Long-circulating DNA-complexed biodegradable multiblock copolymers for gene delivery: degradation profiles and evidence of dysopsonization.
Biodegradable cationic polymers have become promising alternatives to traditional polycationic gene delivery systems in which the high charge densities of high molecular weight polymers contribute significantly to cellular toxicities. Previous research has shown that biodegradable, multiblock copolymers (MBC), PEG-PLL-g-16% His, are efficient gene carriers with negligible cellular toxicities. The present research was designed to characterize the polymer degradation as well as to determine the biodistribution of the MBC after systemic administration. Polymer degradation was performed in buffer as a function of pH, in serum and within polymer/pDNA complexes. The MBC exhibited exponential decay with a half-life (t1/2) of approximately 14 min at pH 9.0, approximately 5 h at pH 7.4 and approximately 2 h in serum. However, there was little or no degradation observed at pH 4.0 and the MBC within the complexes degraded between 4 and 8 h in serum. Biodistribution data performed with fluorescently labeled polymer and pDNA revealed that intact complexes remained in the blood up to 3 days, which was also reflected in the organs as a function of time. Therefore, the cumulative data suggest that PEG may be sterically stabilizing complexes in vivo via dysopsonization in which serum proteins mask the complexes from elements of the reticuloendothelial system (RES).
Bikram
Malavosklish
M
Center for Controlled Chemical Delivery (CCCD), Department of Pharmaceutics and Pharmaceutical Chemistry, University of Utah, Biomedical Polymers Research Building, Room 205, Salt Lake City, UT 84112-5820, USA. MBikram@m.cc.utah.edu
Lee
Minhyung
M
Chang
Chien-Wen
CW
Janát-Amsbury
Margit-María
MM
Kern
Steven E
SE
Kim
Sung Wan
SW
D000818:Animals; D001711:Biotransformation; D004247:DNA / Q000008:administration & dosage / Q000097:blood* / Q000235:genetics*; D004337:Drug Carriers / Q000008:administration & dosage; D005260:Female; D018014:Gene Transfer Techniques; D051379:Mice; D008807:Mice, Inbred BALB C; D011108:Polymers / Q000008:administration & dosage* / Q000378:metabolism
D004337:Drug Carriers; D011108:Polymers; D004247:DNA