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0090-9556/04/3209-983-992$20.00
DMD 32:983-992, 2004

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EFFECT OF POLY(ETHYLENE IMINE) MOLECULAR WEIGHT AND PEGYLATION ON ORGAN DISTRIBUTION AND PHARMACOKINETICS OF POLYPLEXES WITH OLIGODEOXYNUCLEOTIDES IN MICE

Dagmar Fischer, Berit Osburg, Holger Petersen, Thomas Kissel, and Ulrich Bickel

Department of Pharmaceutical Sciences, School of Pharmacy, Texas Tech University Health Sciences Center, Amarillo, Texas (D.F., B.O., U.B.); Department of Pharmaceutics and Biopharmacy, Philipps-University of Marburg, Marburg, Germany (D.F., T.K.); and Novartis Pharma AG, Basel, Switzerland (H.P.)

The in vivo body distribution and the pharmacokinetics of a 20mer double-stranded nuclear factor {kappa}B decoy oligodeoxynucleotide (ODN) complexed with 25-kDa poly(ethylene imine) (PEI), low molecular weight 2.7-kDa PEI, and PEGylated PEI [bPEI(25k)-glPEG(550)50] after intravenous injection were studied in BALB/c mice using a double-labeling technique to follow simultaneously the distribution of both complex components. The polymers were radioactively labeled with 125I by Bolton-Hunter reagent and the decoys with [{gamma}-32P]ATP by an enzymatic 5'-end-labeling technique. After i.v. bolus injections into the jugular vein, organ samples were taken after 15 min, 2 h and 12 h. For pharmacokinetic studies blood and plasma samples were collected from 20 s up to 2 h. Uncomplexed decoy was found to be degraded already after 15 min and was rapidly eliminated renally into urine. Complexation with the homopolymers increased the organ levels and circulation time of ODN after 15 min, with similar organ distribution profiles for 125I and 32P. In contrast to the behavior of free ODN, the complexes were mainly distributed into liver and spleen. Whereas the organ concentrations of 125I remained high over 12 h, the 32P values of ODN decreased in a time-dependent manner, likely due to separation of the complexes and degradation of the DNA. Although PEGylated PEI demonstrated a slower 125I-uptake into the RES organs compared with 25-kDa PEI due to the shielding effect of PEG [poly(ethylene glycol)], it was not able to better stabilize the complexes in the circulation or protect DNA from degradation.

Address correspondence to: Dr. Dagmar Fischer, Department of Pharmaceutics and Biopharmacy, Philipps-University, Ketzerbach 63, D-35032 Marburg/Lahn, Germany. E-mail: fischerd{at}staff.uni-marburg.de




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