ReviewToxicity of cationic lipids and cationic polymers in gene delivery
Introduction
Gene therapy has become a promising strategy for the treatment of many inheritable or acquired diseases that are currently considered incurable. The main objective in gene therapy is successful in vivo transfer of the genetic materials to the targeted tissues [1], [2], [3], [4]. However, naked therapeutic genes are rapidly degraded by nucleases and show poor cellular uptake, so that the development of safe and efficient gene carriers is one of the prerequisites for the success of gene therapy [3], [4], [5], [6].
Biological carriers are viruses, which are naturally evolved to infect cells and transfer their genetic materials into the host cells. Both RNA and DNA viruses have been evaluated as possible gene carriers. They are, however, difficult to produce and toxic (in particular immunogenic), as well as having a limitation in terms of the size of the inserted genetic materials [1], [2], [7]. In attempts to overcome these problems, non-viral vectors, such as cationic lipids and polymers, have been developed as gene carrier molecules. Non-viral vectors are advantageous due to the low immune response that enables repeated administration and the capability of large production with acceptable costs [1], [2], [8]. They have the potential to be widely used in clinic of gene therapy.
However, the present study is mainly focused on the experiments in vitro; toxicity is still an obstacle to the application of non-viral vectors to gene therapy [8], [9], [10], [11], [12], [13]. Toxicity, the capacity of a drug to damage or cause adverse effects in the body [14], is a dose-relative notion. We often evaluate toxicity with lethal dose, threshold dose and maximal no-effect dose. Toxicity effect can be classified into acute effect and delayed effect, and also can be local effect and systemic effect. Local toxicity refers to the adverse effect on the site of injection, while systemic toxicity refers to damage in other organs when the poison is distributed through circulation system in body. Cationic lipids and cationic polymers for gene delivery may cause toxic effect in vitro and in vivo. For example, lipoplexes caused several changes to cells, which included cell shrinking, reduced number of mitoses and vacuolization of the cytoplasm [15]. Certain proteins such as protein kinase C may also be affected detrimentally by cationic amphiphiles [16].
In the following sections, we will discuss the toxicity of main cationic gene vectors (cationic lipids and cationic polymers), emphasis is placed on the relationship between toxicity and structure of these compounds. We evaluate the structural features of cationic compounds and discuss which groups may increase the toxicity, what kind of linkages have relatively short half-life, and how proper modifications will decrease the toxicity of cationic lipids and cationic polymers for gene delivery.
Section snippets
Cationic lipids
In 1987, Felgner et al. [17] first reported the utilization of unnatural diether-linked cationic lipid, N-[1-(2,3-dioleyloxy)propyl]-N,N,N-trimethylammonium chloride (DOTMA), as a synthetic carrier to deliver gene into cells. Since then, a series of cationic lipids have been synthesized for gene delivery. In comparison with other gene delivery modes, such as viral vectors, cationic lipids are simple and quick to formulate, are not as biologically hazardous as viral vectors, are readily
Cationic polymers
Cationic polymer (at physiological pH) can be combined with DNA to form a particulate complex, polyplex, capable of gene transfer into the targeted cells [2]. The most obvious difference between cationic polymers and cationic lipids is that they do not contain a hydrophobic moiety and are completely soluble in water [54]. Compared with cationic liposomes, they have the obvious advantage of compressing DNA molecules to a relatively small size [55], [56]. This can be crucial for gene transfer, as
Discussion
Cationic lipids and cationic polymers are the most probable alternative to viral delivery systems and are increasingly being used in vitro and in vivo. However, in vivo nucleic acid delivery has been traditionally hindered by the toxicity associated with their formulations. In the past few years, modifications to commonly used delivery systems have been made and novel carrier systems have been developed to overcome this problem.
The toxic effect is mainly determined by the cationic nature of the
Acknowledgements
The authors of this paper gratefully thank the financial supports from the Education Bureau of Liaoning Province (20040084) and Postdoctoral Initiation Foundation of Dalian Nationalities University (249016).
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