Novel gallium(III) complexes transported by MDR1 P-glycoprotein: potential PET imaging agents for probing P-glycoprotein-mediated transport activity in vivo

BACKGROUND: Multidrug resistance (MDR) mediated by expression of MDR1 P-glycoprotein (Pgp) represents one of the best characterized barriers to chemotherapy in cancer patients. Positron emission tomography (PET) agents for analysis of Pgp-mediated drug transport activity in vivo would enable noninvasive assessment of chemotherapeutic regimens and MDR gene therapy. RESULTS: Candidate Schiff-base phenolic gallium(III) complexes were synthesized from their heptadentate precursors and gallium(III)acetylacetonate. Crystal structures demonstrated a hexacoordinated central gallium with overall trans-pseudo-octahedral geometry. Radiolabeled (67)Ga-complexes were obtained in high purity and screened in drug-sensitive (Pgp(-)) and MDR (Pgp(+)) tumor cells. Compared with control, lead compound 6. demonstrated antagonist-reversible 55-fold lower accumulation in Pgp-expressing MDR cells. Futhermore, compared with wild-type control, quantitative pharmacokinetic analysis showed markedly increased penetration and retention of 6. in brain and liver tissues of mdr1a/b((-/-)) gene disrupted mice, correctly mapping Pgp-mediated transport activity at the capillary blood-brain barrier and hepatocellular biliary cannalicular surface in vivo. CONCLUSIONS: These results indicate that gallium(III) complex 6. is recognized by MDR1 Pgp as an avid transport substrate, thereby providing a useful scaffold to generate (68)Ga radiopharmaceuticals for molecular imaging of Pgp transport activity in tumors and tissues in vivo using PET.     

Electrical and optical characteristics of a multichannel N2-laser

The influence of electrical parameters on the optical properties of atmospheric pressure transversely excited N₂-lasers of the Blumlein-type is investigated. Experiments are performed using a multichannel laser system providing high repetition rate trains of nanosecond pulses (50 to 100 MHz). Both the high voltage rise and decay times of the order of several kV/ns are determined electro-optically and correlated with the intensity and time lag of the optical pulses. Using an injection technique the intensity and beam divergence could be markedly improved.     

Selective visible light reduction of carbon dioxide over iridium(III)-terpyridine photocatalysts

The CO₂ reduction reaction is an imperative piece of technology that closes the carbon cycle in many critical energy conversion and chemical manufacturing processes. Here, we report two new iridium (III) terpyridine-based photocatalysts capable of selective reduction of CO₂ to CO under visible light (λ ≥ 420 nm). The first photocatalyst, [Ir–COOH], was functionalized with the carboxyl group on the phenylpyridine, whereas the second, [Ir-PhCOOH], was attached to a phenyl spacer on the terpyridine. The [Ir-PhCOOH] was characterized by a higher extinction coefficient than [Ir–COOH], thus allowing more absorption of photons. Although both photocatalysts require two-electron activation, the [Ir-PhCOOH] is more readily activated as a result of the more negatively charged Ir center. These photocatalysts show exclusive selectivities in the production of CO. The turnover frequencies for [Ir–COOH] and [Ir-PhCOOH] were 19 and 10 h^?1, respectively, under visible light irradiation. The e-e-H-H pathway was identified as the most favorable, consisting of the rate-limiting step in the conversion of 1COOH to 1CO, and where the barrier is significantly lower for [Ir-PhCOOH] than for [Ir–COOH].     

Direct observation of single molecule conformational change of tight-turn paperclip DNA triplex in solution

DNA triplex modulates gene expression by forming stable conformation in physiological condition. However, it is not feasible to observe this unique molecular structure of large molecule with 54 oligodeoxynucleotides directly by conventional nuclear magnetic approach. In this study, we observed directly single molecular images of paperclip DNA triplexes formation in a buffer solution of pH 6.0 by atomic force microscopy (AFM). Meanwhile, a diffuse “tail” of unwound DNA was observed in pH 8.0 solution. This designable approach in visualizing the overall structures and shapes of oligo-DNAs at the single molecular level, by AFM, is applicable to other biopolymers as well.     

Proton-neutron final-state interaction in the reaction 2H(p,pp)n at 6.4, 10.0, 15.9, 19.85 and 25.8 MeV

This paper presents and analyzes the results of measurements of the proton-neutron final-state interaction (FSI) at 6.4, 10.0, 15.9, 19.85 and 25.8 MeV. At each energy nine angular combinations were measured and for each experiment the cross section was measured along the whole kinematic curve. The data are compared with the predictions of S-wave rank-one and rank-two separable potential models. The potentials used in one of the models reproduce the experimental S-wave N-N phase shifts. Fairly large differences between experiment and theory are found in the FSI regions and in the other regions of the kinematic curves. These disagreements cannot be attributed to off-shell effects. The inclusion of the tensor force and the P-wave N-N interaction in the calculations reduces the disagreements considerably at the higher energies. However, systematic differences of 10% to 20% remain.