Copper chelation in patients with hypertrophic cardiomyopathy.

BACKGROUND: Disturbances of copper (Cu) homeostasis can lead to hypertrophic cardiac phenotypes (eg, Wilson's disease). We previously identified abnormal Cu homeostasis in patients with hypertrophic cardiomyopathy (HCM) and, therefore, hypothesised that Cu2+-selective chelation with trientine dihydrochloride may slow or reverse disease progression in HCM. The aim of this study was, therefore to explore the clinical efficacy, safety and tolerability of trientine in HCM. METHODS: In this medicines and healthcare products regulatory agency (MHRA) registered open-label pilot study, we treated 20 HCM patients with trientine for 6 months. Patients underwent a comprehensive assessment schedule including separate cardiac magnetic resonance imaging (CMR) and CMR 31P-spectroscopy at baseline and end of therapy. Predefined end points included changes in left ventricular mass (LVM), markers of LV fibrosis, markers of LV performance and myocardial energetics. Ten matched patients with HCM were studied as controls. RESULTS: Trientine treatment was safe and tolerated. Trientine caused a substantial increase in urinary copper excretion (0.42±0.2 vs 2.02±1.0, p=0.001) without affecting serum copper concentrations. Treatment was associated with significant improvements in total atrial strain and global longitudinal LV strain using both Echo and CMR. LVM decreased significantly in the treatment arm compared with the control group (-4.2 g v 1.8 g, p=0.03). A strong trend towards an absolute decrease in LVM was observed in the treatment group (p=0.06). These changes were associated with a significant change in total myocardial volume driven by a significant reduction in extracellular matrix (ECM) volume (43.83±18.42 mL vs 41.49±16.89 mL, p=0.04) as opposed to pure cellular mass reduction and occurred against a background of significant ECM volume increase in the control group (44.59±16.50 mL vs 47.48±19.30 mL, p=0.02). A non-significant 10% increase in myocardial phosphocreatine/adenosine triphosphate (PCr/ATP) ratio with trientine therapy (1.27±0.44 vs 1.4±0.39) was noted. CONCLUSIONS: Cu2+-selective chelation with trientine in a controlled environment is safe and a potential future therapeutic target. A phase 2b trial is now underway.

Anti-melanogenesis and anti-tyrosinase properties of aryl-substituted acetamides of phenoxy methyl triazole conjugated with thiosemicarbazide: Design, synthesis and biological evaluations.

A series of aryl phenoxy methyl triazole conjugated with thiosemicarbazides were designed, synthesized, and evaluated for their tyrosinase inhibitory activities in the presence of l-dopa and l-tyrosine as substrates. All the compounds showed tyrosinase inhibition in the sub-micromolar concentration. Among the derivatives, compound 9j bearing benzyl displayed exceptionally high potency against tyrosinase with IC50 value of 0.11 µM and 0.17 µM in the presence of l-tyrosine and l-dopa as substrates which is significantly lower than that of kojic acid as the positive control with an IC50 value of 9.28 µM for l-tyrosine and 9.30 µM for l-dopa. According to Lineweaver-Burk plot, 9j demonstrated an uncompetitive type of inhibition in the kinetic assay. Also, in vitro antioxidant activities determined by DPPH assay recorded an IC50 value of 68.43 µM for 9i. The melanin content of 9j was determined on B16F10 melanoma human cells which demonstrated a significant reduction of the melanin content. Moreover, the binding energies corresponding to the same ligand as well as computer-aided drug-likeness and pharmacokinetic studies were also carried out. Compound 9j also possessed metal chelation potential correlated to its high anti-TYR activity.

Positron Emission Tomography Imaging of Neurotensin Receptor-Positive Tumors with 68Ga-Labeled Antagonists: The Chelate Makes the Difference Again.

Neurotensin receptor 1 (NTS1) is involved in the development and progression of numerous cancers, which makes it an interesting target for the development of diagnostic and therapeutic agents. A small molecule NTS1 antagonist, named [177Lu]Lu-IPN01087, is currently evaluated in phase I/II clinical trials for the targeted therapy of neurotensin receptor-positive cancers. In this study, we synthesized seven compounds based on the structure of NTS1 antagonists, bearing different chelating agents, and radiolabeled them with gallium-68 for PET imaging. These compounds were evaluated in vitro and in vivo in mice bearing a HT-29 xenograft. The compound [68Ga]Ga-bisNODAGA-16 showed a promising biodistribution profile with mainly signal in tumor (4.917 ± 0.776%ID/g, 2 h post-injection). Its rapid clearance from healthy tissues led to high tumor-to-organ ratios, resulting in highly contrasted PET images. These results were confirmed on subcutaneous xenografts of AsPC-1 tumor cells, a model of NTS1-positive human pancreatic adenocarcinoma.

A New, Second Generation Trithiol Bifunctional Chelate for 72,77As: Trithiol(b)-(Ser)2-RM2.

Trithiol chelates are suitable for labeling radioarsenic (72As: 2.49 MeV ß+, 26 h; 77As: 0.683 MeV ß-, 38.8 h) to form potential theranostic radiopharmaceuticals for positron emission tomography (PET) imaging and therapy. A trithiol(b)-(Ser)2-RM2 bioconjugate and its arsenic complex were synthesized and characterized. The trithiol(b)-(Ser)2-RM2 bioconjugate was radiolabeled with no-carrier-added 77As in over 95% radiochemical yield and was stable for over 48 h, and in vitro IC50 cell binding studies of [77As]As-trithiol(b)-(Ser)2-RM2 in PC-3 cells demonstrated high affinity for the gastrin-releasing peptide (GRP) receptor (low nanomolar range). Limited biodistribution studies in normal mice were performed with HPLC purified 77As-trithiol(b)-(Ser)2-RM2 demonstrating both pancreatic uptake and hepatobiliary clearance.

Multilayer Microcapsules with Shell-Chelated 89Zr for PET Imaging and Controlled Delivery.

Radionuclide-functionalized drug delivery vehicles capable of being imaged via positron emission tomography (PET) are of increasing interest in the biomedical field as they can reveal the in vivo behavior of encapsulated therapeutics with high sensitivity. However, the majority of current PET-guided theranostic agents suffer from poor retention of radiometal over time, low drug loading capacities, and time-limited PET imaging capability. To overcome these challenges, we have developed hollow microcapsules with a thin (<100 nm) multilayer shell as advanced theranostic delivery systems for multiday PET tracking in vivo. The 3 µm capsules were fabricated via the aqueous multilayer assembly of a natural antioxidant, tannic acid (TA), and a poly(N-vinylpyrrolidone) (PVPON) copolymer containing monomer units functionalized with deferoxamine (DFO) to chelate the 89Zr radionuclide, which has a half-life of 3.3 days. We have found using radiochromatography that (TA/PVPON-DFO)6 capsules retained on average 17% more 89Zr than their (TA/PVPON)6 counterparts, which suggests that the covalent attachment of the DFO to PVPON provides stable 89Zr chelation. In vivo PET imaging studies performed in mice demonstrated that excellent stability and imaging contrast were still present 7 days postinjection. Animal biodistribution analyses showed that capsules primarily accumulated in the spleen, liver, and lungs with negligible accumulation in the femur, with the latter confirming the stable binding of the radiotracer to the capsule walls. The application of therapeutic ultrasound (US) (60 s of 20 kHz US at 120 W cm-2) to Zr-functionalized capsules could release the hydrophilic anticancer drug doxorubicin from the capsules in the therapeutic amounts. Polymeric capsules with the capability of extended in vivo PET-based tracking and US-induced drug release provide an advanced platform for development of precision-targeted therapeutic carriers and could aid in the development of more effective drug delivery systems.

Synthesis and Evaluation of 68Ga- and 177Lu-Labeled (R)- vs (S)-DOTAGA Prostate-Specific Membrane Antigen-Targeting Derivatives.

Prostate-specific membrane antigen (PSMA) is overexpressed in prostate cancer cells and therefore is an attractive target for prostate cancer diagnosis and radionuclide therapy. Recently, published results from clinical studies using a new PSMA-targeting PET imaging agent, [68Ga]Ga-PSMA-093 ([68Ga]Ga-HBED-CC-O-carboxymethyl-Tyr-CO-NH-Glu), support the development of this agent for the diagnosis of prostate cancer. In this study, the HBED-CC chelating group in PSMA-093 was replaced by stereoselective (R)- or (S)-DOTAGA. This chelating group serves not only for chelating 68Ga but is also amendable for complexing other radioactive metals for radionuclide therapy. The corresponding optically pure (R)- and (S)-[68Ga/177Lu]-DOTAGA derivatives, (R)-[68Ga/177Lu]-13 and (S)-[68Ga/177Lu]-13, were successfully prepared. Comparison of radiolabeling, binding affinity, cell uptake, and biodistribution between the two isomers was performed. Radiolabeling of (R)-[177Lu]Lu-13 and (S)-[177Lu]Lu-13 at 50 °C suggested that rates of complex formation were time-dependent and the formation of (S)-[177Lu]Lu-13 was distinctly faster. The rates of complex formation for the corresponding 68Ga agents were comparable between structural isomers. The natGa and natLu equivalents showed high binding PSMA affinity (IC50 = 24-111 nM), comparable to that of the parent agent, [natGa]Ga-PSMA-093 (IC50 = 34.0 nM). Results of cell uptake and biodistribution studies in PSMA-expressing PC3-PIP tumor-bearing mice appeared to show no difference between the labeled (R)- and (S)-isomers. This is the first time that a pair of [68Ga/177Lu]-(R)- and (S)-DOTAGA isomers of PSMA agents were evaluated. Results of biological studies between the isomers showed no noticeable difference; however, the distinctions on the rate of Lu complex formation should be considered in the development of new 177Lu-DOTAGA-based radionuclide therapy agents in the future.

Positron emission tomography imaging of novel AAV capsids maps rapid brain accumulation.

Adeno-associated viruses (AAVs) are typically single-stranded deoxyribonucleic acid (ssDNA) encapsulated within 25-nm protein capsids. Recently, tissue-specific AAV capsids (e.g. PHP.eB) have been shown to enhance brain delivery in rodents via the LY6A receptor on brain endothelial cells. Here, we create a non-invasive positron emission tomography (PET) methodology to track viruses. To provide the sensitivity required to track AAVs injected at picomolar levels, a unique multichelator construct labeled with a positron emitter (Cu-64, t1/2 = 12.7 h) is coupled to the viral capsid. We find that brain accumulation of the PHP.eB capsid 1) exceeds that reported in any previous PET study of brain uptake of targeted therapies and 2) is correlated with optical reporter gene transduction of the brain. The PHP.eB capsid brain endothelial receptor affinity is nearly 20-fold greater than that of AAV9. The results suggest that novel PET imaging techniques can be applied to inform and optimize capsid design.

Manipulating the In Vivo Behaviour of 68Ga with Tris(Hydroxypyridinone) Chelators: Pretargeting and Blood Clearance.

Pretargeting is widely explored in immunoPET as a strategy to reduce radiation exposure of non-target organs and allow the use of short-lived radionuclides that would not otherwise be compatible with the slow pharmacokinetic profiles of antibodies. Here we investigate a pretargeting strategy based on gallium-68 and the chelator THPMe as a high-affinity pair capable of combining in vivo. After confirming the ability of THPMe to bind 68Ga in vivo at low concentrations, the bifunctional THPMe-NCS was conjugated to a humanised huA33 antibody targeting the A33 glycoprotein. Imaging experiments performed in nude mice bearing A33-positive SW1222 colorectal cancer xenografts compared pretargeting (100 µg of THPMe-NCS-huA33, followed after 24 h by 8-10 MBq of 68Ga3+) with both a directly labelled radioimmunoconjugate (89Zr-DFO-NCS-huA33, 88 µg, 7 MBq) and a 68Ga-only negative control (8-10 MBq of 68Ga3+). Imaging was performed 25 h after antibody administration (1 h after 68Ga3+ administration for negative control). No difference between pretargeting and the negative control was observed, suggesting that pretargeting via metal chelation is not feasible using this model. However, significant accumulation of "unchelated" 68Ga3+ in the tumour was found (12.9 %ID/g) even without prior administration of THPMe-NCS-huA33, though tumour-to-background contrast was impaired by residual activity in the blood. Therefore, the 68Ga-only experiment was repeated using THPMe (20 µg, 1 h after 68Ga3+ administration) to clear circulating 68Ga3+, producing a three-fold improvement of the tumour-to-blood activity concentration ratio. Although preliminary, these results highlight the potential of THPMe as a 68Ga clearing agent in imaging applications with gallium citrate.

[nat/44Sc(pypa)]-: Thermodynamic Stability, Radiolabeling, and Biodistribution of a Prostate-Specific-Membrane-Antigen-Targeting Conjugate.

44Sc is an attractive positron-emitting radionuclide for PET imaging; herein, a new complex of the Sc3+ ion with nonmacrocyclic chelator H4pypa was synthesized and characterized with high-resolution electrospray-ionization mass spectrometry (HR-ESI-MS), as well as different nuclear magnetic resonance (NMR) spectroscopic techniques (1H, 13C, 1H-13C HSQC, 1H-13C HMBC, COSY, and NOESY). In aqueous solution (pH = 7), [Sc(pypa)]- presented two isomeric forms, the structures of which were predicted using density functional theory (DFT) calculation with a small energy difference of 22.4 kJ/mol, explaining their coexistence. [Sc(pypa)]- was found to have superior thermodynamic stability (pM = 27.1) compared to [Sc(AAZTA)]- (24.7) and [Sc(DOTA)]- (23.9). In radiolabeling, [44Sc][Sc(pypa)]- formed efficiently at RT in 15 min over a range of pH (2-5.5), resulting in a complex that is highly stable (>99%) in mouse serum over at least six half-lives of scandium-44. Similar labeling efficiency was observed with the PSMA (prostate-specific membrane antigen)-targeting H4pypa-C7-PSMA617 at pH = 5.5 (RT, 15 min), confirming negligible disturbance from the bifunctionalization on scandium-44 scavenging. Moreover, the kinetic inertness of the radiocomplex was proved in vivo. Surprisingly, the molar activity was found to have profound influence on the pharmacokinetics of the radiotracers where lower molar activity drastically reduced the background accumulations, particularly, kidney, and thus, yielded a much higher tumor-to-background contrast.

Toward a Rational Design of Polyamine-Based Zinc-Chelating Agents for Cancer Therapies.

In vitro viability assays against a representative panel of human cancer cell lines revealed that polyamines L1a and L5a displayed remarkable activity with IC50 values in the micromolar range. Preliminary research indicated that both compounds promoted G1 cell cycle arrest followed by cellular senescence and apoptosis. The induction of apoptotic cell death involved loss of mitochondrial outer membrane permeability and activation of caspases 3/7. Interestingly, L1a and L5a failed to activate cellular DNA damage response. The high intracellular zinc-chelating capacity of both compounds, deduced from the metal-specific Zinquin assay and ZnL2+ stability constant values in solution, strongly supports their cytotoxicity. These data along with quantum mechanical studies have enabled to establish a precise structure-activity relationship. Moreover, L1a and L5a showed appropriate drug-likeness by in silico methods. Based on these promising results, L1a and L5a should be considered a new class of zinc-chelating anticancer agents that deserves further development.

Chelating ZnO-dopamine on the surface of graphene oxide and its application as pH-responsive and antibacterial nanohybrid delivery agent for doxorubicin.

In this work, a new pH-responsive nanohybrid carrier was prepared with chelating ZnO-dopamine (Zn-d) on the surface of graphene oxide. Doxorubicin (DOX) as a model drug was loaded on the resulted nanohybrid. The characteristics of Zn-d-rGO nanohybrid (NH) determined using Fourier transformed infrared spectroscopy (FT-IR), X-ray Diffraction spectroscopy (XRD), UV-Visible spectroscopy, Scanning Electron Microscope (SEM), EDX and AFM. The BET analysis showed a specific surface area of 37.16 m2/g and the obtained nanohybrid indicated a high loading capacity of DOX up to 99.7%, and the release profile displayed a pH-dependent discharge in the acidic environment for14 days. The cytotoxicity of the prepared nanohybrid was measured against T47D and MCF10A cells and it confirmed that as-prepared nanohybrid has high toxicity against cancer cells and lower effect against human breast cell. Meanwhile, the prepared nanohybrids showed well antimicrobial activity against gram-positive and negative bacteria. The obtained results showed that the prepared nanohybrid (Zn-d-rGO) could potentially be used as a safe carrier for drug delivery systems.

Gallium-68 and scandium-44 labelled radiotracers based on curcumin structure linked to bifunctional chelators: Synthesis and characterization of potential PET radiotracers.

Curcumin metal complexes showed widespread applications in medicine and can be exploited as a lead structure for developing new tracers for nuclear medicine application. Herein, the synthesis, chemical characterization and radiolabelling with gallium-68 and scandium-44 of two new targeting vectors based on curcumin scaffolds and linked to the chelators 1,4,7-triazacyclononane,1-glutaric acid-4,7-acetic acid (NODAGA) and 1,4-bis(carboxymethyl)-6-[bis(carboxymethyl)]amino-6-methylperhydro-1,4-diazepine (AAZTA) are reported. Synthesis of the precursors could be achieved with a 13% and 11% yield and radiolabelling generally afforded rapid incorporation under mild conditions (>95%). Stability in physiological media (~75% after 2 h in human blood for [68Ga]Ga-/[44Sc]Sc-AAZTA-PC21 and ~60% for [68Ga]Ga-NODAGA-C21, respectively) are generally enhanced if compared to the previously radiolabelled analogues. MSn fragmentation experiments showed high stability of the AAZTA-PC21 structure mainly due to the pyrazole derivatization of the curcumin keto-enol moiety and a more feasible radiolabelling was noticed both with gallium-68 and scandium-44 mainly due to the AAZTA-chelator properties. [68Ga]Ga-NODAGA-C21 showed the most favorable lipophilicity value (logD = 1.3). Due to these findings, both compounds appear to be promising candidates for the imaging of colorectal cancer, but further studies such as in vitro uptake and in vivo biodistribution experiments are needed.

Biological Evaluation of 8-Hydroxyquinolines as Multi-Target Directed Ligands for Treating Alzheimer's Disease.

BACKGROUND: Accumulating evidence suggests that multi-target directed ligands have great potential for the treatment of complex diseases such as Alzheimer's Disease (AD). OBJECTIVE: To evaluate novel chimeric 8-hydroxyquinoline ligands with merged pharmacophores as potential multifunctional ligands for AD. METHODS: Nitroxoline, PBT2 and compounds 2-4 were evaluated in-vitro for their inhibitory potencies on cathepsin B, cholinesterases, and monoamine oxidases. Furthermore, chelation, antioxidative properties and the permeability of Blood-Brain Barrier (BBB) were evaluated by spectroscopy-based assays and the inhibition of Amyloid ß (Aß) aggregation was determined in immunoassay. Cell-based assays were performed to determine cytotoxicity, neuroprotection against toxic Aß species, and the effects of compound 2 on apoptotic cascade. RESULTS: Compounds 2-4 competitively inhibited cathepsin B ß-secretase activity, chelated metal ions and were weak antioxidants. All of the compounds inhibited Aß aggregation, whereas only compound 2 had a good BBB permeability according to the parallel artificial membrane permeability assay. Tested ligands 2 and 3 were not cytotoxic to SH-SY5Y and HepG2 cells at 10 µM. Compound 2 exerted neuroprotective effects towards Aß toxicity, reduced the activation of caspase-3/7 and diminished the apoptosis of cells treated with Aß1-42. CONCLUSION: Taken together, our data suggest that compound 2 holds a promise to be used as a multifunctional ligand for AD.

The in vivo fate of 225Ac daughter nuclides using polymersomes as a model carrier.

Increasing attention is given to personalized tumour therapy, where α-emitters can potentially play an important role. Alpha particles are ideal for localized cell killing because of their high linear energy transfer and short ranges. However, upon the emission of an α particle the daughter nuclide experiences a recoil energy large enough to ensure decoupling from any chemical bond. These 'free' daughter nuclides are no longer targeted to the tumour and can accumulate in normal tissue. In this paper, we used polymersomes as model carrier to evaluate the retention of recoiling daughters of 225Ac in vivo, and assessed their suitability as therapeutic agents. Vesicles containing 225Ac were injected intravenously in healthy mice, and intratumourally in tumour-bearing mice, and the relocation of free 213Bi was assessed in different organs upon the injection [225Ac]Ac-polymersomes. The therapeutic effect of 225Ac-containing vesicles was studied upon intratumoural injection, where treatment groups experienced no tumour-related deaths over a 115 day period. While polymersomes containing 225Ac could be suitable agents for long-term irradiation of tumours without causing significant renal toxicity, there is still a significant re-distribution of daughter nuclides throughout the body, signifying the importance of careful evaluation of the effect of daughter nuclides in targeted alpha therapy.

Enhanced Tumor-Specific Disulfiram Chemotherapy by In Situ Cu2+ Chelation-Initiated Nontoxicity-to-Toxicity Transition.

The antitumor activity of disulfiram (DSF), a traditional US Food and Drug Administration-approved drug for the treatment of "alcohol-dependence", is Cu2+-dependent, but the intrinsic anfractuous biodistribution of copper in the human body and copper toxicity induced by exogenous copper supply have severely hindered its in vivo application. Herein, we report an in situ Cu2+ chelation-enhanced DSF-based cancer chemotherapy technique, using a tumor-specific "nontoxicity-to-toxicity" transition strategy based on hollow mesoporous silica nanoparticles as the functional carrier. Cu2+-doped, DSF-loaded hollow mesoporous silica nanoparticles were constructed for the rapid release of Cu2+ ions induced by the mild acidic conditions of the tumor microenvironment. This resulted in the rapid biodegradation of the nanoparticles and accelerated DSF release once the particles were endocytosed into tumor cells. The resulting in situ chelation reaction between the coreleased Cu2+ ions and DSF generated toxic CuET products and concurrently, Fenton-like reactions between the generated Cu+ ions and the high levels of H2O2 resulted in the production of reactive oxygen species (ROS) in the acidic tumor microenvironment. Both in vitro cellular assays and in vivo tumor-xenograft experiments demonstrated the efficient Cu-enhanced and tumor-specific chemotherapeutic efficacy of DSF, with cocontributions from highly toxic CuET complexes and ROS generated within tumors. This work provides a conceptual advancement of nanoparticle-enabled "nontoxicity-to-toxicity" transformation in tumors, to achieving high chemotherapeutic efficacy and biosafety.

Pharmacokinetics and Tissue Distribution of a Novel Bis-Chelated Gold(I) Diphosphine Compound, Bis(2,3-bis(tert-butylmethylphosphino)Quinoxaline)Aurate(I), in Rats.

GC20, a novel soluble bis-chelated gold(I)-diphosphine compound, has been reported as a promising anticancer candidate. Assessing the pharmacokinetic properties of GC20 is critical for its medicinal evaluation. First, a sensitive and specific liquid chromatography tandem mass spectrometry (LC-MS/MS) was developed and well validated to determine GC20 in rat plasma and rat tissue homogenate after one step protein precipitation. Chromatographic separation was achieved on an Angilent ZORBAX-C18 column (3.5 µm, 2.1 × 50 mm) with gradient elution and mass spectrometry was performed on a triple quadrupole in positive ion mode using an electrospray ionization source. This method was then applied to investigate the pharmacokinetics and tissue distribution of GC20 in rats after intravenous administration. The results showed that the plasma exposure of GC20 in vivo increased with increasing doses after a single dose. However, after multiple doses, a significant accumulation and a saturation at elimination were observed for GC20 in rats. Moreover, after intravenous administration, GC20 was widely distributed in various tissues, with the highest levels in the lung, spleen, liver, and pancreas, followed by the kidney and heart, while the lowest level was found in the brain. This is the first report on the pharmacokinetic properties of GC20.

Design, synthesis, and biological evaluation of rutacecarpine derivatives as multitarget-directed ligands for the treatment of Alzheimer's disease.

A series of 3-amino-substituted rutacecarpine derivatives were synthesized to identify novel multitarget-directed ligands (MTDLs) for the treatment of Alzheimer's disease (AD). Biological evaluation showed that most of the synthesized compounds inhibited butyrylcholinesterase (BuChE) and exerted antioxidant effects. Among the synthesized compounds, 6n was subjected to further biological evaluation. Lineweaver-Burk plotting and molecular modeling illustrated that 6n bound simultaneously to the peripheral anionic site (PAS) and catalytic sites (CAS) of BuChE. Furthermore, 6n modulated Aß aggregation; chelated biometals; presented good absorption, distribution, metabolism, excretion, and toxicity properties; and showed remarkable neuroprotective activity. Previous research has shown that the optimized compound 6n has considerable potential for development as an MTDL for the treatment of AD.

Changes in tissue gadolinium biodistribution measured in an animal model exposed to four chelating agents.

PURPOSE: This study investigated the potential to reduce gadolinium levels in rodents after repetitive IV Gadodiamide administration using several chelating agents. MATERIALS AND METHODS: The following six groups of rats were studied. Group 1: Control; Group 2: Gadodiamide only; Group 3: Meso-2,3-Dimercaptosuccinic acid (DMSA) + Gadodiamide; Group 4: N-Acetyl-L-cysteine (NAC) + Gadodiamide; Group 5: Coriandrum sativum extract + Gadodiamide; and Group 6: Deferoxamine + Gadodiamide. Brain, kidney, and blood samples were evaluated via inductively coupled plasma mass spectrometry. The brain was also evaluated histologically. RESULTS: Kidney gadolinium levels in Groups 4 and 5 were approximately double that of Group 2 (p = 0.033 for each). There was almost no calcification in rat hippocampus for Group 4 rodents when compared with Groups 2, 3, 5 and 6. CONCLUSION: Our preliminary study shows that excretion to the kidney has a higher propensity in NAC and Coriandrum sativum groups. It may be possible to change the distribution of gadolinium by administrating several agents. NAC may lower Gadodiamide-induced mineralization in rat hippocampus.

Dual 0.02% chlorhexidine digluconate - 0.1% disodium EDTA loaded thermosensitive ocular gel for Acanthamoeba keratitis treatment.

Poor bioavailability and low residence time limit the efficiency of conventional biguanide-based eye drops against Acanthamoeba keratitis. The aim of this work was to formulate an original anti-amoebic thermoreversible ocular gel combining biguanide and metalloproteases inhibitor - chelating agent. Chlorhexidine digluconate (CHX)-ethylenediaminetetraacetic acid disodium salt (Na2EDTA) were compounded in poloxamer 407 saline solution. 0.02% CHX - 0.1% Na2EDTA loaded thermosensitive ocular gel exhibited appropriate pH (5.73 ±â€¯0.06), iso-osmolality (314 ±â€¯5 mOsm/kg), viscosity (ranged between 15 and 25 mPa.s) and thermal gelation (26.5 °C and 33 °C) properties. Bioadhesion of gel was successfully tested onto isolated bovine eyes as well as the assessment of CHX penetration into the cornea. Intracorneal CHX concentration was found greater than trophozoite minimum amoebicidal concentration and minimal cysticidal concentration after 15-min and 2-h ocular exposure, respectively, while any CHX permeation through the cornea was detected (<51 ng/cm2/h). Improvement of CHX ocular bioavailability was attributed to probable solubilization of tear film lipid layer by poloxamer. In vitro efficiency of CHX-Na2EDTA ocular gel was confirmed from the drastic reduction of trophozoite and cyst survival (to 25% and 2%, respectively), confirming the potential of the multicomponent pharmaceutical material strategy for the treatment of Acanthamoeba keratitis.

Improved Modeling of Plutonium-DTPA Decorporation.

Individuals with significant intakes of plutonium (Pu) are typically treated with chelating agents, such as the trisodium salt form of calcium diethylenetriaminepentaacetate (CaNa3-DTPA, referred to hereafter as Ca-DTPA). Currently, there is no recommended approach for simultaneously modeling plutonium biokinetics during and after chelation therapy. In this study, an improved modeling system for plutonium decorporation was developed. The system comprises three individual model structures describing, separately, the distinct biokinetic behaviors of systemic plutonium, intravenously injected Ca-DTPA and in vivo-formed Pu-DTPA chelate. The system was linked to ICRP Publication 100, "Human Alimentary Tract Model for Radiological Protection" and NCRP Report 156, Development of a Biokinetic Model for Radionuclide-Contaminated Wounds and Procedures for Their Assessment, Dosimetry and Treatment." Urine bioassay and chelation treatment data from an occupationally-exposed individual were used for model development. Chelation was assumed to occur in the blood, soft tissues, liver and skeleton. The coordinated network for radiation dosimetry approach to decorporation modeling was applied using a chelation constant describing the secondorder, time-dependent kinetics of the in vivo chelation reaction. When using the proposed system of models for plutonium decorporation, a significant improvement of the goodness-of-fit to the urinary excretion data was observed and more accurate predictions of postmortem plutonium retention in the skeleton, liver and wound site were achieved.