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Prostate cancer (PC) is an aggressive cancer that can progress rapidly and eventually become castrate-resistant prostate cancer (CRPC). Stage IV metastatic castrate-resistant prostate cancer (mCRPC) is an incurable late-stage cancer type with a low 5-year overall survival rate. Targeted therapeutics such as antibody-drug conjugates (ADCs) based on high-affinity monoclonal antibodies and potent drugs conjugated via smart linkers are being developed for PC management. Conjugating further with in vitro or in vivo imaging agents, ADCs can be used as antibody-theranostic conjugates (ATCs) for diagnostic and image-guided drug delivery. In this study, we have developed a novel ATC for PSMA (+) PC therapy utilizing (a) anti-PSMA 5D3 mAb, (b) Aurora A kinase inhibitor, MLN8237, and (c) for the first time using tetrazine (Tz) and transcyclooctene (TCO) click chemistry-based conjugation linker (CC linker) in ADC development. The resulting 5D3(CC-MLN8237)3.2 was labeled with suitable fluorophores for in vitro and in vivo imaging. The products were characterized by SDS-PAGE, MALDI-TOF, and DLS and evaluated in vitro by optical imaging, flow cytometry, and WST-8 assay for cytotoxicity in PSMA (+/-) cells. Therapeutic efficacy was determined in human PC xenograft mouse models following a designed treatment schedule. After the treatment study animals were euthanized, and toxicological studies, complete blood count (CBC), blood clinical chemistry analysis, and H&E staining of vital organs were conducted to determine side effects and systemic toxicities. The IC50 values of 5D3(CC-MLN8237)3.2-AF488 in PSMA (+) PC3-PIP and PMSA (-) PC3-Flu cells are 8.17 nM and 161.9 nM, respectively. Pure MLN8237 shows 736.9 nM and 873.4 nM IC50 values for PC3-PIP and PC3-Flu cells, respectively. In vivo study in human xenograft mouse models confirmed high therapeutic efficacy of 5D3(CC-MLN8237)3.2- CF750 with significant control of PSMA (+) tumor growth with minimal systemic toxicity in the treated group compared to PSMA (-) treated and untreated groups. Approximately 70% of PSMA (+) PC3-PIP tumors did not exceed the threshold of the tumor size in the surrogate Kaplan-Meyer analysis. The novel ATC successfully controlled the growth of PSMA (+) tumors in preclinical settings with minimal systemic toxicities. The therapeutic efficacy and favorable safety profile of novel 5D3(CC-MLN8237)3.2 ATC demonstrates their potential use as a theranostic against aggressive PC. [ABSTRACT FROM AUTHOR]

In the current work, the RBE of a 212Pb-conjugated anti-HER2/neu antibody construct has been evaluated, in vitro, by colony formation assay. The RBE was estimated by comparing two absorbed dose-survival curves: the first obtained from the conjugated 212Pb experiments (test radiation), the second obtained by parallel experiments of single bolus irradiation of external beam (reference radiation). Mammary carcinoma NT2.5 cells were treated with (0–3.70) kBq/ml of radiolabeled antibody. Nonspecific binding was assessed with addition of excess amount of unlabeled antibody. The colony formation curves were converted from activity concentration to cell nucleus absorbed dose by simulating the decay and transport of all daughter and secondary particles of 212Pb, using the Monte Carlo code GEANT 4. The radiolabeled antibody yielded an RBE of 8.3 at 37% survival and a survival independent RBE (i.e. RBE2) of 9.9. Unbound/untargeted 212Pb-labeled antibody, as obtained in blocking experiments yielded minimal alpha-particle radiation to cells. Conclusions: These results further highlight the importance of specific targeting toward achieving tumor cell kill and low toxicity to normal tissue. [ABSTRACT FROM AUTHOR]

Two new 8-connected 2-D MOFs, UCY-13 and UCY-14, based on Zr6 secondary building units (SBUs) and angular dicarboxylate ligands are reported. UCY-13 and UCY-14 display remarkable stability in various types of aqueous media, an appreciable internal surface area of 925 m2 g−1 and 678 m2 g−1, respectively, and are the first examples of 2-D MOFs investigated for their uranyl sorption capability. They exhibit exceptional UO22+ sorption capacities of 984 mg g−1 for UCY-13 and 471 mg g−1 for UCY-14 and the ability to sorb UO22+ from various types of real-world aqueous media. Both sorbents were proven to immobilize UO22+ ions, thus being unique examples of MOFs that can be potentially employed as barrier materials for environmental application. Their exceptional sorption properties are attributed to the 2-D nature and structural features directly derived from it such as the presence of several easily accessible coordination sites in the Zr6 SBUs. [ABSTRACT FROM AUTHOR]

The removal of U(VI) by biochar fibers from aqueous solutions has been investigated prior and after MnO2 surface-deposition. The removal efficiency has been studied as a function of pH, U(VI) concentration, ionic strength, temperature and contact time. The fibers morphology and surface complexes were analyzed by SEM–EDX and FTIR, respectively. Evaluation of the experimental data indicates that the composite presents extraordinary adsorption capacity (qmax = 3.8 mmol g−1, 904 mg g−1), which is attributed to the formation of inner-sphere surface complexes, and that the adsorption reaction is a relatively fast, endothermic and entropy-driven process. [ABSTRACT FROM AUTHOR]

Prostate cancer (PC) is an aggressive cancer that can progress rapidly and eventually become castrate-resistant prostate cancer (CRPC). Stage IV metastatic castrate-resistant prostate cancer (mCRPC) is an incurable late-stage cancer type with a low 5-year overall survival rate. Targeted therapeutics such as antibody-drug conjugates (ADCs) based on high-affinity monoclonal antibodies and potent drugs conjugated via smart linkers are being developed for PC management. Conjugating further with in vitro or in vivo imaging agents, ADCs can be used as antibody-theranostic conjugates (ATCs) for diagnostic and image-guided drug delivery. In this study, we have developed a novel ATC for PSMA (+) PC therapy utilizing (a) anti-PSMA 5D3 mAb, (b) Aurora A kinase inhibitor, MLN8237, and (c) for the first time using tetrazine (Tz) and trans -cyclooctene (TCO) click chemistry-based conjugation linker (CC linker) in ADC development. The resulting 5D3(CC-MLN8237) 3.2 was labeled with suitable fluorophores for in vitro and in vivo imaging. The products were characterized by SDS-PAGE, MALDI-TOF, and DLS and evaluated in vitro by optical imaging, flow cytometry, and WST-8 assay for cytotoxicity in PSMA (+/-) cells. Therapeutic efficacy was determined in human PC xenograft mouse models following a designed treatment schedule. After the treatment study animals were euthanized, and toxicological studies, complete blood count (CBC), blood clinical chemistry analysis, and H&E staining of vital organs were conducted to determine side effects and systemic toxicities. The IC 50 values of 5D3(CC-MLN8237) 3.2 -AF488 in PSMA (+) PC3-PIP and PMSA (-) PC3-Flu cells are 8.17 nM and 161.9 nM, respectively. Pure MLN8237 shows 736.9 nM and 873.4 nM IC 50 values for PC3-PIP and PC3-Flu cells, respectively. In vivo study in human xenograft mouse models confirmed high therapeutic efficacy of 5D3(CC-MLN8237) 3.2 -CF750 with significant control of PSMA (+) tumor growth with minimal systemic toxicity in the treated group compared to PSMA (-) treated and untreated groups. Approximately 70% of PSMA (+) PC3-PIP tumors did not exceed the threshold of the tumor size in the surrogate Kaplan-Meyer analysis. The novel ATC successfully controlled the growth of PSMA (+) tumors in preclinical settings with minimal systemic toxicities. The therapeutic efficacy and favorable safety profile of novel 5D3(CC-MLN8237) 3.2 ATC demonstrates their potential use as a theranostic against aggressive PC., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Liatsou, Assefa, Liyanage, Surasinghe, Nováková, Bařinka, Gabrielson, Raman, Artemov and Hapuarachchige.)

Purpose: In the current work, the RBE of a 212 Pb-conjugated anti-HER2/ neu antibody construct has been evaluated, in vitro, by colony formation assay. The RBE was estimated by comparing two absorbed dose-survival curves: the first obtained from the conjugated 212 Pb experiments (test radiation), the second obtained by parallel experiments of single bolus irradiation of external beam (reference radiation)., Materials and Methods: Mammary carcinoma NT2.5 cells were treated with (0-3.70) kBq/ml of radiolabeled antibody. Nonspecific binding was assessed with addition of excess amount of unlabeled antibody. The colony formation curves were converted from activity concentration to cell nucleus absorbed dose by simulating the decay and transport of all daughter and secondary particles of 212 Pb, using the Monte Carlo code GEANT 4., Results: The radiolabeled antibody yielded an RBE of 8.3 at 37% survival and a survival independent RBE (i.e. RBE2) of 9.9. Unbound/untargeted 212 Pb-labeled antibody, as obtained in blocking experiments yielded minimal alpha-particle radiation to cells. Conclusions: These results further highlight the importance of specific targeting toward achieving tumor cell kill and low toxicity to normal tissue.