Siderocalin fusion proteins enable a new 86Y/90Y theranostic approach.

The mammalian protein siderocalin binds bacterial siderophores and their iron complexes through cation-π and electrostatic interactions, but also displays high affinity for hydroxypyridinone complexes of trivalent lanthanides and actinides. In order to circumvent synthetic challenges, the use of siderocalin-antibody fusion proteins is explored herein as an alternative targeting approach for precision delivery of trivalent radiometals. We demonstrate the viability of this approach in vivo, using the theranostic pair 90Y (ß-, t1/2 = 64 h)/86Y (ß+, t1/2 = 14.7 h) in a SKOV-3 xenograft mouse model. Ligand radiolabeling with octadentate hydroxypyridinonate 3,4,3-LI(1,2-HOPO) and subsequent protein binding were achieved at room temperature. The results reported here suggest that the rapid non-covalent binding interaction between siderocalin fusion proteins and the negatively charged Y(iii)-3,4,3-LI(1,2-HOPO) complexes could enable purification-free, cold-kit labeling strategies for the application of therapeutically relevant radiometals in the clinic.

Macrocyclic 1,2-Hydroxypyridinone-Based Chelators as Potential Ligands for Thorium-227 and Zirconium-89 Radiopharmaceuticals.

Thorium-227 (227Th) is an α-emitting radionuclide that has shown preclinical and clinical promise for use in targeted α-therapy (TAT), a type of molecular radiopharmaceutical treatment that harnesses high energy α particles to eradicate cancerous lesions. Despite these initial successes, there still exists a need for bifunctional chelators that can stably bind thorium in vivo. Toward this goal, we have prepared two macrocyclic chelators bearing 1,2-hydroxypyridinone groups. Both chelators can be synthesized in less than six steps from readily available starting materials, which is an advantage over currently available platforms. The complex formation constants (log ßmlh) of these ligands with Zr4+ and Th4+, measured by spectrophotometric titrations, are greater than 34 for both chelators, indicating the formation of exceedingly stable complexes. Radiolabeling studies were performed to show that these ligands can bind [227Th]Th4+ at concentrations as low as 10-6 M, and serum stability experiments demonstrate the high kinetic stability of the formed complexes under biological conditions. Identical experiments with zirconium-89 (89Zr), a positron-emitting radioisotope used for positron emission tomography (PET) imaging, demonstrate that these chelators can also effectively bind Zr4+ with high thermodynamic and kinetic stability. Collectively, the data reported herein highlight the suitability of these ligands for use in 89Zr/227Th paired radioimmunotheranostics.

Elemental chalcogen reactions of a tetravalent uranium imidophosphorane complex: cleavage of dioxygen.

Herein we report the first example of a mononuclear uranium complex, [U4+(NP(pip)3)4] (1-U), that selectively reduces dioxygen to produce a terminal oxo complex, [U6+O(NP(pip)3)4] (2-U; [NP(pip)3]1- is tris(piperidinyl)imidophosphorane). Reactions between 1-U and the heavier elemental chalcogens, S8 or Se0, result in six-coordinate U(VI) complexes, [U6+(κ2-E3)(NP(pip)3)4] (E = S (3-U) or Se (4-U)).

Active surveillance in renal tumors: Clinical and oncological outcomes.

CONTEXT: Some patients diagnosed with small renal solid masses or complex cystic lesions may benefit from active surveillance (AS) instead of immediate treatment. AIMS: Report our series of patients undergoing AS for small renal solid and complex cystic lesions, and compare growth rates and outcomes between both types of lesions. MATERIALS AND METHODS: A retrospective review AS database for renal lesions was conducted. From 1995 to 2017, a total of 82 patients with 89 renal lesions were included. We describe our AS protocol, patient and tumor characteristics, comparisons between solid and cystic lesions, and final outcome of patients who underwent delayed intervention (DI). STATISTICAL ANALYSIS USED: Categorical and continuous data were analyzed by the Chi-square and the Student's t-test, respectively. The Wilcoxon/Kruskal-Wallis test was used for growth rate comparisons of solid and complex cystic lesions. RESULTS: Median age of patients at the beginning of AS was 77-year-old, median size for solid and cystic lesions was 2.3 cm (0.08-3.8) and 2.6 cm (1.2-4.0), respectively. No differences in annual growth rate between solid and complex cystic lesions (0.04 cm [0.00-1.5] and 0.05 cm [0.01-1.7]) were observed at a similar median follow-up of 61 months for both groups (range: 15-182, and 14-254). Five patients with solid lesions underwent DI, 3 for rapid growth (>0.5 cm/year), 1 demanded treatment, and 1 due to hematuria. Adherence to AS protocol was high (94%). No cancer-related deaths or metastatic progression was observed, six patients died of another medical condition, being cardiovascular disease the most frequent cause. CONCLUSIONS: AS is a reasonable and safe option for the management of small renal masses. No difference was observed in the growth rate between solid and complex cystic lesions during AS. Centers offering AS should present a standardized protocol and give exhaustive information to patients regarding benefits and risks.

Chalcogen-atom abstraction reactions of a Di-iron imidophosphorane complex.

Reaction of the complexes [Fe2(µ2-NP(pip)3)2(NP(pip)3)2] (1-Fe) and [Co2(µ2-NP(pip)3)2(NP(pip)3)2] (1-Co), where [NP(pip)3]1- is tris(piperidinyl)imidophosphorane, with nitrous oxide, S8, or Se0 results in divergent reactivity. With nitrous oxide, 1-Fe forms [Fe2(µ2-O)(µ2-NP(pip)3)2(NP(pip)3)2] (2-Fe), with a very short Fe3+-Fe3+ distance. Reactions of 1-Fe with S8 or Se0 result in the bridging, side-on coordination (µ-κ1:κ1-E22-) of the heavy chalcogens in complexes [Fe2(µ-κ1:κ1-E2)(µ2-NP(pip)3)2(NP(pip)3)2] (E = S, 3-Fe, or Se, 4-Fe). In all cases, the complex 1-Co is inert.

Homoleptic cerium tris(dialkylamido)imidophosphorane guanidinate complexes.

We report the synthesis of a new potassium tris(piperdino)imidophosphorane N,N'-dicyclohexylguanidinate, K[CyGNP(pip)3], and describe the synthesis and characterization of the tris-homoleptic compounds, [Ce(CyGNP(pip)3)3], 1-Ce, and [Ce(CyGNP(pip)3)3][BPh4], 2-Ce. The latter is an unusual cationic tetravalent cerium complex. Cyclic voltammetry studies of 1-Ce and 2-Ce revealed Epc potentials of -1.56 V and -1.81 V, and Epa potentials of -0.78 V and -0.66 V (200 mV s-1; THF, vs. Fc0/+), respectively. Compounds 1-Ce and 2-Ce were studied by L3-edge X-ray absorption near-edge spectroscopy (XANES), and the fit of the spectrum of 2-Ce revealed a white-line multiplet with an nf value of 0.50(2).

Coinage metal tris(dialkylamido)imidophosphorane complexes as transmetallation reagents for cerium complexes.

We report the synthesis of tetrameric Cu(i) and Ag(i) homoleptic complexes supported by the tris(piperidinyl)imidophosphorane [NP(pip)3]1- and [NP(1,2-bis-tBu-diamidoethane)(NEt2)]1- ligands. These complexes demonstrate the redox stability of the imidophosphorane ligands to oxidizing salts, and the silver complexes can, in turn, serve as oxidative transmetallation reagents for the isolation of tetravalent cerium complexes from cerium metal or trivalent cerium precursors.

Diethyl ether adducts of trivalent lanthanide iodides.

The synthesis and structural characterization of the first molecular complexes of lanthanide iodides supported by the weak-base, diethyl ether, are reported. Single-crystal diffraction studies reveal a conserved [LnI3(mer-Et2O)3] structure (Ln = Ce, Pr, Nd, Sm, Gd, Tb, and Tm). These precursors are prepared from lanthanide metal and iodine in diethyl ether for all lanthanides La to Tm (excluding Pm and Eu) and provide the THF adducts in good to excellent (60-91%) yield in a two-step process.

Optimizing collagenase Clostridium histolyticum therapy for Peyronie's disease using a novel approach with percutaneous needle tunnelling.

OBJECTIVES: To compare the efficacy and safety of a combined treatment of percutaneous needle tunnelling (PNT) and a modified collagenase Clostridium histolyticum (CCH) protocol (PNT/CCH) vs the modified protocol alone (CCH) in the treatment of Peyronie's disease (PD). PATIENTS AND METHODS: A prospective registry of patients treated with a modified CCH protocol was maintained between June 2014 and February 2018. The last 50 patients received PNT as an adjuvant therapy (PNT/CCH), and their data were compared with those of the other 94 patients treated previously (CCH). PNT involves the creation of multiple holes made percutaneously in the plaque before each injection. The modified protocol consisted of two collagenase injections, at 1-week intervals, followed by penile modelling. Patients used penile traction therapy, tadalafil and pentoxifylline for the next 2 months and were followed up for 6 months. The main outcome was improvement of curvature. Secondary outcomes were improvements in erectile function, PD symptoms, stretched penile length and satisfaction. RESULTS: Improvement in curvature was greater in patients in the PNT/CCH group than in the CCH group (mean ± sd 19.2 ± 6.1° vs 12.7 ± 5.0°; P < 0.001 [36.2 ± 12.5% vs 28.1 ± 14.5%; P = 0.001]). Compared with baseline, both interventions were associated with significant improvement in secondary outcomes. The main complications were ecchymosis, bruising and penile pain, with no significant differences between groups. CONCLUSIONS: Treatment of PD with CCH using our modified protocol in combination with PNT is safe and more effective than the modified protocol alone, with the potential for improved cost-effectiveness.

Prone percutaneous nephrolithotomy: its advantages and our technique for puncture.

Percutaneous nephrolithotomy (PCNL) is considered the treatment of choice for large urinary calculi and staghorn lithiasis. The approach for this surgery may be either supine or prone, and different access techniques are described in the literature with the use of ultrasound, fluoroscopy, or both combined. We believe that prone PCNL offers to the urologist key advantages, such as the possibility of puncturing anatomically abnormal urinary tracts, to perform multiple percutaneous tracts in the same kidney, experiencing the vacuum cleaner effect, ease of exploring the upper calyx through the inferior calyx, possibility to perform endoscopic combined intrarenal surgery (ECIRS) and bilateral simultaneous surgery, and to performed over local anesthesia. An adequate training for the endourologist should include both the prone and supine techniques for PCNL and to know which patient can benefit the most from each one.

Proton-hydride tautomerism in hydrogen evolution catalysis.

Efficient generation of hydrogen from renewable resources requires development of catalysts that avoid deep wells and high barriers. Information about the energy landscape for H2 production can be obtained by chemical characterization of catalytic intermediates, but few have been observed to date. We have isolated and characterized a key intermediate in 2e(-) + 2H(+) → H2 catalysis. This intermediate, obtained by treatment of Cp*Rh(bpy) (Cp*, η(5)-pentamethylcyclopentadienyl; bpy, κ(2)-2,2'-bipyridyl) with acid, is not a hydride species but rather, bears [η(4)-Cp*H] as a ligand. Delivery of a second proton to this species leads to evolution of H2 and reformation of η(5)-Cp* bound to rhodium(III). With suitable choices of acids and bases, the Cp*Rh(bpy) complex catalyzes facile and reversible interconversion of H(+) and H2.