Institute of Medicinal Chemistry, Hoshi University, Tokyo, Japan.
J Drug Target. 2013 Aug;21(7):639-47. doi: 10.3109/1061186X.2013.789035. Epub 2013 Apr 17.
In this study, we developed an anionic lipoplex by coating cationic lipoplex with anionic polymers such as hyaluronan (HA), chondroitin sulfate C (CS) and poly-l-glutamic acid (PLE) to deliver the plasmid DNA efficiently into the tumor by avoiding interaction with erythrocytes. The sizes of HA-, CS- and PLE-coated lipoplexes were ∼200 nm and the ζ-potentials were negative. CS- and PLE-coated lipoplexes did not induce agglutination after mixing with erythrocytes, but cationic and HA-coated lipoplexes exhibited agglutination. In terms of biodistribution and gene expression after intravenous administration, cationic and HA-coated lipoplexes largely accumulated and induced gene expression in the lung. In contrast, CS- and PLE-coated lipoplexes did not exhibit high gene expression in the lung and mainly accumulated in the liver. However, in tumor, differences in lipoplex accumulation and gene expression were not observed among the lipoplexes. In terms of toxicity after intravenous injection, CS- and PLE-coated lipoplexes did not increase tumor necrosis factor-α, aspartate aminotransferase and alanine aminotransferase concentrations in blood. From these findings, CS and PLE coatings for cationic lipoplex might produce safe systemic vectors, although they did not increase gene expression in tumor.
在这项研究中，我们通过用阴离子聚合物如透明质酸（HA）、硫酸软骨素 C（CS）和聚谷氨酸（PLE）包覆阳离子脂质体，开发了一种阴离子脂质体，以避免与红细胞相互作用，将质粒 DNA 有效地递送到肿瘤中。HA、CS 和 PLE 包覆的脂质体的粒径约为 200nm，ζ-电位为负。CS 和 PLE 包覆的脂质体与红细胞混合后不会引起聚集，但阳离子和 HA 包覆的脂质体则会引起聚集。在静脉给药后的体内分布和基因表达方面，阳离子和 HA 包覆的脂质体大量积聚并在肺部诱导基因表达。相比之下，CS 和 PLE 包覆的脂质体在肺部没有表现出高基因表达，主要在肝脏中积聚。然而，在肿瘤中，脂质体的积聚和基因表达没有观察到差异。就静脉注射后的毒性而言，CS 和 PLE 包覆的脂质体不会增加血液中肿瘤坏死因子-α、天冬氨酸转氨酶和丙氨酸转氨酶的浓度。从这些发现可以看出，CS 和 PLE 包覆阳离子脂质体可能产生安全的全身载体，尽管它们没有增加肿瘤中的基因表达。
