin receptor-dependent fashion within 4 hours after injection. Seventeen patients with WHO grade III or IV glioma received 3.7-10.2 mCi 68Ga-citrate and were imaged with PET/MR 123-307 minutes after injection to establish that the radiotracer can localize to human tumors. Multiple contrast-enhancing lesions were PET avid, and tumor to adjacent normal white matter ratios were consistently greater than 10:1. Several contrast-enhancing lesions were not PET avid. One minimally enhancing lesion and another tumor with significantly reduced enhancement following bevacizumab therapy were PET avid. Advanced MR imaging analysis of one patient with contrast-enhancing glioblastoma showed that metabolic hallmarks of viable tumor spatially overlaid with 68Ga-citrate accumulation. These early data underscore that high-grade glioma may be detectable with a radiotracer that targets Fe(III) transport.

PET/CT to detect adverse reactions to metal debris in patients with metal-on-metal hip arthroplasty: an exploratory prospective study.

Metal-on-metal (MoM) bearings in total hip arthroplasties and hip resurfacing arthroplasties have recently shown a new type of complication: adverse reactions to metal debris (ARMD). ARMD is characterized by local severe inflammation and tissue necrosis leading to implant failures. The gluteal muscle region is important for the patient outcome after revision surgery. This prospective positron emission tomography/computed tomography (PET/CT) study was undertaken to evaluate the characteristics of 2-deoxy-2-[18 F]fluoro-d-glucose ([18 F]FDG) and [68 Ga]Gallium citrate ([68 Ga]Citrate) PET/CT in ARMD patients. [18 F]FDG and [68 Ga]Citrate PET/CT were performed in 18 hip arthroplasty patients: 12 ARMD patients (with 16 MoM hips) and six arthroplasty controls without ARMD. Tracer uptake was evaluated visually, and maximum standardized uptake (SUVmax ) was measured in the gluteal muscle region. ARMD severity was graded by metal artefact reduction sequence-magnetic resonance imaging (MARS-MRI). Periprosthetic [18 F]FDG uptake was observed in 15 of 16 hips, [68 Ga]Citrate uptake in three of 16 hips, respectively. The distribution of tracer uptake resembled infection in three hips. In the gluteal muscle region, the SUVmax of [18 F]FDG was significantly greater in hips with moderate and severe ARMD compared with the controls (P = 0·009 for [18 F]FDG and P = 0·217 for [68 Ga]Citrate). In patients who needed revision surgery, an intraoperative finding of gluteal muscle necrosis was associated with increased local SUVmax as detected by preoperative [18 F]FDG (P = 0·039), but not by [68 Ga]Citrate (P = 0·301). In conclusion, the inflammatory reaction to metal debris in hip arthroplasty patients is best visualized with [18 F]FDG.

Proof of Concept: Design and Initial Evaluation of a Device to Measure Gastrointestinal Transit Time.

Chronic constipation and gastrointestinal motility disorders constitute a large part of a gastroenterology practice and have a significant impact on a patient's quality of life and lifestyle. In most cases, medications are prescribed to alleviate symptoms without there being an objective measurement of response. Commonly used investigations of gastrointestinal transit times are currently limited to radiopaque markers or electronic capsules. Repeated use of these techniques is limited because of the radiation exposure and the significant cost of the devices. We present the proof of concept for a new device to measure gastrointestinal transit time using commonly available and inexpensive materials with only a small amount of radiotracer. Methods: We assembled gelatin capsules containing a 67Ga-citrate-radiolabeled grain of rice embedded in paraffin for use as a point-source transit device. It was tested for stability in vitro and subsequently was given orally to 4 healthy volunteers and 10 patients with constipation or diarrhea. Imaging was performed at regular intervals until the device was excreted. Results: The device remained intact and visible as a point source in all subjects until excretion. When used along with a diary of bowel movement times and dates, the device could determine the total transit time. The device could be visualized either alone or in combination with a barium small-bowel follow-through study or a gastric emptying study. Conclusion: The use of a point-source transit device for the determination of gastrointestinal transit time is a feasible alternative to other methods. The device is inexpensive and easy to assemble, requires only a small amount of radiotracer, and remains inert throughout the gastrointestinal tract, allowing for accurate determination of gastrointestinal transit time. Further investigation of the device is required to establish optimum imaging parameters and reference values. Measurements of gastrointestinal transit time may be useful in managing patients with dysmotility and in selecting the appropriate pharmaceutical treatment.

Enhanced Afterglow Performance of Persistent Luminescence Implants for Efficient Repeatable Photodynamic Therapy.

Persistent luminescence nanoparticles (PLNPs) have been used for bioimaging without autofluorescence background interference, but the poor afterglow performance impedes their further applications in cancer therapy. To overcome the Achilles' heel of PLNPs, herein we report the construction of injectable persistent luminescence implants (denoted as PL implants) as a built-in excitation source for efficient repeatable photodynamic therapy (PDT). The injectable ZGC (ZnGa1.996O4:Cr0.004) PL implants were prepared by dissolving ZGC PLNPs in poly(lactic-co-glycolic acid)/N-methylpyrrolidone oleosol, which demonstrated much stronger persistent luminescence (PersL) intensity and longer PersL lifetime than that of ZGC PLNPs both in vitro and in vivo. More importantly, the intratumorally fixed ZGC PL implants can serve as a built-in excitation source for repeatable light emitting diode (LED) and PersL-excited PDT upon and after periodic LED irradiation, which leads to the overall improvement of therapeutic effectiveness for efficient tumor growth suppression. This work represents efficient repeatable PDT based on the injectable yet periodically rechargeable ZGC PL implants.

Positron Emission Tomography and Single-Photon Emission Computed Tomography Imaging in the Diagnosis of Cardiac Implantable Electronic Device Infection: A Systematic Review and Meta-Analysis.

BACKGROUND: The use of cardiac implantable electronic devices (CIED) is increasing, and their associated infections result in significant morbidity and mortality. The introduction of better cardiac imaging techniques could be useful for diagnosing this condition and guiding therapy. Our objective was to systematically assess the diagnostic accuracy of Fluor-18-fluorodeoxyglucose positron emission tomography and computed tomography, labeled leukocyte scintigraphy (LS), and Gallium-67 citrate scintigraphy for the diagnosis of CIED infection. METHODS AND RESULTS: A systematic review of the literature and meta-analysis on the use of all 3 modalities in CIED infection were conducted. Pooled sensitivity, specificity, and summary receiver operating characteristic curves of each imaging modalities were determined. The literature search identified 2493 articles. A total of 13 articles (11 studies for 18F-FDG PET-CT and 2 for LS), met the inclusion criteria. No studies for 67Ga citrate scintigraphy met the inclusion criteria. The pooled sensitivity of 18F-FDG PET-CT for the diagnosis of CIED infection was 87% (95% CI, 82%-91%) and pooled specificity was 94% (95% CI, 88%-98%). The summary receiver operating characteristic curve analysis demonstrated good overall accuracy, with an area under the curve of 0.935. There were insufficient data to do a meta-analysis for LS, but both studies reported sensitivity above 90% and specificity of 100%. CONCLUSIONS: Both 18F-FDG PET-CT and LS yield high sensitivity, specificity, and accuracy, and thus seem to be useful for the diagnosis of CIED infection, based on robust data for 18F-FDG PET-CT but limited data for LS. When available,18F-FDG PET-CT may be preferred.

SPECT-computed tomography in rats with TNBS-induced colitis: A first step toward functional imaging.

AIM: To assess the feasibility of SPECT-computed tomography (CT) in rats with trinitrobenzene sulfonic acid (TNBS)-induced acute colitis and confront it with model inflammatory characteristics. METHODS: Colitis was induced in Sprague-Dawley rats by intrarectal injection of TNBS (n = 10) while controls received vehicle (n = 10). SPECT-CT with intravenous injection of 10 MBq of 67Ga-Citrate was performed at day 2. SPECT-CT criteria were colon wall thickness and maximal wall signal intensity. Laboratory parameters were assessed: colon weight:length ratio, colon cyclooxygenase-2 expression by western blot and histological inflammatory score. RESULTS: Colon weight/length ratio, colon COX-2 expression and histological inflammatory score were significantly higher in the TNBS group than in the control group (P = 0.0296, P < 0.0001, P = 0.0007 respectively). Pixel max tend to be higher in the TNBS group than in the control group but did not reach statistical significance (P = 0.0662). Maximal thickness is significantly increased in the TNBS group compared to the control group (P = 0.0016) while colon diameter is not (P = 0.1904). Maximal thickness and colon diameter were correlated to colon COX-2 expression (P = 0.0093, P = 0.009 respectively) while pixel max was not (P = 0.22). Maximal thickness was significantly increased when inflammation was histologically observed (P = 0.0043) while pixel max and colon diameter did not (P = 0.2452, P = 0.3541, respectively). CONCLUSION: SPECT-CT is feasible and easily distinguished control from colitic rats.

Serum and tissue concentrations of gallium after oral administration of gallium nitrate and gallium maltolate to neonatal calves.

OBJECTIVE: To determine serum and tissue concentrations of gallium (Ga) after oral administration of gallium nitrate (GaN) and gallium maltolate (GaM) to neonatal calves. ANIMALS: 8 healthy neonatal calves. PROCEDURES: Calves were assigned to 1 of 2 groups (4 calves/group). Gallium (50 mg/kg) was administered as GaN or GaM (equivalent to 13.15 mg of Ga/kg for GaN and 7.85 mg of Ga/kg for GaM) by oral gavage once daily for 5 days. Blood samples were collected 0, 0.25, 0.5, 1, 2, 4, 8, 12, and 24 hours after Ga administration on day 1; 4 and 24 hours after Ga administration on days 2, 3, and 4; and 4, 12, and 24 hours after Ga administration on day 5. On day 6, calves were euthanized and tissue samples were obtained. Serum and tissue Ga concentrations were measured by use of mass spectrometry. RESULTS: Data were adjusted for total Ga dose, and comparisons were made between the 2 groups. Calves receiving GaM had a significantly higher dose-adjusted area under the curve and dose-adjusted maximum serum Ga concentration than did calves receiving GaN. Despite receiving less Ga per dose, calves receiving GaM had tissue Ga concentrations similar to those for calves receiving GaN. CONCLUSIONS AND CLINICAL RELEVANCE: In this study, calves receiving GaM had significantly higher Ga absorption than did calves receiving GaN. These findings suggested that GaM might be useful as a prophylactic agent against Mycobacterium avium subsp paratuberculosis infection in neonatal calves.

Crystal structure and chemotherapeutic efficacy of the novel compound, gallium tetrachloride betaine, against breast cancer using nanotechnology.

The objective of this study was to investigate the antitumor efficacy of a novel synthesized compound, betaine gallium-tetrachloride (BTG), alone or combined with ZnO-nanoparticles (BTG + ZnO-NPs) on the incidence of 7, 12-dimethylbenz-anthrathene-induced mammary tumor in female rats. Crystal and molecular structure of the prepared BTG were identified using X-ray crystallography. In vitro study revealed BTG more cytotoxic than BTG + ZnO-NPs on human breast cancer (MCF-7) cell line. In vivo study demonstrated that the blood antioxidant status of tumor-bearing rats (DMBA group) was significantly lower than normal noticeable by a significant decrease in GSH content, GPx, SOD, and CAT activities associated with a significantly high MDA content. Both treatments have significantly elevated SOD and CAT activities with a concomitant decrease of MDA level compared to DMBA group. However, BTG + ZnO-NPs accentuated the decrease of GSH regarding DMBA group. The results showed also that both treatments significantly activate caspase-3 enzyme and apoptosis in mammary glands. Their administration to tumor-bearing rats was found to significantly reduce plasma iron and iron-binding capacity (TIBC) compared to DMBA group. Regarding liver function, both treatments significantly reduced the increase of ALT and AST activities compared to DMBA group. However, BTG + ZnO-NPs decreased albumin below normal level. Histopathological studies showed that normalization of tissue structures was higher in BTG than BTG + ZnO-NPs treatment. According to the results obtained, it is observed that the antitumor effect of BTG alone was as strong as BTG + ZnO-NPs and even more efficient in some aspects accordingly, a combination is not needed. Thus, the novel synthetic gallium derivatives may potentially present a new hope for the development of breast cancer therapeutics, which should attract further scientific and pharmaceutical interest.

An In Vitro Comparison of PMMA and Calcium Sulfate as Carriers for the Local Delivery of Gallium(III) Nitrate to Staphylococcal Infected Surgical Sites.

Antibiotic-loaded bone cements, including poly(methyl methacrylate) (PMMA) and calcium sulfate (CaSO4), are often used for treatment of orthopaedic infections involving Staphylococcus spp., although the effectiveness of this treatment modality may be limited due to the emergence of antimicrobial resistance and/or the development of biofilms within surgical sites. Gallium(III) is an iron analog capable of inhibiting essential iron-dependent pathways, exerting broad antimicrobial activity against multiple microorganisms, including Staphylococcus spp. Herein, we evaluated PMMA and CaSO4 as carriers for delivery of gallium(III) nitrate (Ga(NO3)3) to infected surgical sites by assessing the release kinetics subsequent to incorporation and antimicrobial activity against S. aureus and S. epidermidis. PMMA and to a lesser extent CaSO4 were observed to be compatible as carriers for Ga(NO3)3, eluting concentrations with antimicrobial activity against planktonic bacteria, inhibiting bacterial growth, and preventing bacterial colonization of beads, and effective against established bacterial biofilms of S. aureus and S. epidermidis. Collectively, our in vitro results indicate that PMMA is a more suitable carrier compared to CaSO4 for delivery of Ga(NO3)3; moreover they provide evidence for the potential use of Ga(NO3)3 with PMMA as a strategy for the prevention and/or treatment for orthopaedic infections.