Development and evaluation of a 166holmium labelled porphyrin complex as a possible therapeutic agent

Porphyrins are interesting derivatives with low toxicity, tumor avidity and rapid wash-out suggested as potential radiopharmaceuticals in radiolabeled form. In this work, [¹⁶⁶Ho] labeled 5,10,15,20-tetrakis(phenyl) porphyrin ([¹⁶⁶Ho]-TPP) was prepared using [¹⁶⁶Ho]HoCl₃ and 5,10,15,20-tetrakis(phenyl)porphyrin (H₂TPP) for 12 h at 50 °C (radiochemical purity: >95 ± 2 % ITLC, >99 ± 0.5 % HPLC, specific activity: 0.9–1.1 GBq/mmol). Stability of the complex was checked in final formulation and human serum for 48 h. The partition coefficient was calculated for the compound (log P = 2.01). The biodistribution of the labeled compound in vital organs of wild-type rats was studied using scarification studies and SPECT. A detailed comparative pharmacokinetic study performed for ¹⁶⁶Ho cation and [¹⁶⁶Ho]-TPP performed up to 24 h. The complex is mostly washed out from the circulation through kidneys and in less extends from the liver. The kidney:blood, kidney:liver and kidney:muscle ratios 4 h post injection were 14, 3.6 and 7.38 respectively.     

Radiosynthesis and biological evaluation of 166Ho labeled methoxylated porphyrins as possible therapeutic agents

¹⁶⁶Ho labeled 5,10,15,20-tetrakis(3,4-dimethoxyphenyl) porphyrin, and 5,10,15,20-tetrakis(3,4,5-trimethoxyphenyl) porphyrin ([¹⁶⁶Ho]–TDMPP and [¹⁶⁶Ho]–TTMPP respectively) were prepared with acceptable radiochemical purity and specific activities. Stability and partition coefficient of the complexes were determined in the final formulations and biodistribution studies in mouse demonstrated high accumulation of [¹⁶⁶Ho]–TDMPP in the lung and liver and less excretion through the kidney. while [¹⁶⁶Ho]–TTMPP was mostly excreted into intestines and kidneys while lungs were a minor accumulation site. In contrast to other reported radiolanthanide labeled porphyrins these two complexes showed less liver accumulation. Further investigation of their potential therapeutic properties is of interest.     

Preparation of [<Superscript>66</Superscript>Ga]bleomycin complex as a possible PET radiopharmaceutical

Summary Gallium-66 (T_1/2 = 9.49 h) is an interesting radionuclide that has potential use for positron emission tomography (PET) imaging of biological processes in intermediate to slow target tissue uptake. ⁶⁶Ga was produced in the NRCAM cyclotron as a result of 15 MeV proton bombardment of ⁶⁶Zn with current intensity of 180 μA (yield 11.2 mCi/μAh). Bleomycin (BLM) was labeled with [⁶⁶Ga]GaCl₃     

Preparation of Chitosan microspheres containing 166Dy/166Ho in vivo generators and their theranostic potential

Journal of Radioanalytical and Nuclear Chemistry - Chitosan microsphere (MS) loaded with 166Dy/166Ho were designed for therapy of unresectable liver tumor through an in vivo generator system. The...     

Production and quality control of [<Superscript>166</Superscript>Ho]-DOTA-bevacizumab for therapeutic applications

Antiangiogenic monoclonal antibodies in combination with therapeutic radionuclides are potential targeted therapy agents in cancer. In this study, bevacizumab was successively labeled with [¹⁶⁶Ho]HoCl₃ after conjugation with DOTA-NHS-ester with a radiochemical purity of higher than 95% (RTLC). The conjugates were purified by molecular filtration, the average number of DOTA conjugated per mAb was calculated and total concentration was determined by spectrophotometric method and the average chelate to antibody ratio (c/a) for the conjugate used in this study was 5.8:1 and protein integrity experiments (SDS-PAGE). The biodistribution studies in wild-type rats demonstrate a similar pattern to the other radiolabeled anti-vascular endothelial growth factor A (VEGF-A) immunoconjugates. ¹⁶⁶Ho-DOTA-bevacizumab is a potential compound for therapy/imaging of VEGF-A expression in oncology.     

DFT analysis of interligand vibrations in a hydroperoxo complex of cobalt bleomycin

Density functional theory (DFT) has been applied to the analysis of interligand vibrations in two chiral isomers of hydroperoxo complex of cobalt bleomycin (BLM-Co(III)-OOH, BLM = bleomycin). The DFT-based normal coordinate analysis reveals that 16O/18O isotope-sensitive modes associated with the Co-OOH moiety uniquely reflect the chiral organization of ligands around the cobalt atom. This study provides an independent probe of cobalt chirality coordinated to BLM and shows that interligand modes associated with the Co-OOH moiety could be used as a structural marker of the chiral isomers.     

Separation of carrier-free166Ho from Dy2O3 targets by partition chromatography and electrophoresis

A partial separation of carrier-free¹⁶⁶Ho from milligram quantities of neutron-irradiated Dy₂O₃ targets was achieved from aqueous acidic solutions with HDEHP or TBP as the chromatographic stationary phase, and with electrophoresis using -HIBA as complexing agent.     

A possible construction of a complex chemical reaction network

A procedure is suggested for the construction of chemical reaction networks. We define the kinetic communication as a transfer of atoms or atomic groups between two species and determine all the kinetic communications occurring in the possible mechanism of a complex chemical process. The set of kinetic communications is the basis of the communication matrices resulting in the complete network of the overall reaction.Limiting the consideration for certain types of kinetic communications we obtain the reaction subnetworks and selecting arbitrarily species among those participating in the possible mechanism we introduced the concept of the partial subnetworks which correspond to subsets of the complete network.By the simple analysis of the subnetworks it is easy to obtain the sequence network indicating the pathways via which the selected species are formed in the course of the overall process, by the transfer of chosen atoms or atomic groups.     

Inhibition of angiogenesis by bleomycin and its copper complex.

The effects of bleomycin (BLM) and its copper complex on embryonic angiogenesis were studied in the chorioallantoic membranes of 4.5-day-old chick embryos. Copper-free BLM inhibited embryonic angiogenesis in a dose-dependent manner, with activity detectable at 1 ng/egg and maximal at 1000 ng/egg. Also, treatment with copper-BLM complex dose-dependently caused inhibition of embryonic angiogenesis in a lower dose range. Since tumor growth is believed to depend on angiogenesis, the present results may indicate that the antiangiogenic activity of BLM is, at least in part, implicated in the antitumor activity of the drug.     

Ion pairing as a possible clue for discriminating between sodium and potassium in biological and other complex environments

For a series of biologically relevant anions, we present free energy changes upon replacing potassium with sodium in a contact ion pair. Calculations performed using a combination of molecular dynamics simulations and ab initio methods demonstrate the ordering of anions in a Hofmeister series. Small anionic groups such as carboxylates preferentially pair with sodium, while intermediate cases such as chloride or monovalent phosphate exhibit almost no specificity, and large anions (e.g., methylsulfonate) prefer potassium over sodium. These results can rationalize different behavior of Na+ versus K+ at the surface of hydrated proteins, DNA, and reversed micelles.     

Development of a well-defined silica-supported tungstenocarbyne complex as efficient heterogeneous catalyst for alkyne metathesis

The interaction of [W(C-tBu)(CH₂-tBu)(OAr)₂] (Ar = 2,6-iPr₂C₆H₃) (1), with the hydroxyl groups of a silica dehydroxylated at 700 °C leads to [(SiO)W(OAr)₂(C-tBu)] (2) which was characterized by IR, solid-state NMR and mass balance analysis. This well-defined surface species is an efficient catalyst for the metathesis of pent-2-yne.     

Telomerase as a possible target for anticancer therapy

Telomeres, the termini of chromosomes, provide essential stability to linear eukaryotic chromosomes. The enzyme telomerase is one mechanism that maintains telomeres, and is activated in 85% of human cancer cells. New studies on peptide nucleic acids (PNAs) that inhibit telomerase have demonstrated that unexpected regions of the enzyme can serve as targets for inhibitors. The novel delivery method used expands the utility of PNAs.     

NMR diffusion spectroscopy as a measure of host-guest complex association constants and as a probe of complex size

The complexes of cyclohexylacetic acid and cholic acid with beta-cyclodextrin were studied by NMR diffusion coefficient measurements. The diffusion coefficient of the 1:1 cyclohexylacetic acid/beta-cyclodextrin complex, K(a) = 1800 +/- 100 M(-1), is slightly slower (3.23 +/- 0.07 x 10(-6) cm(2) s(-1)) than that of beta-cyclodextrin (3.29 +/- 0.07 x 10(-6) cm(2) s(-1)). The diffusion coefficient of the 1:1 cholic acid/beta-cyclodextrin complex, K(a) = 5900 +/- 800 M(-1), is significantly slower (2.93 +/- 0.07 x 10(-6) cm(2) s(-1)) than that of beta-cyclodextrin. The results indicate that caution should be exercised when studying host-guest complexation by the so-called 'single point' technique. A novel data treatment is introduced which takes into account the diffusion behavior of all of the species when determining K(a). Experimentally determined diffusion coefficients of complexes are also a useful probe of the size of host-guest complexes.     

Production, nano-purification, radiolabeling and biodistribution study of [140Nd] 5,10,15,20-tetraphenylporphyrin complex as a possible imaging agent

[¹⁴⁰Nd] labeled 5,10,15,20-tetraphenylporphyrin ([¹⁴⁰Nd]-TPP) as a tumor–avid complex with a β-emitting radionuclide for evaluating its potential for target tumor therapy is reported. This complex was prepared using freshly prepared [¹⁴⁰Nd] NdCl₃ (purified by amino functionalized MCM-41 nano resin and commercial cation exchanger resins) and 5,10,15,20-tetraphenylporphyrin (H₂TPP).Stability of the complex was investigated in final formulation and human serum for 24 h and the partition coefficient was calculated. The biodistribution of the labeled compound in vital organs of Swiss mice bearing fibro sarcoma tumor was studied using scarification studies and positron emission tomography imaging up to 4 h.     

Development of a new silicone base transdermal therapeutic system

The diffusion properties of L-deprenyl base and its hydrochloride salt were investigated in various silicone elastomers. The effect of liquid ingredients such as glycerol and propylene-glycol, together with trifunctional silicon compounds containing polar (basic) groups, were studied for drug delivery applications. On the basis of diffusion investigations and thermoanalytical testing, the silicone composition (R5 oligomer, propylene glycol, trifunctional silicon compound GF-91), having optimal properties for pharmaceutical delivery, was selected.     

Development of complex approach to the synthesis of trimethylene carbonate as a monomer for biodegradable polymers

With the aim of production of polymers for medicine a new preparation method was developed for trimethylene carbonate based on transesterification with trimethylene glycol of dialkyl carbonates obtained without the use of phosgene. As initial reagents alkylene carbonates or polycarbonates and titanium alkoxides can be utilized. The advantages of this approach consist in obtaining some additional useful substances and the possibility of reprocessing polycarbonate wastes.     

A study of potassium dicyanoguanidine as a possible analytical reagent

Summary The following ions: Cu⁺⁺, Ag⁺, Hg₂ ⁺⁺, Hg⁺⁺, PtCl₆ ^–-, Pd⁺⁺, Au⁺⁺⁺ in acid solution, produced insoluble compounds with an aqueous solution of potassium dicyanoguanidine. Ferric ion produced a red coloration with the same reagent. The results obtained with PtCl₆ ^–-, Pd⁺⁺ and Fe⁺⁺⁺ are sufficiently characteristic to be used for the detection of these ions.

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Zusammenfassung Folgende Ionen geben in saurem Milieu mit einer wässerigen Lösung von Kalium-dicyanoguanidin unlösliche Verbindungen: Cu⁺⁺, Ag⁺, Hg₂ ⁺⁺, Hg⁺⁺, PtCl₆ ^–-, Pd⁺⁺ und Au⁺⁺⁺. Ferriionen geben mit demselben Reagens Rotfärbung. Die mit PtCl₆ ^–-, Pd⁺⁺ und Fe⁺⁺⁺ erhaltenen Reaktionsprodukte sind ausreichend charakteristisch, um für den Nachweis dieser Ionen verwendet werden zu können.

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Résumé Les ions suivants: Cu⁺⁺, Ag⁺, Hg₂ ⁺⁺, Hg⁺⁺, PtCl₆ ^–-, Pd⁺⁺, Au⁺⁺⁺, en solution acide, ont donné des composés insolubles avec une solution aqueuse du dérivé potassé de la dicyanoguanidine. L'ion ferrique a donné une coloration rouge avec le même réactif. Les résultats obtenus avec PtCl₆ ^–-, Pd⁺⁺ et Fe⁺⁺⁺ sont suffisamment caractéristiques pour être employés dans la recherche de ces ions.

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With 2 figures.