Molecular hurdles in polyfectin design and mechanistic background to polycation induced cytotoxicity

被引:412
作者
Hunter, A. Christy [1 ]
机构
[1] Univ Brighton, Sch Pharm & Biomol Sci, Mol Targeting & Polymer Toxicol Grp, Brighton BN2 4GJ, E Sussex, England
关键词
polyfectin; polymer toxicity; gene therapy; apoptosis; MTT assay; poly(ethylenimine); poly(L-lysine); biodegradable polymer; gene transfection;
D O I
10.1016/j.addr.2006.09.008
中图分类号
R9 [药学];
学科分类号
1007 ;
摘要
Synthetic polymer based Polyfectins (cationic polymer-DNA complex) have received intensive scientific research as they can potentially circumvent problems associated with viral vectors for gene therapy. These cationic macromolecules can readily condense DNA or RNA into stable nanostructures for use in gene delivery. Recently two commonly used polycations, poly (ethylenimine) (PEI) and poly(L-lysine) have demonstrated their ability to induce apoptosis in a range of human cell lines. This may be the explanation for short-term gene transfection observed with polyfectins. It is the aim of this review to discuss these and other factors behind observed toxicities including the inherent polydisperse nature of polymeric macromolecules and their behaviour in vivo. Strategies for reduction of toxicity are included such as new polymeric synthetic technologies and vector pegylation. There is a clear and immediate need for understanding of the mechanisms which cause polyfectin toxicity which will ultimately facilitate improved vector design and safer gene delivery. (c) 2006 Elsevier B.V. All rights reserved.
引用
收藏
页码:1523 / 1531
页数:9
相关论文
共 112 条
[31]   Report of a second serious adverse event in a clinical trial of gene therapy for X-linked severe combined immune deficiency (X-SCID) - Position of the European Society of Gene Therapy (ESGT) [J].
Gansbacher, B .
JOURNAL OF GENE MEDICINE, 2003, 5 (03) :261-262
[32]   Evaluation of polyplexes as gene transfer agents [J].
Gebhart, CL ;
Kabanov, AV .
JOURNAL OF CONTROLLED RELEASE, 2001, 73 (2-3) :401-416
[33]   Nanoscopic cationic methacrylate star homopolymers: Synthesis by group transfer polymerization, characterization and evaluation as transfection reagents [J].
Georgiou, TK ;
Vamvakaki, M ;
Patrickios, CS ;
Yamasaki, EN ;
Phylactou, LA .
BIOMACROMOLECULES, 2004, 5 (06) :2221-2229
[34]   Tracking the intracellular path of poly(ethylenimine)/DNA complexes for gene delivery [J].
Godbey, WT ;
Wu, KK ;
Mikos, AG .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 1999, 96 (09) :5177-5181
[35]   Cytochrome c release occurs via Ca2+-dependent and Ca2+-independent mechanisms that are regulated by Bax [J].
Gogvadze, V ;
Robertson, JD ;
Zhivotovsky, B ;
Orrenius, S .
JOURNAL OF BIOLOGICAL CHEMISTRY, 2001, 276 (22) :19066-19071
[36]   Evaluation of hepatic subcellular fractions for Alamar blue and MTT reductase activity [J].
Gonzalez, RJ ;
Tarloff, JB .
TOXICOLOGY IN VITRO, 2001, 15 (03) :257-259
[37]   Pro-apoptotic Bid induces membrane perturbation by inserting selected lysolipids into the bilayer [J].
Goonesinghe, A ;
Mundy, ES ;
Smith, M ;
Khosravi-Far, R ;
Martinou, JC ;
Esposti, MD .
BIOCHEMICAL JOURNAL, 2005, 387 :109-118
[38]   Kinetics of living radical polymerization [J].
Goto, A ;
Fukuda, T .
PROGRESS IN POLYMER SCIENCE, 2004, 29 (04) :329-385
[39]   Polyethylenimine-based intravenous delivery of transgenes to mouse lung [J].
Goula, D ;
Benoist, C ;
Mantero, S ;
Merlo, G ;
Levi, G ;
Demeneix, BA .
GENE THERAPY, 1998, 5 (09) :1291-1295
[40]   A serious adverse event after successful gene therapy for X-linked severe combined immunodeficiency [J].
Hacein-Bey-Abina, S ;
von Kalle, C ;
Schmidt, M ;
Le Deist, F ;
Wulffraat, N ;
McIntyre, E ;
Radford, I ;
Villeval, JL ;
Fraser, CC ;
Cavazzana-Calvo, M ;
Fischer, A .
NEW ENGLAND JOURNAL OF MEDICINE, 2003, 348 (03) :255-256