Explore the vast range of titles available.

This review summarizes recent progress and developments as well as the most important pitfalls in targeted alpha-particle therapy, covering single alpha-particle emitters as well as in vivo alpha-particle generators. It discusses the production of radionuclides like 211At, 223Ra, 225Ac/213Bi, labelling and delivery employing various targeting vectors (small molecules, chelators for alpha-emitting nuclides and their biomolecular targets as well as nanocarriers), general radiopharmaceutical issues, preclinical studies, and clinical trials including the possibilities of therapy prognosis and follow-up imaging. Special attention is given to the nuclear recoil effect and its impacts on the possible use of alpha emitters for cancer treatment, proper dose estimation, and labelling chemistry. The most recent and important achievements in the development of alpha emitters carrying vectors for preclinical and clinical use are highlighted along with an outlook for future developments.

BackgroundRecent advances in nanotechnology have offered new hope for cancer detection, prevention, and treatment. Nanomedicine, a term for the application of nanotechnology in medical and health fields, uses nanoparticles for several applications such as imaging, diagnostic, targeted cancer therapy, drug and gene delivery, tissue engineering, and theranostics. ResultsHere, we overview the current state-of-the-art of radiolabeled nanoparticles for molecular imaging and radionuclide therapy. Nanostructured radiopharmaceuticals of technetium-99m, copper-64, lutetium-177, and radium-223 are discussed within the scope of this review article.ConclusionNanoradiopharmaceuticals may lead to better development of theranostics inspired by ingenious delivery and imaging systems. Cancer nano-theranostics have the potential to lead the way to more specific and individualized cancer treatment.

The target diosgenin–betulinic acid conjugates are reported to investigate their ability to enhance and modify the pharmacological effects of their components. The detailed synthetic procedure that includes copper(I)-catalyzed Huisgen 1,3-dipolar cycloaddition (click reaction), and palladium-catalyzed debenzylation by hydrogenolysis is described together with the results of cytotoxicity screening tests. Palladium-catalyzed debenzylation reaction of benzyl ester intermediates was the key step in this synthetic procedure due to the simultaneous presence of a 1,4-disubstituted 1,2,3-triazole ring in the molecule that was a competing coordination site for the palladium catalyst. High pressure (130 kPa) palladium-catalyzed procedure represented a successful synthetic step yielding the required products. The conjugate 7 showed selective cytotoxicity in human T-lymphoblastic leukemia (CEM) cancer cells (IC50 = 6.5 ± 1.1 µM), in contrast to the conjugate 8 showing no cytotoxicity, and diosgenin (1), an adaptogen, for which a potential to be active on central nervous system was calculated in silico. In addition, 5 showed medium multifarious cytotoxicity in human T-lymphoblastic leukemia (CEM), human cervical cancer (HeLa), and human colon cancer (HCT 116). Betulinic acid (2) and the intermediates 3 and 4 showed no cytotoxicity in the tested cancer cell lines. The experimental data obtained are supplemented by and compared with the in silico calculated physico-chemical and absorption, distribution, metabolism, and excretion (ADME) parameters of these compounds.

Positron-emitting 68 Ga has become an integral part of nuclear medicine. It is a radionuclide obtained from 68 Ge/ 68 Ga radionuclide generators. Apart from other qualities, it is a feature that have caused its growing popularity in medical practice. Nevertheless, the increasing demand for 68 Ga supply results in the need of new and improved separation systems to obtain it. Hydrous oxides such as titanium or zirconium dioxide are usually the preferred separation materials, but other oxidic materials are under study. Thorough testing of the sorption behaviour is often overlooked in these studies, though it is indispensable for the applicability and suitability assessment. This work is focused on the sorption behaviour description of cerium dioxide prepared by calcination of ceric nitrate. Both batch and kinetic sorption experiments were conducted. Such a thorough study has never been carried out for this material. In batch experiments, the optimal conditions for separation of 68 Ga and 68 Ge were found. Kinetic experimental data were used for mathematical modelling. Six kinetic models derived from various rate-controlling processes were used and their applicability was demonstrated. The diffusion in an inert layer is the rate-controlling process of both gallium and germanium sorption and desorption. This model description of sorption kinetics will further enable us to optimise the sorption and desorption processes numerically. Thus far, it was found out that the prepared cerium dioxide can quantitatively adsorb germanium in very short time of 10 min from 1mM hydrochloric acid and the most convenient medium for 68 Ge and 68 Ga separation is 0.1 M hydrochloric acid. Article highlights • Prepared cerium dioxide is a suitable sorbent for 68 Ga/ 68 Ge generator. • The applicability of chosen kinetic models on Ga and Ge sorption on CeO 2 was demonstrated. • The diffusion is the rate-controlling step of Ga and Ge sorption and desorption.

Background Overexpression of human epidermal growth factor receptor type 2 (HER2) occurs in multiple carcinomas. For example, up to 20% of breast cancer cases are classified as HER2 positive (HER2+). Treatment of this condition typically involves immunotherapy using monoclonal antibodies, such as trastuzumab or pertuzumab. The precise targeting of monoclonal antibodies to HER2+ tumour lesions can be used as well in radioimmunotherapy to deliver medical radionuclides exactly to the afflicted area and therefore minimize radiation exposure of healthy tissues. In this study, DOTA conjugates of monoclonal antibodies trastuzumab and pertuzumab were prepared and tested in vitro. One of these, 225 Ac-DOTA-pertuzumab, was also the subject of an ex vivo biodistribution study with normal as well as HER2+ and HER2- tumour-xenografted mice. This radioconjugate has not been previously described. Results Three DOTA-conjugates of HER2 targeting monoclonal antibodies, one of trastuzumab and two of pertuzumab, were prepared and radiolabelled with 225 Ac in different molar ratios. This procedure led to an optimisation of the preparation and radiolabelling process. The radioconjugates were shown to be highly stable in vitro in both fetal bovine serum and phosphate buffered saline under room temperature and decreased temperature for 10 days. In vitro cell studies with HER2-overexpressing cell-line (SKOV-3) and low HER2-expressing cell line (MDA-MB-231) proved that radioconjugates of both antibodies have high binding specificity and affinity towards HER2 receptors. These findings were confirmed for a novel radioconjugate 225 Ac-DOTA-pertuzumab in an ex vivo biodistribution study, where uptake in HER2+ tumour was 50 ± 14% ID/g and HER2- tumour showed uptake comparable with healthy tissues (max. 5.0 ± 1.7% ID/g). The high uptake observed in the spleen can be attributed to the elimination of the antibody, as well as the use of an immunedeficient mouse strain (SCID). Conclusions During this study, the optimization of preparation and radiolabelling of HER2 targeting antibodies with 225 Ac was accomplished. Furthermore, the radioconjugate 225 Ac-DOTA-pertuzumab was prepared and evaluated for the first time. The radioconjugates of both tested antibodies demonstrated excellent qualities in terms of stability and HER2 receptor affinity. Initial ex vivo studies indicated that especially the radioconjugate 225 Ac-DOTA-pertuzumab is a very promising candidate for further more detailed in vivo studies.

Clustered DNA damage induced by 10, 20 and 30 MeV protons in pBR322 plasmid DNA was investigated. Besides determination of strand breaks, additional lesions were detected using base excision repair enzymes. The plasmid was irradiated in dry form, where indirect radiation effects were almost fully suppressed, and in water solution containing only minimal residual radical scavenger. Simultaneous irradiation of the plasmid DNA in the dry form and in the solution demonstrated the contribution of the indirect effect as prevalent. The damage composition slightly differed when comparing the results for liquid and dry samples. The obtained data were also subjected to analysis concerning different methodological approaches, particularly the influence of irradiation geometry, models used for calculation of strand break yields and interpretation of the strand breaks detected with the enzymes. It was shown that these parameters strongly affect the results.

Nanoparticles (NPs) represent an emerging platform for diagnosis and treatment of various diseases such as cancer, where they can take advantage of enhanced permeability and retention (EPR) effect for solid tumor accumulation. To improve their colloidal stability, prolong their blood circulation time and avoid premature entrapment into reticuloendothelial system, coating with hydrophilic biocompatible polymers is often essential. Most studies, however, employ just one type of coating polymer. The main purpose of this study is to head-to-head compare biological behavior of three leading polymers commonly used as “stealth” coating materials for biocompatibilization of NPs poly(ethylene oxide), poly(2-ethyl-2-oxazoline) and poly[N-(2-hydroxypropyl)methacrylamide] in an in vivo animal solid tumor model. We used radiolabeled biodegradable hydroxyapatite NPs as a model nanoparticle core within this study and we anchored the polymers to the NPs core by hydroxybisphosphonate end groups. The general suitability of polymers for coating of NPs intended for solid tumor accumulation is that poly(2-ethyl-2-oxazoline) and poly(ethylene oxide) gave comparably similar very good results, while poly[N-(2-hydroxypropyl)methacrylamide] was significantly worse. We did not observe a strong effect of molecular weight of the coating polymers on tumor and organ accumulation, blood circulation time, biodistribution and biodegradation of the NPs.

Hydroxyapatite and titanium dioxide are widely used materials in a broad spectrum of branches. Due to their appropriate properties such as a large specific surface area, radiation stability or relatively low toxicity, they could be potentially used as nanocarriers for medicinal radionuclides for diagnostics and therapy. Two radiolabelling strategies of both nanomaterials were carried out by 99mTc for diagnostic purposes and by 223Ra for therapeutic purposes. The first one was the radionuclide sorption on ready-made nanoparticles and the second one was direct radionuclide incorporation into the structure of the nanoparticles. Achieved labelling yields were higher than 94% in all cases. Afterwards, in vitro stability tests were carried out in several solutions: physiological saline, bovine blood plasma, bovine blood serum, 1% and 5% human albumin solutions. In vitro stability studies were performed as short-term (59 h for 223Ra and 31 h for 99mTc) and long-term experiments (five half-lives of 223Ra, approx. 55 days). Both radiolabelled nanoparticles with 99mTc have shown similar released activities (about 20%) in all solutions. The best results were obtained for 223Ra radiolabelled titanium dioxide nanoparticles, where overall released activities were under 6% for 59 h study in all matrices and under 3% for 55 days in a long-term perspective.

Nanoparticles of various materials were proposed as carriers of nuclides in targeted alpha particle therapy to at least partially eliminate the nuclear recoil effect causing the unwanted release of radioactive progeny originating in nuclear decay series of so-called in vivo generators. Here, we report on the study of [sup.211]Pb and [sup.211]Bi recoils release from the [sup.223]Ra surface-labelled TiO[sub.2] nanoparticles in the concentration range of 0.01-1 mg/mL using two phase separation methods different in their kinetics in order to test the ability of progeny resorption. We have found significant differences between the centrifugation and the dialysis used for labelled NPs separation as well as that the release of [sup.211]Pb and [sup.211]Bi from the nanoparticles also depends on the NPs dispersion concentration. These findings support our previously proposed recoils-retaining mechanism of the progeny by their resorption on the NPs surface. At the 24 h time-point, the highest overall released progeny fractions were observed using centrifugation (4.0% and 13.5% for [sup.211]Pb and [sup.211]Bi, respectively) at 0.01 mg/mL TiO[sub.2] concentration. The lowest overall released fractions at the 24 h time-point (1.5% and 2.5% for [sup.211]Pb and [sup.211]Bi respectively) were observed using dialysis at 1 mg/mL TiO[sub.2] concentration. Our findings also indicate that the in vitro stability tests of such radionuclide systems designed to retain recoil-progeny may end up with biased results and particular care needs to be given to in vitro stability test experimental setup to mimic in vivo dynamic conditions. On the other hand, controlled and well-defined progeny release may enhance the alpha-emitter radiation therapy of some tumours.

Nanoparticles of various materials were proposed as carriers of nuclides in targeted alpha particle therapy to at least partially eliminate the nuclear recoil effect causing the unwanted release of radioactive progeny originating in nuclear decay series of so-called in vivo generators. Here, we report on the study of Pb and Bi recoils release from the Ra surface-labelled TiO nanoparticles in the concentration range of 0.01-1 mg/mL using two phase separation methods different in their kinetics in order to test the ability of progeny resorption. We have found significant differences between the centrifugation and the dialysis used for labelled NPs separation as well as that the release of Pb and Bi from the nanoparticles also depends on the NPs dispersion concentration. These findings support our previously proposed recoils-retaining mechanism of the progeny by their resorption on the NPs surface. At the 24 h time-point, the highest overall released progeny fractions were observed using centrifugation (4.0% and 13.5% for Pb and Bi, respectively) at 0.01 mg/mL TiO concentration. The lowest overall released fractions at the 24 h time-point (1.5% and 2.5% for Pb and Bi respectively) were observed using dialysis at 1 mg/mL TiO concentration. Our findings also indicate that the in vitro stability tests of such radionuclide systems designed to retain recoil-progeny may end up with biased results and particular care needs to be given to in vitro stability test experimental setup to mimic in vivo dynamic conditions. On the other hand, controlled and well-defined progeny release may enhance the alpha-emitter radiation therapy of some tumours.