Implications of pharmacokinetic behavior of lipoplex for its inflammatory toxicity
Introduction
Cationic lipids are the most extensively studied nonviral vectors for gene delivery. This kind of vectors, in virtue of their positive charges, is capable of complexing with negatively charged DNA. The resulting cationic liposome/DNA complex (lipoplex) has shown a great promise in introduction of DNA into cells both in vitro and in vivo [1], [2]. Several lipoplex formulations have been evaluated in clinical treatment of cancer [3], [4] and cystic fibrosis [5], [6], [7]. Specially, systemic administration of lipoplex symbolizes a progress in the development of liposomal vectors, which could efficiently express a therapeutic gene in the lung in animal models, as well as other major organs with moderate levels of gene expression [8], [9], [10], [11]. However, the application of lipoplex has been complicated by the occurrence of acute inflammatory toxicity, which was observed in animal studies and human clinical trials at effective dose [12]. Further improvements in the nonviral gene delivery formulations rely on understanding the lipoplex-associated inflammatory toxicity [13]. Currently, many studies have focused on exploring the mechanism of the inflammatory toxicity and looking for means to overcome the toxicity [12]. A valuable progress has been made in understanding the lipoplex-induced the immune response [14]; thereafter, several strategies have been successful in animal models [12].
In this review, we provide an overview of the understanding of systemic lipoplex-induced inflammatory toxicity. Emphasis is placed on the discussion of the correlation between the pharmacokinetic behavior of DNA and the inflammatory toxicity by comparing the differences in the pharmacokinetics of DNA following lipoplex injection and sequential injection. Sequential injection is one of the strategies used to ablate diminish the toxicity associated with the application of cationic liposomes for gene transfection in vivo [15]. This review intends to provide a more comprehensive understanding of the relationship between the pharmacokinetic behavior of lipoplex and their inflammatory toxicity. We also want to demonstrate the usefulness of pharmacokinetics in evaluating the benefit of a novel gene delivery system.
Section snippets
General observations on the lipoplex-induced toxicity
Little toxicity was observed, in early studies, when lipoplex was administered in moderate doses by either local or systemic injection [12]. However, mortality occurs in animals after systemic administration of several cationic lipid-based gene delivery systems at high dose [9], [11], [16]. The systemic toxicity of lipoplex has been comprehensively studied, in which various cationic lipids were explored, such as GL-67, GL-62, DMRIE, DOTMA, DOTAP [17], [18], [19]. The toxicities observed in
Biodistribution of DNA delivered via lipoplex
While it is clear that CpG motifs in the plasmid DNA contribute to the inflammatory toxicity of lipoplex, it is also important to understand the biodistribution of plasmid DNA after lipoplex injection. The methods for monitoring plasmid DNA include Southern blotting, PCR analysis and isotope tracking of 32P- or 125I-labeled plasmid DNA [9], [47], [48], [49]. Although the organ distribution of DNA varies with different cationic lipids, a general distribution profile can be illustrated in Table 1
Reduction in inflammatory toxicity with sequential injection
The normal practice of gene transfer by cationic liposome in vivo involves mixing plasmid DNA and cationic liposome to form a complex, i.e., lipoplex, and then inject the complex into the test animal. However, it was reported by Song et al. that equal or higher level of gene expression in the lung could be obtained if one injected cationic liposome first, a few minutes later, injected DNA [72]. Later, it was found by our laboratory that this sequential injection method, with an optimized
Conclusions
Pharmacokinetic studies can provide us with useful information about the mechanisms underlying inflammatory toxicity associated with the systemic administration of lipoplex. We assume that opsonization of lipoplex by certain serum proteins may assist the immunostimulatory plasmid DNA in being selectively guided to Kupffer cells; therein resulting in high level of cytokine induction. As a successful example of minimizing the inflammatory toxicity, sequential injection of liposomes and DNA leads
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