Comprehensive analysis of the acute toxicities induced by systemic administration of cationic lipid: Plasmid DNA complexes in mice
Comprehensive analysis of the acute toxicities induced by systemic administration of cationic lipid: Plasmid DNA complexes in mice
复制标题
DOI：
10.1089/10430340050207984
复制
发表时间：
2000-12-01
影响因子：
4.2
通讯作者：
Scheule, RK
中科院分区：
文献类型：
--
作者：
Tousignant, JD;Gates, AL;Scheule, RK
与全身施用阳离子脂质：质粒DNA（pDNA）复合物相关的主要限制是在产生治疗相关水平的转基因表达所需的剂量下的载体毒性。对这些毒性的系统评价显示，静脉注射阳离子脂质：pDNA复合物的小鼠发生显著的剂量依赖性血液学和血清学变化，典型表现为严重的白细胞减少症、血小板减少症和血清转氨酶水平升高，提示肝细胞坏死。载体给药还诱导了强有力的炎症反应，其特征是补体激活和细胞因子IFN-γ、TNF-α、IL-6和IL-12的诱导。发现这些毒性是一过性的，在治疗后14天以不同的动力学消退至治疗前水平。观察到的毒性综合征是独立的阳离子脂质：pDNA的比例，阳离子脂质的种类，和达到的转基因表达水平。机制研究确定，补体级联反应和TNF-α均不是这些特征性毒性发生的关键介质。施用等效剂量的各个载体组分揭示了单独的阳离子脂质体或pDNA不产生用阳离子脂质：pDNA复合物观察到的毒性反应。仅中度白细胞减少症与单独施用阳离子脂质体或pDNA相关，而在pDNA处理的动物中仅观察到轻度血小板减少症。这些结果建立了一组客观参数，其可用于量化由全身施用阳离子脂质：pDNA复合物引起的急性毒性，这反过来提供了比较这些载体的治疗指数的手段。
A major limitation associated with systemic administration of cationic lipid: plasmid DNA (pDNA) complexes is the vector toxicity at the doses necessary to produce therapeutically relevant levels of transgene expression. Systematic evaluation of these toxicities has revealed that mice injected intravenously with cationic lipid: pDNA complexes develop significant, dose-dependent hematologic and serologic changes typified by profound leukopenia, thrombocytopenia, and elevated levels of serum transaminases indicative of hepatocellular necrosis. Vector administration also induced a potent inflammatory response characterized by complement activation and the induction of the cytokines IFN-gamma, TNF-alpha, IL-6, and IL-12. These toxicities were found to be transient, resolving with different kinetics to pretreatment levels by 14 days posttreatment. The toxic syndrome observed was independent of the cationic lipid: pDNA ratio, the cationic lipid species, and the level of transgene expression attained. Mechanistic studies determined that neither the complement cascade nor TNF-alpha were key mediators in the development of these characteristic toxicities. Administration of equivalent doses of the individual vector components revealed that cationic liposomes or pDNA alone did not generate the toxic responses observed with cationic lipid: pDNA complexes. Only moderate leukopenia was associated with administration of cationic liposomes or pDNA alone, while only mild thrombocytopenia was noted in pDNA-treated animals. These results establish a panel of objective parameters that can be used to quantify the acute toxicities resulting from systemic administration of cationic lipid: pDNA complexes, which in turn provides a means to compare the therapeutic indices of these vectors.