Intravenous fate of poly(2-(dimethylamino)ethyl methacrylate)-based polyplexes.
The objective of this study was to assess the in vivo fate of poly(2-(dimethylamino)ethyl methacrylate) (pDMAEMA)-based polyplexes after intravenous administration into mice. Circulation kinetics and tissue distribution in terms of plasmid localization and transfection efficiency were assessed. To gain more insight into the observed biodistribution and gene expression profile, the interaction of pDMAEMA-based polyplexes with blood components (erythrocytes and albumin) was investigated in vitro. In the case of i.v. injection of positively charged polyplexes at a dose of 30 microg DNA most of the radioactivity was found in the lungs and the liver 60 min after injection. In the case of pDMAEMA/DNA polyplexes with a negative charge, uptake occurred mainly by the liver. Administration of positively charged complexes at a 30 microg DNA dose resulted in reporter gene expression primarily in the lungs. Injection of negatively charged complexes and naked plasmid did not result in luciferase expression in any of the organs examined. In vitro turbidity experiments showed the induction of a charge dependent aggregation process upon addition of albumin to the polyplexes pointing out to the involvement of aggregate formation in the dominant lung uptake of the positively charged polyplexes. Also, incubations of polyplexes after pre-incubation with a physiological concentration of albumin with washed erythrocytes confirmed that polyplexes induce the formation of extremely large structures. This paper underlines the need for the design of systems with reduced interaction with blood components to promote the delivery of DNA to target tissues outside the lungs.
Verbaan
Ferry
F
Department of Pharmaceutics, Utrecht Institute for Pharmaceutical Sciences (UIPS), Utrecht University, P.O. Box 80082, 3508 TB, Utrecht, The Netherlands.
van Dam
Inger
I
Takakura
Yoshinubu
Y
Hashida
Mitsuru
M
Hennink
Wim
W
Storm
Gert
G
Oussoren
Christien
C
D000818:Animals; D055598:Chemical Phenomena; D002627:Chemistry, Physical; D004247:DNA / Q000008:administration & dosage* / Q000493:pharmacokinetics; D004903:Erythrocyte Aggregation / Q000187:drug effects; D004912:Erythrocytes / Q000378:metabolism; D005260:Female; D015870:Gene Expression; D018014:Gene Transfer Techniques; D007275:Injections, Intravenous; D008156:Luciferases / Q000235:genetics; D008689:Methacrylates / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000494:pharmacology; D051379:Mice; D008807:Mice, Inbred BALB C; D009757:Nylons / Q000493:pharmacokinetics* / Q000494:pharmacology; D010316:Particle Size; D012709:Serum Albumin / Q000378:metabolism; D014018:Tissue Distribution; D014162:Transfection
D008689:Methacrylates; D009757:Nylons; D012709:Serum Albumin; C407037:poly(2-(dimethylamino)ethyl methacrylate); D004247:DNA; D008156:Luciferases