Structural investigations of novel triblock cationic copolymer/DNA complexes
A series of biodegradable triblock copolymers poly (ethylene glycol)-g-polyethylenimine-b-poly (dimethylaminoethyl l-glutamine) (PEG-g-PEI-b-PDMAEG) as novel vectors for gene therapy were synthesized and evaluated. Poly (ethylene glycol)-g-polyethylenimie
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School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou, China 2 The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China
Abstract — A series of biodegradable triblock copolymers poly (ethylene glycol)-g-polyethylenimine-b-poly (dimethylaminoethyl l-glutamine) (PEG-g-PEI-b-PDMAEG) as novel vectors for gene therapy were synthesized and evaluated. Poly (ethylene glycol)-g-polyethylenimiene (PEG-g-PEI) was firstly obtained by linking of PEG and PEI using isophorone diisocyanate (IPDI) as coupling reagent. The anionic copolymerization of Ȗ-benzyl l-glutamtae N-carboxyanhydride (BLG-NCA) using PEG-g-PEI as a macroinitiator was carried out, followed by aminolysis with 2-dimethylaminoethylamine to obtain the target water soluble triblock copolymer. The structures from PEG-g-PEI precursor to the triblock copolymers were confirmed by FT-IR. The particle sizes, zeta potentials of polyplexes were evaluated. All polyethylenimine derivates were revealed to compact plasmid DNA effectively to give polyplexes with suitable size (~100 nm) and moderate ȗ-potentials (10-15 mV) at N/P ratios of 30. The relationship between the composition of PEG-g-PEI-b-PDMAEG and the size, the ȗpotentials of corresponding copolymer/DNA complexes were also investigated. Keywords — Polyethylenimiene, poly (ethylene glycol, cationic polymer, cytotoxicity, gene delivery.
I. INTRODUCTION Gene therapy has been regarded as the promising and ultimate cure for many life-threatening diseases, acquired and inherited, such as AIDS, cancer, genetic disordered etc [1] and [2]. To achieve successful gene therapy, development of proper gene delivery systems should be one of the most significant factors [3] and [4]. Among non-viral carriers, polyethylenimine (PEI) has been one of the most widely studied synthetic cationic gene vectors due to its superior transfection efficiency [3] and [4]. The high transfection efficiency of PEI/DNA complexes is attributed to the unique capacity of PEI to buffer endosomes according to “proton sponge hypothesis”. Nevertheless, the use of PEI both in vitro and vivo remains limited due to its low colloidal stability and considerable cytotoxic effects [4]. In the past several years, many studies attempted to modify PEI with poly(ethylene glycol) (PEG) to decrease its cytotoxicity due to the shielding effect of the high positive charges of PEI [8] and [9]. However, the “stealth” effect of PEG often leads to a diminished transfection ascribing to
decreased cellular association and internalization. Additionally, PEGylated PEI complex is incapable to compress DNA effectively into small particles [4]. It is reported that large complex particles are difficult to be cellular uptake resulting in low transfection efficiency [6]. Recently, employing new block to PEI to improve its transfection efficiency has been actively pursued. Tian and co-workers designed novel gene vector by introducing hydrophobic amino acid segment poly(Ȗ-benzyl l-glutamate) at the PEI chain ends for enhancement of gene transfer [6]. M.P. Xio
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