Stabilized plasmid-lipid particles: Pharmacokinetics and plasmid delivery to distal tumors following intravenous injection
Stabilized plasmid-lipid particles: Pharmacokinetics and plasmid delivery to distal tumors following intravenous injection
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DOI：
10.3109/10611860009102218
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发表时间：
2000-01-01
影响因子：
4.5
通讯作者：
Scherrer, P
中科院分区：
文献类型：
--
作者：
Monck, MA;Mori, A;Scherrer, P
先前的一项研究表明，质粒DNA可以被包裹在直径约70 nm的脂质颗粒（SPLP，“稳定质粒脂质颗粒”）中，该脂质颗粒由1,2-二酰-3-磷脂酰-乙醇胺（DOPE）、阳离子脂质N、N-二酰-N、N-二甲基氯化铵（DODAC）和聚乙二醇偶联神经酰胺（PEG-Cer）组成，使用洗涤剂透析过程（Wheeler等人（1999）基因治疗6,271-281）。在这项工作中，我们评估了这些SPLPs作为系统基因治疗载体的潜力，确定了它们的药代动力学和质粒和脂质成分的生物分布。结果表明，作为聚乙二醇聚合物的脂质锚点的神经酰胺基团的酰基链长可以调节SPLPs的清除和生物分布。PEG-CerC（14）和PEG-CerC（20）的splp循环寿命分别为t(1/2) = 1和10 h。与PEG-CerC(20) SPLPs相比，PEG-CerC（14）对SPLPs的加速清除伴随着肝脏和脾脏SPLPs积累的增加。检测完整质粒递送至肝脏和脾脏的情况。静脉注射后，观察到含有PEG-CerC（20）的长循环SPLPs在远端肿瘤（小鼠侧腹Lewis肺肿瘤）中显著积累（约占注射剂量的10%），并以约6%的注射剂量/g组织将完整的质粒递送到肿瘤组织。
A previous study has shown that plasmid DNA can be encapsulated in lipid particles (SPLP, "stabilized plasmid lipid particles") of approximately 70 nm diameter composed of 1,2-dioleoyl-3-phosphatidyl-ethanolamine (DOPE), the cationic lipid N,N-dioleoyl-N,N-dimethylammonium chloride (DODAC) and poly(ethylene glycol) conjugated to ceramide (PEG-Cer) using a detergent dialysis process (Wheeler et al. (1999) Gene Therapy 6, 271-281). In this work we evaluated the potential of these SPLPs as systemic gene therapy vectors, determining their pharmacokinetics and the biodistribution of the plasmid and lipid components. It is shown that the brood clearance and the biodistribution of the SPLPs can be modulated by varying the acyl chain length of the ceramide group used as lipid anchor for the PEG polymer. Circulation lifetimes observed for SPLPs with PEG-CerC(14) and PEG-CerC(20) were t(1/2) = similar to 1 and similar to 10 h, respectively. The SPLPs are stable while circulating in the blood and the encapsulated DNA is fully protected from degradation by serum nucleases, The accelerated clearance of SPLPs with PEG-CerC(14) is accompanied by increased accumulation in liver and spleen as compared to PEG-CerC(20) SPLPs. Delivery of intact plasmid to liver and spleen was detected. Significant accumulation (approximately 10% of injected dose) of the long circulating SPLPs with PEG-CerC(20) in a distal tumor (Lewis lung tumor in the mouse flank) was observed following iv application and delivery of intact plasmid to tumor tissue at approximately 6% injected dose/g tissue is demonstrated.