期刊
BIOCHIMICA ET BIOPHYSICA ACTA-BIOMEMBRANES
卷 1669, 期 2, 页码 155-163出版社
ELSEVIER SCIENCE BV
DOI: 10.1016/j.bbamem.2005.02.001
关键词
gene therapy; stabilized plasmid lipid particle; systemic drug delivery; poly(ethylene glycol-lipid conjugated; lipid exchange
Stabilized plasmid lipid particles (SPLP) consist of a single copy of DNA surrounded by a lipid bilayer, The particles are small (similar to 100 nm), stable, monodisperse and have a low surface charge. A diffusible polyethylene glycol (PEG) coating attached to a lipid anchor is critical to the SPLP's functionality. The PEG-lipid exchanges out of the bilayer at a rate determined by the size of the lipid anchor. Here we show that SPLP can be prepared using a series of PEG-diacylglycerol lipids (PEG-S-DAGs). SPLP were prepared incorporating PEG-dimyristoylglycerol (C-14), PEG-dipalmitoylglycerol (C-16) or PEG-distearoylglycerol (C-18) and the rate of PEG-lipid diffusion from the bi-layer determined using a FRET assay. SPLP pharmacokinetics confirm a correlation between the stability of the PEG-lipid component and circulation lifetime. PEG-S-DAGs with longer lipid anchors yield more stable SPLP particles with longer circulation half-lives yielding an increase in tumor delivery and gene expression. PEG-distearoylglycerol (C Is) containing SPLP bypass so-called 'first pass' organs, including the lung, and elicit levels of gene expression in distal tumor tissue 100- to 1000-fold greater than that observed in any other tissue. The incorporation of PEG-S-DAG in SPLP confirms that small size, low surface charge and extended circulation lifetimes are prerequisite to the accumulation and tumor selective expression of plasmid DNA following systemic administration. (C) 2005 Elsevier B.V. All rights reserved.
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