title: Application of polyglycerol coating to plasmid DNA lipoplex for the evasion of the accelerated blood clearance phenomenon in nucleic acid delivery.
abstract: Cationic liposomes (CLs) have shown promise as nonviral delivery systems. To achieve in vivo stability and long circulation, most liposomes are modified with hydrophilic polymer polyethylene glycol (PEG). However, we have reported that repeated administration of PEG-coated CLs containing plasmid DNA (pDNA; PEGylated lipoplexes) induces what is referred to as "the accelerated blood clearance (ABC) phenomenon" and, consequently, subsequently administered lipoplexes lose their prolonged circulation characteristics. Anti-PEG IgM produced in response to the first dose of PEG-coated pDNA-lipoplexes (PEG-DCL) has proven to be a major cause of the ABC phenomenon. In this study, to evade and/or attenuate this unexpected immune response, we modified the surface of a lipoplex with polyglycerol (PG)-derived lipid. The PG-coated pDNA-lipoplex (PG-DCL) attenuated the production of anti-polymer IgM, whereas PEG-coated pDNA-lipoplex (PEG-DCL) did not. In addition, a second dose of PG-DCL maintained the accumulation level in the tumor tissue of a tumor-bearing mouse model, comparable to that of the first dose, whereas the tumor accumulation level of a second dose of PEG-DCL was significantly compromised, compared with the first dose of PEG-DCL. Our results indicate that surface modification of lipoplex with PG represents a viable means for the attenuation, and/or evasion, of the ABC phenomenon that is encountered upon repeated administrations of nucleic acids containing PEG-coated nanocarriers.
authors.affiliation: Department of Pharmacokinetics and Biopharmaceutics, Subdivision of Biopharmaceutical Sciences, Institute of Health Biosciences, The University of Tokushima, Tokushima, 770-8505, Japan; Department of Pharmaceutics and Industrial Pharmacy, Faculty of Pharmacy, Zagazig University, Zagazig, Egypt.
authors.forename: Amr S
authors.initials: AS
authors.lastname: Abu Lila
authors.forename: Yumi
authors.initials: Y
authors.lastname: Uehara
authors.forename: Tatsuhiro
authors.initials: T
authors.lastname: Ishida
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Kiwada
mesh_terms: D000818:Animals; D000963:Antimetabolites; D001402:B-Lymphocytes / Q000378:metabolism; D001973:Bromodeoxyuridine; D049109:Cell Proliferation / Q000187:drug effects; D016207:Cytokines / Q000378:metabolism; D004247:DNA / Q000008:administration & dosage* / Q000737:chemistry; D004337:Drug Carriers / Q000737:chemistry*; D016503:Drug Delivery Systems; D005079:Excipients; D005456:Fluorescent Dyes; D015316:Genetic Therapy / Q000379:methods*; D005990:Glycerol / Q000737:chemistry*; D007075:Immunoglobulin M / Q000032:analysis / Q000096:biosynthesis; D008081:Liposomes / Q000737:chemistry*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D009368:Neoplasm Transplantation; D010957:Plasmids / Q000097:blood / Q000235:genetics*; D011092:Polyethylene Glycols / Q000737:chemistry; D011108:Polymers / Q000737:chemistry*; D051381:Rats; D017208:Rats, Wistar
chemical_list: D000963:Antimetabolites; D016207:Cytokines; D004337:Drug Carriers; D005079:Excipients; D005456:Fluorescent Dyes; D007075:Immunoglobulin M; D008081:Liposomes; D011108:Polymers; C043941:polyglycerol; D011092:Polyethylene Glycols; D004247:DNA; D001973:Bromodeoxyuridine; D005990:Glycerol
keywords: PEGylation; accelerated blood clearance (ABC) phenomenon; anti-PEG IgM; clearance; lipoplexes; non-viral gene delivery; plasmid DNA (pDNA); polyethylene glycol (PEG); polyglycerol (PG)