The tissue biodistribution and expression of [33P]DNA-1-[2-[9-(Z)-octadecenoyloxy]ethyl]]-2-[8](Z)-heptadece nyl]-3 -[hydroxyethyl]imidazolinium chloride (DOTIM):cholesterol complexes and 33P-radiolabeled DNA expressing chloramphenicol acetyl transferase (CAT; 4.7 kB) were studied after intravenous (iv) injection in ICR mice. Mice were injected with 200 microL of complex containing DNA at 3 mg/kg or DNA alone. One group received 8 microCi of radioactivity and were sacrificed at 5 and 20 min, and 1, 2, 4 and 24 h post-dose (n = 4/time point). A second group received the equivalent of 3.9 microCi of radioactivity and were sacrificed at 20 min, and 2 and 24 h for subsequent whole body autoradiographic analysis (WBA; n = 2/time point). The tissue distribution of intact DNA was assessed by Southern blot at 24 h post-dose, whereas the integrity of complexes and DNA incubated in heparinized whole blood was studied separately. In further studies, the time course of expression in lung tissue over a 48-h period was examined, and the relative lung-expression of purified open circular (OC) versus supercoiled (SC) DNA at 24 h was evaluated. Approximately 42% of the radioactivity was found in the lungs 5 min after injection and about half this percentage was found in the liver. By 2 h, only 5% remained in the lungs, but 48% was present in the liver. No other tissue accumulated >5% of the dose throughout the duration of the study. WBA radiograms confirmed the tissue distribution results and highlighted significant accumulation of radioactivity in bone over time. Southern Blot analysis demonstrated intact DNA in many tissues 24 h after dosing. In contrast, the majority of DNA incubated in blood was degraded within 2 h, although the complexes afforded some protection relative to DNA alone. The OC DNA expressed equivalently to SC DNA in lung tissue (OC = 1035 +/- 183 pg; SC = 856 +/- 257 pg/mg soluble protein, n = 6, mean +/- SEM) at 24 h, and detectable levels of CAT were present within 2 h of dosing (21.3 +/- 7.2 pg, n >/= 8, mean +/- SD). The results confirm that DNA-DOTIM:cholesterol complexes are initially deposited in the lungs after iv administration.
A Yo hv [hS PhS = I Ph a) [Cp(Co)~Feh, hv b) CrS04, 0 "C a) 65 o/o C) 78 Yo 1 -p h +~+ & I b) 10 % Me The development of new, selective )-NHNH~ ~
An uncomplexed liposome population exists within DOTIM:cholesterol-DNA complexes that influences the expression of complexes administered i.v. but not i.t..
ZUSCHRIFTEN[6] Die diastereoselektive Radikal-Radikal-Redktion eines chirdlen Nitroxyl-Radikals mit einem prochiralen Kohlenstoffrddikal wurde kiirzlich beschriehen: R. Braslau, L. Burrill, L. Mahdl, T. Wedeking, Ahsrr. Pap. 7th In!. Symp. Org. Free Radicals, Bardolino, 1996, S . 45. Schumann a]. berichteten iiber die enantioselektive Reduktion yon tertiaren Halogenalkanen mit chirdlen Diorganoalkoxyzinnhydriden: H. Schumann, B. Pachaly, B. C. Schiitze, J. Orgunomet. Chem. 1984, 265, 145-152. Reagens unter selektiver Bildung cines neuen stereogenen Zentrums reagiert. wir haben uns daher mit der Fahigkeit nichtgebundener optisch aktiver Reagentien beschaftigt, zwischen den beiden Seiten eines prochiralen Radikals zu unterscheiden (Schema 1). Nitroxylradikale sind kinetisch stabile Spezies,['' Zinnhydride mit Zinn als einzigem Chiralitatszentrum racemisieren unter den Bedingungen einer Radikalkettenreaktion: a) M. Gielen, Y Tondeur, J. Orgunomef. Chem. 1979, 169, 265-281; b) M. Gielen, Pure Appl. Chem. 1980,52, 657-667. J. 0. Metzger, K. Schwarzkopf, M. Blumenstein, 25. Huuptversammlung der Gesdschafr Deutscher Chemiker, Miinster, Kurzreferate, S. 403; J. 0. Metzger, M. Blumenstein, A. Hayen, K. Schwarzkopf, Abstr. Pap. 7rh Inr. Symp. Org. Free Radicals, Bardolino, 1996, S. 124. Uber die enantioselektive Abstraktion von Wasserstoffatomen durch chirale Radikale von chirdlen, racemischen Substraten wurde berichtet: H:S. Dang, V. Diart, B. P. Roberts, D. Kiirzlich wurde unabhangig von und gleichzeitig mit uns iiber die Synthese eines Bhnlichen chirdlen Zinnhydrids mit einem C,-symmetrischen Binaphthylsubstituenten auf einem anderen Weg und seinen Einsatz in der endntioselektiven Reduktion eines a-Bromketons (10-41 YO ee) berichtet: D. P. Curran, D. Nanni, Ahstr. Pup. 7th Inl. Sq'mp. bSchema 1. Annaherung eines optisch aktiven Reagens R* an die beiden enantiotopen Seiten eines prochialen Kohlenstoffradikals.
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