Freeze-dried nanocrystal dispersion of novel deuterated pyrazoloquinolinone ligand (DK-I-56-1): Process parameters and lyoprotectant selection through the stability study.

Recently, nanocrystal dispersions have been considered as a promising formulation strategy to improve the bioavailability of the deuterated pyrazoloquinolinone ligand DK-I-56-1 (7­methoxy-2-(4­methoxy-d3-phenyl)-2,5-dihydro-3H-pyrazolo[4,3-c]quinolin-3-one). In the current study, the freeze-drying process (formulation and process parameters) was investigated to improve the storage stability of the previously developed formulation. Different combinations of lyoprotectant (sucrose or trehalose) and bulking agent (mannitol) were varied while formulations were freeze-dried under two conditions (primary drying at -10 or -45 °C). The obtained lyophilizates were characterized in terms of particle size, solid state properties and morphology, while the interactions within the samples were analyzed by Fourier transform infrared spectroscopy. In the preliminary study, three formulations were selected based on the high redispersibility index values (around 95%). The temperature of primary drying had no significant effect on particle size, but stability during storage was impaired for samples dried at -10 °C. Samples dried at lower temperature were more homogeneous and remained stable for three months. It was found that the optimal ratio of sucrose or trehalose to mannitol was 3:2 at a total concentration of 10% to achieve the best stability (particle size < 1.0 µm, polydispersity index < 0.250). The amorphous state of lyoprotectants probably provided a high degree of interaction with nanocrystals, while the crystalline mannitol provided an elegant cake structure. Sucrose was superior to trehalose in maintaining particle size during freeze-drying, while trehalose was more effective in keeping particle size within limits during storage. In conclusion, results demonstrated that the appropriate combination of sucrose/trehalose and mannitol together with the appropriate selection of lyophilization process parameters could yield nanocrystals with satisfactory stability.

Synthesis, Characterization, and Therapeutic Efficacy of 177Lu-DMSA@SPIONs in Nanobrachytherapy of Solid Tumors.

As an alternative to classical brachytherapy, intratumoral injection of radionuclide-labeled nanoparticles (nanobrachytherapy, NBT) has been investigated as a superior delivery method over an intravenous route for radionuclide therapy of solid tumors. We created superparamagnetic iron oxide nanoparticles (SPIONs) coated with meso-1,2-dimercaptosuccinic acid (DMSA) and radiolabeled with Lutetium-177 (177Lu), generating 177Lu-DMSA@SPIONs as a potential antitumor agent for nanobrachytherapy. Efficient radiolabeling of DMSA@SPIONS by 177Lu resulted in a stable bond with minimal leakage in vitro. After an intratumoral injection to mouse colorectal CT-26 or breast 4T1 subcutaneous tumors, the nanoparticles remained well localized at the injection site for weeks, with limited leakage. The dose of 3.70 MBq/100 µg/50 µL of 177Lu-DMSA@SPIONs applied intratumorally resulted in a high therapeutic efficacy, without signs of general toxicity. A decreased dose of 1.85 MBq/100 µg/50 µL still retained therapeutic efficacy, while an increased dose of 9.25 MBq/100 µg/50 µL did not significantly benefit the therapy. Histopathology analysis revealed that the 177Lu-DMSA@SPIONs act within a limited range around the injection site, which explains the good therapeutic efficacy achieved by a single administration of a relatively low dose without the need for increased or repeated dosing. Overall, 177Lu-DMSA@SPIONs are safe and potent agents suitable for intra-tumoral administration for localized tumor radionuclide therapy.

90Y-CA/SPIONs for dual magnetic hyperthermia-radionuclide nanobrachytherapy of solid tumours.

Radiolabelled superparamagnetic iron oxide nanoparticles (SPIONs) are a promising nanomaterial for the development of dual radiation/hyperthermia cancer therapy. To that purpose, flower-shaped SPIONs with an exceptional heating capability were synthesised and coated with citrate, dextran or (3-aminopropyl)triethoxysilane. Both non-coated and coated SPIONs were nontoxic to CT-26 mouse colon cancer cells up to 1.0 mg ml-1in vitro. In an oscillating magnetic field, citrate-coated SPIONs (CA/SPIONs) displayed the highest heating rate (SAR âˆ¼ 253 W g-1) and the strongest hyperthermia effects against CT-26 cells. Labelling of the CA/SPIONs by the90Y radionuclide, emitting ß-radiation with an average/maximum energy of 0.94/2.23 MeV, and deep tissue penetration generated90Y-CA/SPIONs intended for the therapy of solid tumours. However, intravenous injection of90Y-CA/SPIONs in CT-26 xenograft-bearing mice resulted in low tumour accumulation. On the contrary, intratumoural injection resulted in long-term retention at the injection site. A single intratumoural injection of 0.25 mg CA/SPIONs followed by 30-min courses of magnetic hyperthermia for four consecutive days caused a moderate antitumour effect against CT-26 and 4T1 mouse tumour xenografts. Intratumoural application of 1.85 MBq/0.25 mg90Y-CA/SPIONs, alone or combined with hyperthermia, caused a significant (P ≤ 0.01) antitumour effect without signs of systemic toxicity. The results confirm the suitability of90Y-CA/SPIONs for monotherapy or dual magnetic hyperthermia-radionuclide nanobrachytherapy (NBT) of solid tumours.

Design and preparation of 90Y-labeled imidodiphosphate- and inositol hexaphosphate-coated magnetic nanoparticles for possible medical applications.

Radiolabeled magnetic nanoparticles (MNPs) coated with hydrophilic phosphate ligands, i.e., imidodiphosphate (IDP) and inositol hexaphosphate (IHP), were developed as multifunctional agents to localize both radioactivity and magnetic energy at a tumor site. The coating of MNPs with phosphates made them biocompatible, increased their colloidal stability and allowed binding of the radionuclide 90Y to the available functional groups on the surface of the MNPs. IDP and IHP have not hitherto been used for the coating of MNPs and the results of this study of the functionalized MNPs showed that the phosphate groups influenced the modification of the surface of MNPs. Characterization of the MNPs was performed using X-ray powder diffraction, transmission electron microscopy, Fourier transform infrared spectroscopy, dynamic light scattering and laser Doppler electrophoresis. The specific power absorption values obtained for MNPs (46.95-80.76 W g-1) in different physiological media indicated their possible application in hyperthermia treatment. Both types of coated MNPs were 90Y-labeled in a reproducible high yield (>98%). In vitro studies of 90Y-MNPs in saline and human serum showed their high stability after 72 h. The biodistribution pattern of the MNPs after intravenous administration to healthy Wistar rats was followed by the radiotracer method, revealing that 90Y-Fe3O4-IDP and 90Y-Fe3O4-IHP MNPs were predominantly found in the liver (85.21% ID and 86.22% ID), followed by the spleen (9.23% ID and 8.82% ID) and the lungs (1.53% ID and 1.53% ID). The results of this comprehensive study showed that radiolabeled biocompatible phosphate magnetic complexes hold great promise for therapeutic uses combining magnetic hyperthermia and radiotherapy.

Effect of cobalt doping level of ferrites in enhancing sensitivity of analytical performances of carbon paste electrode for simultaneous determination of catechol and hydroquinone.

This work presents the simultaneous determination of catechol (CC) and hydroquinone (HQ), employing a modified carbon paste electrode (CPE) with ferrite nanomaterial. Ferrite nanomaterial was doped with different amount of cobalt and this was investigated toward simultaneous oxidation of CC and HQ. It was shown that this modification strongly increases electrochemical characteristics of the CPE. Also, electrocatalytic activity of such materials strongly depends on the level of substituted Co in the ferrite nanoparticles. The modified electrodes, labeled as CoFerrite/CPE, showed two pairs of well-defined redox peaks for the electrochemical processes of catechol and hydroquinone. Involving of ferrite material in the structure of CPE, cause increase in the potentials differences between redox couples of the investigated compounds, accompanied with increases in peaks currents. Several important parameters were optimized and calibration curves, with limits of detection (LOD) of 0.15 and 0.3µM for catechol and hydroquinone, respectively, were constructed by employing amperometric detection. Effect of possible interfering compounds was also studied, and proposed method was successfully applied for CC and HQ quantification in real samples.