Steric stabilization of poly-L-Lysine/DNA complexes by the covalent attachment of semitelechelic poly[N-(2-hydroxypropyl)methacrylamide].
The concept of steric stabilization was utilized for self-assembling polyelectrolyte poly-L-lysine/DNA (pLL/DNA) complexes using covalent attachment of semitelechelic poly[N-(2-hydroxypropyl)methacrylamide] (pHPMA). We have examined the effect of coating of the complexes with pHPMA on their physicochemical stability, phagocytic uptake in vitro, and biodistribution in vivo. The coated complexes showed stability against aggregation in 0.15 M NaCl and reduced binding of albumin, chosen as a model for the study of the interactions of the complexes with plasma proteins. The presence of coating pHPMA had no effect on the morphology of the complexes as shown by transmission electron microscopy. However, results of the study of polyelectrolyte exchange reactions with heparin and pLL suggested decreased stability of the coated complexes in these types of reactions compared to uncoated pLL/DNA complexes. Coated complexes showed decreased phagocytic capture by mouse peritoneal macrophages in vitro. Decreased phagocytosis in vitro, however, did not correlate with results of in vivo study in mice showing no reduction in the liver uptake and no increase in the circulation times in the blood. We propose that the rapid plasma elimination of coated pLL/DNA complexes is a result of binding serum proteins and also of their low stability toward polyelectrolyte exchange reactions as a consequence of their equilibrium nature.
Oupický
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D
CRC Institute for Cancer Studies, University of Birmingham, Birmingham B15 2TA, UK. davido@cancer.bham.ac.uk
Howard
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KA
Konák
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C
Dash
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PR
Ulbrich
K
K
Seymour
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LW
D000818:Animals; D004247:DNA / Q000737:chemistry* / Q000493:pharmacokinetics; D005260:Female; D008099:Liver / Q000378:metabolism; D008264:Macrophages / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D008854:Microscopy, Electron; D015394:Molecular Structure; D011107:Polylysine / Q000737:chemistry* / Q000493:pharmacokinetics; D011109:Polymethacrylic Acids / Q000737:chemistry*; D014018:Tissue Distribution
D011109:Polymethacrylic Acids; D011107:Polylysine; C011533:Duxon; D004247:DNA