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The autoxidation of 3,5-di-tert-butylcatechol (H2DTBC) was catalyzed by the dicopper (II) complex, Cu2(dppn)(OH)Cl3·H2O (Cu2(dppn)(OH)3+). Kinetic studies determined that the reactants were first order in the concentrations of the catalytic dinuclear copper species, molecular oxygen, and H2DTBC and inverse first order in the proton concentration. An experimental rate law, consistent with the kinetic data, was proposed and suggested that both O2 and HDTBC− were associated with the dinuclear copper complex in the transition state. The second order rate constant was calculated to be 189±19M−1 s−1. Furthermore, the stoichiometry of the catalyzed reaction was the same as tyrosinase-catalyzed oxidations and O2 was reduced to water in a four electron process. The 3,6-bis(2′-pyridyl)pyridazine (dppn) chelate served as the binucleating ligand and provided a rigid and sterically unencumbered platform for catalytic interaction of the dicopper core with O2 and HDTBC−. The dppn chelate also afforded the dicopper core the necessary coordination flexibility required for each copper ion to simultaneously cycle between square pyramidal cupric and tetrahedral cuprous ligand field geometries. [ABSTRACT FROM AUTHOR]

Abstract: Clinical trials using -particle radiolabeled antibodies require a rapid and reproducible assay of the immunoreactivity of drugs. While live cell assays are typically used to determine the immunoreactive drug fraction, a fixed cell assay may replace the traditional live cell assay and offer the advantages of rapidity, easy availability and consistency for qualifying drugs for preclinical or clinical studies. We have identified optimal cell fixation and immunoreactivity assay conditions and have validated them by performing the fixed-cell assay in clinical trials. [Copyright &y& Elsevier]

The alpha-particle-emitting radionuclides 213Bi, 211At, 224Ra are under investigation for the treatment of leukemias, gliomas, and ankylosing spondylitis, respectively. 213Bi and 211At were attached to monoclonal antibodies and used as targeted immunotherapeutic agents while unconjugated 224Ra chloride selectively seeks bone. 225Ac possesses favorable physical properties for radioimmunotherapy (10 d half-life and 4 net alpha particles), but has a history of unfavorable radiolabeling chemistry and poor metal-chelate stability. We selected functionalized derivatives of DOTA as the most promising to pursue from out of a group of potential 225Ac chelate compounds. A two-step synthetic process employing either MeO–DOTA–NCS or 2B–DOTA–NCS as the chelating moiety was developed to attach 225Ac to monoclonal antibodies. This method was tested using several different IgG systems. The chelation reaction yield in the first step was 93±8% radiochemically pure (n=26). The second step yielded 225Ac–DOTA–IgG constructs that were 95±5% radiochemically pure (n=27) and the mean percent immunoreactivity ranged from 25% to 81%, depending on the antibody used. This process has yielded several potential novel targeted 225Ac-labeled immunotherapeutic agents that may now be evaluated in appropriate model systems and ultimately in humans. [Copyright &y& Elsevier]

Purpose: Internal irradiation of kidneys as a consequence of radioimmunotherapy, radiation accidents, or nuclear terrorism can result in radiation nephropathy. We attempted to modify pharmacologically, the functional and morphologic changes in mouse kidneys after injection with the actinium (225Ac) nanogenerator, an in vivo generator of α- and β-particle emitting elements. Methods and Materials: The animals were injected with 0.35 μCi of the 225Ac nanogenerator, which delivers a dose of 27.6 Gy to the kidneys. Then, they were randomized to receive captopril (angiotensin-converting enzyme inhibitor), L-158,809 (angiotensin II receptor-1 blocker), spironolactone (aldosterone receptor antagonist), or a placebo. Results: Forty weeks after the 225Ac injection, the placebo-control mice showed a significant increase in blood urea nitrogen (BUN) (87.6 ± 6.9 mg/dL), dilated Bowman spaces, and tubulolysis with basement membrane thickening. Captopril treatment accentuated the functional (BUN 119.0 ± 4.0 mg/dL; p <0.01 vs. placebo controls) and histopathologic damage. In contrast, L-158,809 offered moderate protection (BUN 66.6 ± 3.9 mg/dL; p = 0.02 vs. placebo controls). Spironolactone treatment, however, significantly prevented the development of histopathologic and functional changes (BUN 31.2 ± 2.5 mg/dL; p <0.001 vs. placebo controls). Conclusions: Low-dose spironolactone and, to a lesser extent, angiotensin receptor-1 blockade can offer renal protection in a mouse model of internal α-particle irradiation. [Copyright &y& Elsevier]

The use of novel materials in the nano-scale size range for applications in devices, drugs and diagnostic agents comes with a number of new opportunities, and also serious challenges to human applications. The larger size of particulate-based agents, as compared to traditional drugs, allows for the significant advantages of multivalency and multi-functionality. However, the human use of nanomaterials requires a thorough understanding of the biocompatibility of the synthetic molecules and their complex pharmacology. Possible toxicities created by the unusual properties of the nanoparticles are neither well-understood, nor predictable yet. A key to the successful use of the burgeoning field of nanomaterials as diagnostic and therapeutic agents will be to appropriately match the biophysical features of the particle to the disease system to be evaluated or treated. [ABSTRACT FROM AUTHOR]

Lutetium-177 (177Lu) radiolabeled ultrasmall (~6 nm dia.) fluorescent core-shell silica nanoparticles (Cornell prime dots or C′ dots) were developed for improving efficacy of targeted radiotherapy in melanoma models. PEGylated C′ dots were surface engineered to display 10–15 alpha melanocyte stimulating hormone (αMSH) cyclic peptide analogs for targeting the melanocortin-1 receptor (MC1-R) over-expressed on melanoma tumor cells. The 177Lu-DOTA-αMSH-PEG-C′ dot product was radiochemically stable, biologically active, and exhibited high affinity cellular binding properties and internalization. Selective tumor uptake and favorable biodistribution properties were also demonstrated, in addition to bulk renal clearance, in syngeneic B16F10 and human M21 xenografted models. Prolonged survival was observed in the treated cohorts relative to controls. Dosimetric analysis showed no excessively high absorbed dose among normal organs. Correlative histopathology of ex vivo treated tumor specimens revealed expected necrotic changes; no acute pathologic findings were noted in the liver or kidneys. Collectively, these results demonstrated that 177Lu-DOTA-αMSH-PEG-C′ dot targeted melanoma therapy overcame the unfavorable biological properties and dose-limiting toxicities associated with existing mono-molecular treatments. The unique and tunable surface chemistries of this targeted ultrasmall radiotherapeutic, coupled with its favorable pharmacokinetic properties, substantially improved treatment efficacy and demonstrated a clear survival benefit in melanoma models, which supports its further clinical translation. Image 1 • Unique particle surface chemistry yields favorable targeting and pharmacokinetics. • Nanoparticle therapy results in reduced tumor growth and prolonged survival. • Overcomes dose-limiting toxicities associated with existing therapeutics. • Yields improved treatment efficacy and reduced off-target side effects. [ABSTRACT FROM AUTHOR]