α,β-poly(asparthylhydrazide)–glycidyltrimethylammonium chloride copolymers (PAHy–GTA): novel polymers with potential for DNA delivery

• Published in: Journal of controlled release Vol. 77; no. 1; pp. 139 - 153
• Main Authors: Pedone, Elisa, Cavallaro, Gennara, Richardson, Simon C.W, Duncan, Ruth, Giammona, Gaetano
• Format: Journal Article
• Language: English
• Published: Amsterdam Elsevier B.V 09.11.2001; Elsevier
• Subjects: Animals; Biocompatibility; Biological and medical sciences; DNA - administration & dosage; Endodeoxyribonucleases - pharmacology; Epoxy Compounds - administration & dosage; Gene delivery; General pharmacology; Genetic Therapy; Glycidyltrimethylammonium chloride; Hemolysis - drug effects; Male; Medical sciences; Mice; Non-viral vector; Peptides - administration & dosage; Pharmaceutical technology. Pharmaceutical industry; Pharmacology. Drug treatments; Polycations; Quaternary Ammonium Compounds - administration & dosage; Rats; Rats, Wistar; Tissue Distribution; Transfection; Tumor Cells, Cultured; α,β-poly(asparthylhydrazide); Glycidyltrimethylammonium chloride; Gene delivery; α,β-poly(asparthylhydrazide); Biocompatibility; Non-viral vector; Polycations; Hemolysis; Pharmaceutical technology; Intravenous administration; Rat; Control release polymer; Toxicity; Rodentia; Molecular interaction; Drug carrier; In vitro; Plasmid; Hydrazide polymer; In vivo; Vertebrata; Mammalia; Transfection; Animal; DNA; Dosage form; Copolymer; Pharmacokinetics; Release; Ammonium Chlorides
• ISSN: 0168-3659; 1873-4995
• DOI: 10.1016/S0168-3659(01)00459-X

Hydrophilic polycations form complexes when mixed with plasmids. Following functionalisation with glycidyltrimethylammonium chloride (GTA) α,β-poly(asparthylhydrazide) (PAHy), a water-soluble synthetic macromolecule, becomes polycationic and potentially useful for systemic gene delivery. Initially the biocompatibility of PAHy and PAHy–GTA derivatives with different degrees of positive charge substitution were studied and it was shown that PAHy–GTA was neither haemolytic nor cytotoxicity up to 1 mg/ml. After intravenous injection 125I-labelled PAHy–GTA derivative containing 46 mol% (PAHy–GTA(b)) of trimethylammonium groups did not accumulate in the liver (4.1±0.9% of the recovered dose after 1 h) but was subjected to renal excretion (45±21% of the recovered dose was in the kidneys after 1 h). PAHy–GTA formed complexes with DNA (gel retardation) and they protected against degradation by DNase II. Finally the ability of the PAHy–GTA(b) derivative to mediate the transfection of HepG2 cells using the marker gene β-galactosidase was studied. The optimum plasmid/polymer mass ratio was examined in comparison to LipofectACE™, Lipofectin ® and polyethylenimine.