A family of cationic polyamides for in vitro and in vivo gene transfectionby Chengnan Zhang, Rong Jin, Peng Zhao, Chao Lin

Acta Biomaterialia

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Year
2015
DOI
10.1016/j.actbio.2015.04.025
Subject
Biotechnology / Biochemistry / Molecular Biology / Biomaterials / Biomedical Engineering

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Text

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Received 20 November 2014

Received in revised form 16 April 2015

Accepted 19 April 2015

Available online 25 April 2015

Keywords:

Polyamide

Disulfide

Polycondensation

Transfection

Stem cell elucidate their structural effects on gene transfection activity. To this end, a group of novel cationic polycationic polymers gain additional advantages including low immunogenicity, non-oncogenicity, relatively high gene-carrying capacity, large-scale production and low cost. Thus, a large number of cationic polymers such as 25 kDa branched polyethylenimine (BPEI) and poly(amido amine)s have been studied as polymeric gene delivery vectors recently [5]. These polymers can bind gene to form nanosized polyplexes and mediate their endosomal escape, nger trans ability than 25 kDa BPEI, over the past decade a lot of rese have been focused on the development of cationic polyme different chemical functionalities, thereby optimizing gene ery properties and obtaining enhanced transfection efficacy [6]. A typical work is the library of poly(amino ester)s prepared by

Michael-type addition reaction [7]. By screening the poly(amino ester)s with different functional side groups, aminobutanol was found as a hit structure which offered cationic polyesters with superior in vitro gene transfection activity to 25 kDa BPEI [8,9]. In the other work [10], poly(amido amine)s with the aminobutanol ⇑ Corresponding author. Tel.: +86 21 65988029; fax: +86 21 65983706 0.

E-mail address: chaolin@tongji.edu.cn (C. Lin).

Acta Biomaterialia 22 (2015) 120–130

Contents lists availab m sevmade to develop functionalized cationic polymers as non-viral gene delivery vectors [3]. Compared to potent viral vectors [4], of their relatively low transfection ability.

In order to develop cationic polymers with strohttp://dx.doi.org/10.1016/j.actbio.2015.04.025 1742-7061/ 2015 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.fection arches rs with deliv-1. Introduction

Gene therapy has been considered as an innovative method for the treatment of human being diseases such as cancer [1].

However, for successful gene therapy, the availability of low-toxic and highly efficient gene delivery vectors remains a huge challenge [2]. Over the past two decades, much effort has been thereby inducing detectable in vitro and in vivo transfection efficiency. Typically, 25 kDa BPEI has been regarded as one of the most potent polymeric gene carriers in vitro, being a gold standard when assessing in vitro transfection ability of cationic polymers.

Although linear polyethylenimine (LPEI) has been evaluated in clinical gene therapy trails, most of cationic polymer systems reported have not been advanced for clinical trials mainly becauseamides were synthesized by polycondensation reaction between different di-p-nitrophenyl esters and tertiary amine-containing primary diamines. These linear polyamides have flexible alkylene group (ethylene or propylene), protonable amino group and bioreducible disulfide linkage in the polyamide main chain. The alkylene group and disulfide linkage in these polyamides have a distinct effect on their gene delivery properties including buffering capacity, gene binding ability and intracellular gene release profile. Those cationic polyamides containing disulfide linkage and 1,4-bis(3-aminopropyl)piperazine (BAP) residue exhibited high buffering capacity (endosomal escape ability), high gene binding ability, and intracellular gene release ability, thus inducing fast gene nucleus translocation and robust gene transfection in vitro against different cell lines and rat bone marrow mesenchymal stem cells. Moreover, the transfection efficiencies in vitro were comparable or higher than those of 25 kDa branched polyethylenimine and

Lipofectamine 2000 transfection agent as positive controls. These cationic polyamides and their polyplexes were of low cytotoxicity when an optimal transfection efficacy was achieved. In vivo transfection tests showed that bioreducible BAP-based polyamides were applicable for intravenous gene delivery in a mouse model, leading to higher level of transgene expression in the liver as compared to 22 kDa linear polyethylenimine as a positive control. These cationic polyamides provide a useful platform to elucidate the relationship between chemical functionalities and gene transfection activity.  2015 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.Article history: The purpose of this study is to develop biodegradable cationic polyamides for non-viral gene delivery andA family of cationic polyamides for in vitr

Chengnan Zhang a, Rong Jin b, Peng Zhao a, Chao Lin a a Shanghai East Hospital, The Institute for Biomedical Engineering and Nanoscience, Ton of China b Institute of Nanochemistry and Nanobiology, Shanghai University, Shanghai 200444, P a r t i c l e i n f o a b s t r a c t

Acta Bio journal homepage: www.eland in vivo gene transfection niversity School of Medicine, Tongji University, Shanghai 200092, People’s Republic e’s Republic of China le at ScienceDirect aterialia ier .com/locate /ac tabiomat side group were also able to induce higher transfection efficacy than the BPEI in COS-7 cells. Furthermore, the transfection efficacy of these cationic polymers like poly(amido amine)s can be markedly augmented by integrating disulfide linkage into aliphatic segment because disulfide-based (bioreducible) poly(amido amine)s may facilitate intracellular gene release by the cleavage of disulfide bond inside the cytoplasm and nucleus which typically maintain a highly reducing condition [9,11]. Moreover, the biodegradability of bioreducible cationic polymers inside the cells endows their lower cytotoxicity compared to their counterparts without disulfide linkage. In addition to aminobutanol and disulfide linkage, other hit functionalities used for the design of potent polymeric gene delivery vectors largely encompass oligoamine, low-molecular weight such as buffering capacity, gene binding ability, endocytic pathway and intracellular gene release behavior. Structural effects of these cationic polyamides on their gene transfection activity were investigated in different cells. Moreover, in vivo gene transfection of these polyamides was evaluated by intravenous injection of their polyplexes in a mouse model. 2. Materials and methods 2.1. Materials