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Background: Radioimmunotherapy with cetuximab and conjugates with various radioisotopes is a feasible treatment option for different tumor models. Scandium-47 (47Sc), one of several β−-particle-emitting radioisotopes, displays favorable physical and chemical properties for conjugation to monoclonal antibodies. However, the therapeutic efficacy of 47Sc in preclinical and clinical studies is largely unknown. Given that intrinsic alterations in tumors greatly contribute to resistance to anti-epidermal growth factor receptor (EGFR)-targeted therapy, research on overcoming resistance to radioimmunotherapy using cetuximab is required. Methods: 47Sc was produced by irradiation of a CaCO3 target at the HANARO research reactor in KAERI (Korea Atomic Energy Research Institute) and prepared by chromatographic separation of the irradiated target. Cetuximab was conjugated with 47Sc using the bifunctional chelating agent DTPA. Radiochemical purity was determined using instant thin-layer chromatography. The immunoreactivity of 47Sc-DTPA-cetuximab was evaluated using the Lindmo method and an in vitro cell-binding assay. The inhibitory effects of cetuximab and 47Sc-DTPA-cetuximab were confirmed using cell growth inhibition and BrdU cell proliferation assays. Differences in protein expression levels between cetuximab- and 47Sc-DTPA-cetuximab-treated cells were confirmed using western blotting. Complex formation between RUNX3 and DNA repair components was confirmed using immunoprecipitation and western blotting. Results: Cetuximab induces cell cycle arrest and cell death in EGFR-overexpressing NSCLC cells. Radiolabeling of cetuximab with 47Sc led to increased therapeutic efficacy relative to cetuximab alone. Application of 47Sc-DTPA-cetuximab induced DNA damage responses, and activation of RUNX3 significantly enhanced the therapeutic efficacy of 47Sc-DTPA-cetuximab. RUNX3 mediated susceptibility to EGFR-targeted NSCLC therapy using 47Sc-DTPA-cetuximab via interaction with components of the DNA damage and repair machinery. Conclusions: 47Sc-DTPA-cetuximab promoted cell death in EGFR-overexpressing NSCLC cells by targeting EGFR and inducing DNA damage as a result of β irradiation emitted from the conjugated 47Sc. Activation of RUNX3 played a key role in DNA damage and repair processes in response to the ionizing radiation and inhibited cell growth, thus leading to more effective tumor suppression. RUNX3 can potentially moderate susceptibility to 47Sc-conjugated cetuximab by modulating DNA damage and repair process mechanisms. [ABSTRACT FROM AUTHOR]

This separation study employed reversed-phase ion-pair liquid chromatography, which uses a silica gel containing polar groups such as nitrile and alkyl siloxane as a stationary phase to prepare high-purity Lu from an enriched Yb target. Adequate mobile phases were identified for the selected columns, and the reproducibility of separation was assessed during a continuous use of the columns. No-carrier added (nca) Lu was perfectly separated from 10 mg of the YbO target that had been neutron-irradiated in the HANARO reactor, and the separation performance of the column was unaffected after 10 repeated separations. The results of this study are expected to be useful when applied to produce nca Lu of a few hundred mCi using a several milligram Yb target, or an additional purification stage to produce curies-level Lu with bulk a YbO target. [ABSTRACT FROM AUTHOR]

Abstract: Organo-ceramic hybrid materials have been developed as the separation media for a 90Sr/90Y generator system. Currently available 90Y is generally extracted from a mother solution by a solvent extraction or a successive column operation. Both processes are successfully applied to produce 90Y with a high quality standard. However, such processes are highly dependent on what kind of extracting materials are employed. Hence, some of the previously developed technologies are not adequate for a 90Y production because of a waste generation or leaching of radiolytic end-products from the extracting materials. In this study, high performance organo-ceramic hybrid materials have been applied for the extraction of 90Y. The hybrid materials have properties of both a ceramic and a solvent extractant by molecularly implanting the extracting molecules on to the ceramic surfaces. In this study, organo-phosphorus functionalized hybrid materials are synthesized and tested as the separation media for the 90Y/90Sr generator system. An adsorptive extraction with a small Sep-Pak type column can recover more than 92% of 90Y with a contamination ratio of 90Sr/90Y=1.2×10−5 from the mother solution and 70% with 5×10−7. [Copyright &y& Elsevier]

Abstract: A synthetic alumina functionalized with a sulfate moiety has been developed as the column material of 99Mo/99mTc and 188W/188Re generators. This material is synthesized by a sol–gel processing. In order to characterize the adsorbent for the 188W/188Re separation, both batch and column contact experiments were conducted. As a result of the experiments, it is found that the maximum capacity of the adsorbent for tungsten is higher than 450mg/g. Hence it is possible to produce ∼3Ci 188W/188Re generator with only 1g of the adsorbent from 188W solutions supplied from ORNL, USA or RIAR, Russia. A demonstration study was conducted to show the performance of an 188W/188Re generator column. In this study, 1Ci of 188W purchased from RIAR, Russia, is loaded on a 0.9cm ID column packed with 0.7g of the adsorbent. Elution of 188Re is performed every 4–7 days by using the saline solution for more than three months. Nearly 100% of tungsten is loaded by passing 5ml of the 188W solution (pH=8) through the dry packed column at a 1ml/min flow rate. Elution efficiency of 188Re is 70–90% by using 5ml of the saline solution. The ratio of 188W/188Re in the eluted solution is 0.002–0.003%. When a Sep-Pak® containing 0.26g of acid alumina is installed as a tandem column, the ratio is decreased to less than 10−3%. Thin layer chromatography for the eluted 188Re solution shows 100% radiochemical purity. Also, alumina content in the eluted solution shows less than 10ppm. Through this study, the performance of this adsorbent was successfully demonstrated. By using the developed adsorbent, minimization of the generator column and consequently the volume of eluant could be possible while maintaining the quality of 188Re just as much as that available in the market. [Copyright &y& Elsevier]