Functionalized TiO<Subscript>2</Subscript> nanoparticles labelled with <Superscript>225</Superscript>Ac for targeted alpha radionuclide therapy

The ²²⁵Ac radioisotope exhibits very attractive nuclear properties for application in radionuclide therapy. Unfortunately, the major challenge for radioconjugates labelled with ²²⁵Ac is that traditional chelating moieties are unable to sequester the radioactive daughters in the bioconjugate which is critical to minimize toxicity to healthy, non-targeted tissues. In the present work, we propose to apply TiO₂ nanoparticles (NPs) as carrier for ²²⁵Ac and its decay products. The surface of TiO₂ nanoparticles with 25 nm diameter was modified with Substance P (5-11), a peptide fragment which targets NK1 receptors on the glioma cells, through the silan-PEG-NHS linker. Nanoparticles functionalized with Substance P (5-11) were synthesized with high yield in a two-step procedure, and the products were characterized by transmission electron microscopy (TEM), dynamic light scattering (DLS) and thermogravimetric analysis (TGA). The obtained results show that one TiO₂-bioconjugate nanoparticle contains in average 80 peptide molecules on its surface. The synthesized TiO₂-PEG-SP(5-11) conjugates were labelled with ²²⁵Ac by ion-exchange reaction on hydroxyl (OH) functional groups on the TiO₂ surface. The labelled bioconjugates almost quantitatively retain ²²⁵Ac in phosphate-buffered saline (PBS), physiological salt and cerebrospinal fluid (CSF) for up to 10 days. The leaching of ²²¹Fr, a first decay daughter of ²²⁵Ac, in an amount of 30% was observed only in CSF after 10 days. The synthesized ²²⁵Ac-TiO₂-PEG-SP(5-11) has shown high cytotoxic effect in vitro in T98G glioma cells; therefore, it is a promising new radioconjugate for targeted radionuclide therapy of brain tumours.     

N-Phenacyldibromobenzimidazoles—Synthesis Optimization and Evaluation of Their Cytotoxic Activity

Antifungal N-phenacyl derivatives of 4,6- and 5,6-dibromobenzimidazoles are interesting substrates in the synthesis of new antimycotics. Unfortunately, their application is limited by the low synthesis yields and time-consuming separation procedure. In this paper, we present the optimization of the synthesis conditions and purification methods of N-phenacyldibromobenzimidazoles. The reactions were carried out in various base solvent-systems including K₂CO₃, NaH, KOH, t-BuOK, MeONa, NaHCO₃, Et₃N, Cs₂CO₃, DBU, DIPEA, or DABCO as a base, and MeCN, DMF, THF, DMSO, or dioxane as a solvent. The progress of the reaction was monitored using HPLC analysis. The best results were reached when the reactions were carried out in an NaHCO₃–MeCN system at reflux for 24 h. Additionally, the cytotoxic activity of the synthesized compounds against MCF-7 (breast adenocarcinoma), A-549 (lung adenocarcinoma), CCRF-CEM (acute lymphoblastic leukemia), and MRC-5 (normal lung fibroblasts) was evaluated. We observed that the studied cell lines differed in sensitivity to the tested compounds with MCF-7 cells being the most sensitive, while A-549 cells were the least sensitive. Moreover, the cytotoxicity of the tested derivatives towards CCRF-CEM cells increased with the number of chlorine or fluorine substituents. Furthermore, some of the active compounds, i.e., 2-(5,6-dibromo-1H-benzimidazol-1-yl)-1-(3,4-dichlorophenyl)ethanone (4f), 2-(4,6-dibromo-1H-benzimidazol-1-yl)-1-(2,4,6-trichlorophenyl)ethanone (5g), and 2-(4,6-dibromo-1H-benzimidazol-1-yl)-1-(2,4,6-trifluorophenyl)ethanone (5j) demonstrated pro-apoptotic properties against leukemic cells with derivative 5g being the most effective.     

Percolation in Two‐Dimensional Copolymer Systems

The aim of the study is the investigation of the percolation phenomena in some model copolymer systems. Diblock, triblock, random copolymers, and a blend of homopolymers are studied. For this purpose, we developed an idealized model of polymeric systems. The positions of polymer segments are restricted to vertices of a simple cubic lattice. The chains are at good solvent conditions – the excluded volume is the only interaction between the segments of the chain. The properties of the model chains are determined by means of Monte Carlo simulations with a sampling algorithm based on chain's local changes of conformation. The differences and similarities in the percolation behavior are shown and discussed. The percolation threshold is found to be very weakly dependent on the chain length, however, it appears that the main factor that influenced the percolation threshold is the screening effect of other parts of chains.

     

Effect of amino acid modifications on the molecular structure of adsorbed and nonadsorbed bombesin 6–14 fragments on an electrochemically roughened silver surface

This work used infrared absorption and Raman spectroscopy to determine the structure of seven modified fragments (residues 6–14 of the polypeptide chain) of bombesin (BN^6–14). The peptides studied are cyclo[D ‐Phe⁶, His⁷, Leu¹⁴]BN^6–14, [D ‐Phe⁶, Leu‐NHEt¹³, des‐Met¹⁴]BN^6–14, [D ‐Phe⁶, Leu¹³‐®‐p‐chloro‐Phe¹⁴]BN^6–14, [D ‐Phe⁶, β‐Ala¹¹, Phe¹³, Nle¹⁴]BN^6–14, [D ‐Tyr⁶, β‐Ala¹¹, Phe¹³, Nle¹⁴]BN^6–14, [D ‐Tyr⁶, β‐Phe¹¹, Phe¹³, Nle¹⁴OH]BN^6–14 and [D ‐Cys⁶, Asn⁷, D ‐Ala¹¹, Cys¹⁴]BN^6–14. These peptides are potent bombesin agonists useful in the treatment of tumors. Surface‐enhanced Raman scattering (SERS) spectroscopy was also used to examine the behavior of these molecules on an electrochemically roughened silver surface. The SERS spectra reveal that substituting native amino acids in these molecules with synthetic ones changes their adsorption state slightly on an electrochemically roughened surface of silver. The peptides [D ‐Tyr⁶, β‐Ala¹¹, Phe¹³, Nle¹⁴]BN^6–14 and [D ‐Tyr⁶, β‐Phe¹¹, Phe¹³, Nle¹⁴OH]BN^6–14 tend to adsorb strongly on this surface via C fragment (∼1400 cm⁻¹). The observed medium enhancement of the Trp⁸ residue and amide bond Raman signals indicate further interactions between these fragments and the surface. [D ‐Phe⁶, Leu‐NHEt¹³, des‐Met¹⁴]BN^6–14 and [D ‐Cys⁶, Asn⁷, D ‐Ala¹¹, Cys¹⁴]BN^6–14 are shown to be coordinated to the silver through  CONH , CO, and the indole ring. The strongest SERS bands (∼1506, ∼1275, ∼1149, and ∼1007 cm⁻¹) of [D ‐Phe⁶, Leu¹³‐®‐p‐chloro‐Phe¹⁴]BN^6–14 and [D ‐Phe⁶, β‐Ala¹¹, Phe¹³, Nle¹⁴]BN^6–14 suggest that these two peptides bind to the silver via Trp⁸ and  CONH . In the case of cyclo[D ‐Phe⁶, His⁷, Leu¹⁴]BN^6–14, the formation of a peptide/Ag complex is confirmed by the strong SERS bands involving Trp⁸ and  CONH vibrations, which are accompanied by a SERS signal due to the CO vibrations. For these analogs, the relative potency for inhibition of binding of ¹²⁵I‐[Tyr⁴]BN to rat pancreas acini cells was correlated with the behavior of the amide bond on the silver surface, while the contribution of the structural components to the ability to interact with the rGRP‐R was correlated with the SERS patterns. Copyright © 2008 John Wiley & Sons, Ltd.