Octadentate catecholamide ligands for Pu(IV) based on linear or preorganized molecular backbones

1996 ◽  
Vol 15 (4) ◽  
pp. 352-360 ◽  
Author(s):  
PW Durbin ◽  
B. Kullgren ◽  
N. Jeung ◽  
J. Xu ◽  
SJ Rodgers ◽  
...  
Keyword(s):  
Metal Binding ◽  
Intraperitoneal Injection ◽  
Equimolar Amount ◽  
The Body ◽  
Whole Body ◽  
Great Stability ◽  
Gastric Intubation ◽  
Octadentate Ligand

Nine new octadentate ligands based on cyclic, spermine (3,4,3-LI), desferrioxamine (DFO), or H-shaped tetrakis amine (penten) molecular backbones were prepared containing catecholamide (CAM), carboxycatecholamide (CAM(C)), or terephthalamide (TAM) chelating units. Mice were injected intravenously with 238Pu(IV) citrate, treated with 30 μmol kg-1 of a ligand by intraperitoneal injection at 1 h or by gastric intubation at 3 min, and Pu retention in tissues and Pu transfer to excreta were measured at 24 h. Given by injection, three soluble ligands composed of MeTAM (3,4,3-LIMeTAM, DFO-MeTAM, H(2,2)-MeTAM) reduced Pu retention in the body to 27- 28% of control compared with 32 and 37% of control obtained in mice similarly treated with 3,4,3-LICAM(C) or CaNa3-DTPA, respectively. The MeTAM ligands reduced Pu retention in the skeleton as much as an equimolar amount of CaNa 3-DTPA, while Pu retention in the liver (on average, 16% of control) was significantly less than was obtained with CaNa3-DTPA (35% of control). Given orally, H(2,2)-MeTAM reduced Pu retention in the whole body to 58% of control compared with reductions to 62 and 94% of control achieved with 3,4,3-LICAM(C) or CaNa3-DTPA, respectively. Penten is both partially preorganized for metal binding and spatially suitable for encapsulation of actinide(IV), and ligands with the penten backbone are easier and less costly to prepare than those based on spermine or DFO. The biological results confirmed that penten is a suitable as well as practical structural backbone for new octadentate ligands. In agreement with the great stability of the ferric complex with MeTAM, as determined in vitro, the small, simple, soluble penten- based octadentate ligand, H(2,2)-MeTAM, was shown to be, overall, the most effective catecholamide ligand for enhancing Pu excretion. Either combined in H(2,2)- MeTAM or separately, the penten backbone and the MeTAM chelating unit are potentially useful additions to the set of backbones and binding units of multidentate ligands identified as effective for in vivo chelation of the actinides.

High Resolution NMR Spectroscopy on Whole-Body Imagers:Optimized Single-and Multi-Pulse Experiments in Vitro

1995 ◽  
Vol 50 (10) ◽  
pp. 942-948
Author(s):  
Fritz Schick
Keyword(s):  
Aqueous Solutions ◽  
Spin Echo ◽  
Single Pulse ◽  
Spin Systems ◽  
The Body ◽  
Coupling Constants ◽  
Whole Body ◽  
Receiver Coil

Abstract From 100 ml spherical glass bottles filled with aqueous solutions and suspended in a homogeneous magnetic field, NMR spectra with linewidths of about 0.7 Hz were achieved in single-pulse and multi-pulse spectra. A relatively wide receiver coil as the body coil or the standard head coil of the manufacturer were employed to acquire spectra after different non-localized pulse sequences. Examples of single-pulse spectra and double spin-echo spectra of aqueous solutions with lactate, citrate, or glucose are demonstrated and discussed. The fact that all experiments can be performed using well-defined pulse angles acting on the entire sample at the field strenght of the whole-body unit allows to determine the characteristics (e.g. chemical shift differences, coupling constants) of spin systems of biologically important molecules precisely, without need for additional spectrometers. Constant flip angles are advantageous for adequate theoretical analysis of spectra from coupled spin systems. The effects of a defined "misadjustment" of the transmitter on the spectra can be measured directly, whereas localized methods always yield a superposition of signals due to the distribution of flip angles inside the selected volume. In some cases, optimized sequence parameters for localized examinations in vivo can be derived numerically from the analyzed coupling data.

In vivo n.m.r. imaging in medicine: the Aberdeen approach, both physical and biological

1980 ◽  
Vol 289 (1037) ◽  
pp. 519-533 ◽  
Keyword(s):  
Pulse Sequence ◽  
The Body ◽  
Spin Lattice Relaxation ◽  
Surrounding Tissue ◽  
Whole Body ◽  
Spin Concentration ◽  
Stage Of Development ◽  
Wide Range

A novel magnetic field and radio frequency (1.7 MHz) pulse sequence is described for a whole body n.m.r. imaging machine under construction. Selective excitation is used to obtain signals from successive lines of proton spins (water) across the body to build up an image of a transverse section. The images display spin concentration and spin-lattice relaxation time, T 1 , separately. For a 50 % change in T 1 to be discerned in the human trunk, a spatial resolution of 2 cm 3 is expected for a 2 min scan and 0.5 cm 3 for a 30 min scan. Very preliminary images at the present incomplete stage of development show the geometrical accuracy and T 1 discrimination: an in vivo image demonstrates some of the difficulties to be overcome. In vitro measurements of normal rabbit tissue samples have been made at 24 MHz to map the T 1 distributions that can be expected from normal subjects. The transposition of this information from rabbit to man, and from 24 MHz to 2.5 MHz have been checked and the comparison shown to be meaningful. Of pathological samples, human breast tumour and human liver metastases offer a good contrast to their surrounding tissue, and an experimental investigation has shown that tissue immediately surrounding a tumour also has an elevated T 1 value. A wide range of abnormalities that are associated with abnormal fluid formation in the body may be amenable to imaging by the n.m.r. technique. Potential hazards are believed to be small in the present generation of equipment.

scholarly journals Evaluation of Aminopolycarboxylate Chelators for Whole-Body Clearance of Free 225Ac: A Feasibility Study to Reduce Unexpected Radiation Exposure during Targeted Alpha Therapy

Pharmaceutics ◽  
2021 ◽  
Vol 13 (10) ◽  
pp. 1706
Author(s):  
Mitsuyoshi Yoshimoto ◽  
Yukie Yoshii ◽  
Hiroki Matsumoto ◽  
Mitsuhiro Shinada ◽  
Masashi Takahashi ◽  
...  
Keyword(s):  
Radiation Exposure ◽  
Feasibility Study ◽  
The Body ◽  
Whole Body ◽  
Targeted Alpha Therapy ◽  
Carboxylic Groups ◽  
Alpha Therapy ◽  
Body Clearance

Actinium-225 (225Ac) is a promising radionuclide used in targeted alpha therapy (TAT). Although 225Ac labeling of bifunctional chelating ligands is effective, previous in vivo studies reported that free 225Ac can be released from the drugs and that such free 225Ac is predominantly accumulated in the liver and could cause unexpected toxicity. To accelerate the clinical development of 225Ac TAT with a variety of drugs, preparing methods to deal with any unexpected toxicity would be valuable. The aim of this study was to evaluate the feasibility of various chelators for reducing and excreting free 225Ac and compare their chemical structures. Nine candidate chelators (D-penicillamine, dimercaprol, Ca-DTPA, Ca-EDTA, CyDTA, GEDTA TTHA, Ca-TTHA, and DO3A) were evaluated in vitro and in vivo. The biodistribution and dosimetry of free 225Ac were examined in mice before an in vivo chelating study. The liver exhibited pronounced 225Ac uptake, with an estimated human absorbed dose of 4.76 SvRBE5/MBq. Aminopolycarboxylate chelators with five and six carboxylic groups, Ca-DTPA and Ca-TTHA, significantly reduced 225Ac retention in the liver (22% and 30%, respectively). Significant 225Ac reductions were observed in the heart and remainder of the body with both Ca-DTPA and Ca-TTHA, and in the lung, kidney, and spleen with Ca-TTHA. In vitro interaction analysis supported the in vivo reduction ability of Ca-DTPA and Ca-TTHA. In conclusion, aminopolycarboxylate chelators with five and six carboxylic groups, Ca-DTPA and Ca-TTHA, were effective for whole-body clearance of free 225Ac. This feasibility study provides useful information for reducing undesirable radiation exposure from free 225Ac.

scholarly journals Aminopolycarboxylate Chelators Are Effective for Whole-body Clearance of Free 225ac: A Method to Reduce Unexpected Radiation Exposure During Targeted Alpha Therapy

2021 ◽  
Author(s):  
Mitsuyoshi Yoshimoto ◽  
Yukie Yoshii ◽  
Hiroki Matsumoto ◽  
Mitsuhiro Shinada ◽  
Masashi Takahashi ◽  
...  
Keyword(s):  
Radiation Exposure ◽  
The Body ◽  
Whole Body ◽  
Targeted Alpha Therapy ◽  
Carboxylic Groups ◽  
In Vitro Interaction ◽  
Alpha Therapy ◽  
Body Clearance

Abstract Purpose: Actinium-225 (225Ac) is a promising radionuclide used in targeted alpha therapy (TAT). Although 225Ac labelling of bifunctional chelating ligands is effective, previous in vivo studies have reported that free 225Ac can be released from the drugs. Notably, such free 225Ac predominantly accumulates in the liver and can cause unexpected toxicity. To accelerate the clinical development of 225Ac TAT, methods for addressing unexpected toxicity are therefore needed. In this study, we evaluated various chelators in vitro and in vivo with regard to reducing and excreting free 225Ac and compared their chemical structures. Methods: Nine candidate chelators (D-penicillamine, dimercaprol, Ca-DTPA, Ca-EDTA, CyDTA, GEDTA TTHA, Ca-TTHA, and DO3A) were tested. In vitro interaction of 225Ac and chelators was investigated. Biodistribution and dosimetry of free 225Ac were examined in mice prior to the in vivo chelating study. For in vivo chelation, nine candidate chelators were administered 1 h after free 225Ac injection, and biodistribution was compared 4 h after 225Ac injection in mice. Two favourable chelators were then investigated intensively for biodistribution 24 h after the 225Ac injection.Results: The liver exhibited pronounced 225Ac uptake corresponding to an estimated human absorbed dose of 4.76 SvRBE5/MBq. Aminopolycarboxylate chelators with five and six carboxylic groups, Ca-DTPA and Ca-TTHA, significantly reduced 225Ac retention in the liver (22% and 30%, respectively). Significant 225Ac reductions were observed in the heart and the remainder of the body with both Ca-DTPA and Ca-TTHA, and in the lung, kidney, and spleen for Ca-TTHA. In vitro interaction analysis supported the in vivo reduction ability of Ca-DTPA and Ca-TTHA.Conclusions. Aminopolycarboxylate chelators with five and six carboxylic groups, Ca-DTPA and Ca-TTHA, were effective for whole-body clearance of free 225Ac, with a significant reduction in the liver. This method could reduce undesirable radiation exposure from free 225Ac during 225Ac TAT.

scholarly journals Atomically precise silver clusterzymes protect mice from radiation damages

2021 ◽  
Vol 19 (1) ◽  
Author(s):  
Jiao Guo ◽  
Haiyu Yang ◽  
Ya Liu ◽  
Wei Liu ◽  
Ruiying Zhao ◽  
...  
Keyword(s):  
Cell Viability ◽  
High Efficiency ◽  
Disease Diagnosis ◽  
The Body ◽  
Water Soluble ◽  
Whole Body ◽  
Dna Damages ◽  
Γ Ray

Abstract Background As we know, radiotherapy plays an irreplaceable role in the clinical management on solid tumors. However, due to the non-specific killing effects of ionizing radiation, normal tissues damages would be almost simultaneous inevitably. Therefore, ideal radioprotective agents with high efficiency and low toxicity are always desirable. In this work, atomically precise Ag14 clusterzymes were developed, and their applications in radioprotection were studied in vitro and in vivo for the first time. Methods The ultra-small glutathione supported Ag14 clusterzymes were synthesized by convenient sodium borohydride (NaBH4) reduction of thiolate-Ag (I) complexes and then they were purified by desalting columns. The enzyme-like activity and antioxidant capacity of Ag14 clusterzymes have been tested by various commercial kits, salicylic acid method and electron spin resonance (ESR). Next, they were incubated with L929 cells to evaluate whether they could increase cell viability after γ-ray irradiation. And then Ag14 clusterzymes were intravenously injected into C57 mice before 7 Gy whole-body γ-ray irradiation to evaluate the radioprotection effects in vivo. At last, the in vivo toxicities of Ag14 clusterzymes were evaluated through biodistribution test, hematological details, serum biochemical indexes and histological test in female Balb/c mice with intravenous injection of Ag14 clusterzymes. Results Our studies suggested atomically precise Ag14 clusterzymes were potential radioprotectants. Ag14 clusterzymes exhibited unique superoxide dismutase (SOD)-like activity, strong anti-oxidative abilities, especially on •OH scavenging. The Ag14 clusterzymes could effectively improve cell viability through eliminating ROS and prevent DNA damages in cells dealt with γ-ray irradiation. In vivo experiments showed that Ag14 clusterzymes could improve the irradiated mice survival rate by protecting hematological systems and repairing tissue oxidative stress damage generated by γ-ray irradiation. In addition, bio-distribution and toxicological experiments demonstrated that the ultrasmall Ag14 clusterzymes could be excreted quickly from the body by renal clearance and negligible toxicological responses were observed in mice up to 30 days. Conclusion In summary, atomically precise, ultrasmall and water soluble Ag14 clusterzymes with SOD-like activity were successfully developed and proved to be effective both in vitro and in vivo for radioprotection. Furthermore, with atomically precise molecular structure, Ag14 clusterzymes, on aspect of the catalytic and optical properties, may be improved by structure optimization on atom-scale level for other applications in disease diagnosis and treatment. Graphical Abstract

scholarly journals The catabolism of intravenously injected heparan N-[35S]sulphate in the rat

1977 ◽  
Vol 166 (3) ◽  
pp. 373-379 ◽  
Author(s):  
Martin A. Perry ◽  
Gillian M. Powell ◽  
Frederick S. Wusteman ◽  
C. Gerald Curtis
Keyword(s):  
Heparan Sulphate ◽  
The Body ◽  
Whole Body ◽  
General Distribution ◽  
In Vitro Experiments ◽  
Metabolic Fate ◽  
Inorganic Sulphate ◽  
Anaesthetized Rats

The metabolic fate of heparan N-[35S]sulphate was studied in rats. Heparan sulphate was obtained from either bovine aorta or lung and labelled with 35S by desulphation and subsequent resulphation in vitro. Experiments in which heparan N-[35S]sulphate was administered intravenously to either free-range or wholly anaesthetized rats with ureter cannulae established that substantial desulphation occurs in vivo, with elimination of inorganic [35S]sulphate in urine. Oligosaccharides labelled with 35S, possible intermediates in heparan sulphate degradation, could not be detected in urine or blood. The general distribution of radioactivity after administration of heparan N-[35S]sulphate, as demonstrated by whole-body radioautography, suggested that desulphation was not restricted to one organ in particular. Support for this view was obtained in experiments in which heparan N-[35S]sulphate was administered to animals after the removal of kidneys, liver, spleen, pancreas or gastrointestinal tract. In all cases inorganic [35S]sulphate was still produced. The ability of rats of desulphate heparan N-[35S]sulphate was progressively impaired by increasing concentrations of heparin administered simultaneously. It was concluded that heparan sulphate is metabolized at a number of sites in the body by a sequence of degradative events leading to the formation of inorganic sulphate. It is also concluded that at least some of these events are common to heparan sulphate and heparin.

The Role of Polyphenols in the Modulation of Plasma Non-Enzymatic Antioxidant Capacity (NEAC)

2012 ◽  
Vol 82 (3) ◽  
pp. 228-232 ◽  
Author(s):  
Mauro Serafini ◽  
Giuseppa Morabito
Keyword(s):  
Antioxidant Capacity ◽  
Dietary Intervention ◽  
Ex Vivo ◽  
The Body ◽  
Dietary Polyphenols ◽  
Enzymatic Antioxidant ◽  
Endogenous Antioxidant

Dietary polyphenols have been shown to scavenge free radicals, modulating cellular redox transcription factors in different in vitro and ex vivo models. Dietary intervention studies have shown that consumption of plant foods modulates plasma Non-Enzymatic Antioxidant Capacity (NEAC), a biomarker of the endogenous antioxidant network, in human subjects. However, the identification of the molecules responsible for this effect are yet to be obtained and evidences of an antioxidant in vivo action of polyphenols are conflicting. There is a clear discrepancy between polyphenols (PP) concentration in body fluids and the extent of increase of plasma NEAC. The low degree of absorption and the extensive metabolism of PP within the body have raised questions about their contribution to the endogenous antioxidant network. This work will discuss the role of polyphenols from galenic preparation, food extracts, and selected dietary sources as modulators of plasma NEAC in humans.

A Simple and Inexpensive Clinical Whole Body Counter

1976 ◽  
Vol 15 (05) ◽  
pp. 248-253
Author(s):  
A. K. Basu ◽  
S. K. Guha ◽  
B. N. Tandon ◽  
M. M. Gupta ◽  
M. ML. Rehani
Keyword(s):  
The Body ◽  
Whole Body ◽  
Vitro Assay ◽  
Body Counter ◽  
Optimum Parameters ◽  
Whole Body Counter ◽  
Single Detector ◽  
Background Index ◽  
Iodide Crystal

SummaryThe conventional radioisotope scanner has been used as a whole body counter. The background index of the system is 10.9 counts per minute per ml of sodium iodide crystal. The sensitivity and derived sensitivity parameters have been evaluated and found to be suitable for clinical studies. The optimum parameters for a single detector at two positions above the lying subject have been obtained. It has been found that for the case of 131I measurement it is possible to assay a source located at any point in the body with coefficient of variation less than 5%. To add to the versatility, a fixed geometry for in-vitro counting of large samples has been obtained. The retention values obtained by the whole body counter have been found to correlate with those obtained by in-vitro assay of urine and stool after intravenous administration of 51Cr-albumin.

Репрограммированые in vitro на М3 фенотип макрофаги останавливают рост солидной карциномы in vivo

2018 ◽  
pp. 41-46
Author(s):  
А.А. Раецкая ◽  
С.В. Калиш ◽  
С.В. Лямина ◽  
Е.В. Малышева ◽  
О.П. Буданова ◽  
...  
Keyword(s):  
Solid Tumor ◽  
Antitumor Effect ◽  
Tumor Development ◽  
Significant Inhibition ◽  
The Body ◽  
Ehrlich Carcinoma ◽  
Solid Carcinoma ◽  
Ec Cells

Цель исследования. Доказательство гипотезы, что репрограммированные in vitro на М3 фенотип макрофаги при введении в организм будут существенно ограничивать развитие солидной карциномы in vivo . Методика. Рост солидной опухоли инициировали у мышей in vivo путем подкожной инъекции клеток карциномы Эрлиха (КЭ). Инъекцию макрофагов с нативным М0 фенотипом и с репрограммированным M3 фенотипом проводили в область формирования солидной КЭ. Репрограммирование проводили с помощью низких доз сыворотки, блокаторов факторов транскрипции STAT3/6 и SMAD3 и липополисахарида. Использовали две схемы введения макрофагов: раннее и позднее. При раннем введении макрофаги вводили на 1-е, 5-е, 10-е и 15-е сут. после инъекции клеток КЭ путем обкалывания макрофагами с четырех сторон область развития опухоли. При позднем введении, макрофаги вводили на 10-е, 15-е, 20-е и 25-е сут. Через 15 и 30 сут. после введения клеток КЭ солидную опухоль иссекали и измеряли ее объем. Эффект введения макрофагов оценивали качественно по визуальной и пальпаторной характеристикам солидной опухоли и количественно по изменению ее объема по сравнению с группой без введения макрофагов (контроль). Результаты. Установлено, что M3 макрофаги при раннем введении от начала развития опухоли оказывают выраженный антиопухолевый эффект in vivo , который был существенно более выражен, чем при позднем введении макрофагов. Заключение. Установлено, что введение репрограммированных макрофагов M3 ограничивает развитие солидной карциномы в экспериментах in vivo . Противоопухолевый эффект более выражен при раннем введении М3 макрофагов. Обнаруженные в работе факты делают перспективным разработку клинической версии биотехнологии ограничения роста опухоли, путем предварительного программирования антиопухолевого врожденного иммунного ответа «в пробирке». Aim. To verify a hypothesis that macrophages reprogrammed in vitro to the M3 phenotype and injected into the body substantially restrict the development of solid carcinoma in vivo . Methods. Growth of a solid tumor was initiated in mice in vivo with a subcutaneous injection of Ehrlich carcinoma (EC) cells. Macrophages with a native M0 phenotype or reprogrammed towards the M3 phenotype were injected into the region of developing solid EC. Reprogramming was performed using low doses of serum, STAT3/6 and SMAD3 transcription factor blockers, and lipopolysaccharide. Two schemes of macrophage administration were used: early and late. With the early administration, macrophages were injected on days 1, 5, 10, and 15 following the injection of EC cells at four sides of the tumor development area. With the late administration, macrophages were injected on days 10, 15, 20, and 25. At 15 and 30 days after the EC cell injection, the solid tumor was excised and its volume was measured. The effect of macrophage administration was assessed both qualitatively by visual and palpation characteristics of solid tumor and quantitatively by changes in the tumor volume compared with the group without the macrophage treatment. Results. M3 macrophages administered early after the onset of tumor development exerted a pronounced antitumor effect in vivo , which was significantly greater than the antitumor effect of the late administration of M3 macrophages. Conclusion. The observed significant inhibition of in vivo growth of solid carcinoma by M3 macrophages makes promising the development of a clinical version of the biotechnology for restriction of tumor growth by in vitro pre-programming of the antitumor, innate immune response.

Nanocurcumin: A Double-Edged Sword for Microcancers

2020 ◽  
Vol 26 (45) ◽  
pp. 5783-5792
Author(s):  
Kholood Abid Janjua ◽  
Adeeb Shehzad ◽  
Raheem Shahzad ◽  
Salman Ul Islam ◽  
Mazhar Ul Islam
Keyword(s):  
Intracellular Signaling ◽  
Dosage Forms ◽  
The Body ◽  
In Vivo Studies ◽  
Mrna Levels ◽  
Anticancer Activities ◽  
Road Map ◽  
Anticancer Effects

There is compelling evidence that drug molecules isolated from natural sources are hindered by low systemic bioavailability, poor absorption, and rapid elimination from the human body. Novel approaches are urgently needed that could enhance the retention time as well as the efficacy of natural products in the body. Among the various adopted approaches to meet this ever-increasing demand, nanoformulations show the most fascinating way of improving the bioavailability of dietary phytochemicals through modifying their pharmacokinetics and pharmacodynamics. Curcumin, a yellowish pigment isolated from dried ground rhizomes of turmeric, exhibits tremendous pharmacological effects, including anticancer activities. Several in vitro and in vivo studies have shown that curcumin mediates anticancer effects through the modulation (upregulation and/or downregulations) of several intracellular signaling pathways both at protein and mRNA levels. Scientists have introduced multiple modern techniques and novel dosage forms for enhancing the delivery, bioavailability, and efficacy of curcumin in the treatment of various malignancies. These novel dosage forms include nanoparticles, liposomes, micelles, phospholipids, and curcumin-encapsulated polymer nanoparticles. Nanocurcumin has shown improved anticancer effects compared to conventional curcumin formulations. This review discusses the underlying molecular mechanism of various nanoformulations of curcumin for the treatment of different cancers. We hope that this study will make a road map for preclinical and clinical investigations of cancer and recommend nano curcumin as a drug of choice for cancer therapy.

Sign in / Sign up

Export Citation Format

Share Document