Mori Amika, Kobayashi Yuki, Nirasawa Kei, Negishi Yoichi, Asayama Shoichiro
Department of Applied Chemistry, Tokyo Metropolitan University, Hachioji, Tokyo 192-0397, Japan.
Department of Drug Delivery and Molecular Biopharmaceutics, Tokyo University of Pharmacy and Life Sciences, Hachioji, Tokyo 192-0392, Japan.
Pharmaceutics. 2021 Jan 8;13(1):78. doi: 10.3390/pharmaceutics13010078.
The structure-activity relationship of mono-ion complexes (MICs) for plasmid DNA (pDNA) delivery by muscular injection is demonstrated. MICs were formed between pDNA and monocationic poly(ethylene glycol) (PEG) macromolecules. As monocationic PEGs, the ω-amide-pentylimidazolium (APe-Im) end-modified PEGs with a stable amide (Am) and hydrolytic ester (Es) bond, that is, APe-Im-Am-PEG and APe-Im-Es-PEG, respectively, are synthesized. The difference between the APe-Im-Am-PEG and APe-Im-Es-PEG was only a spacer structure between a terminal cation and a PEG chain. The resulting pDNA MICs with APe-Im-Am-PEG at a charge ratio (+/-) of 32 or 64 were more stable than those with APe-Im-Es-PEG in the presence of serum proteins. The highest gene expression by muscular injection was achieved using the APe-Im-Am-PEG/pDNA MIC at a charge ratio (+/-) of 32 with a smaller particle diameter of approximately 50 nm, as compared to that charge ratio of 64. Consequently, the pDNA MIC with the monocationic PEG with a stable amide spacer, as compared to a hydrolytic ester spacer, is considered to be suitable for the highest gene expression by muscular injection.
本文展示了用于肌肉注射递送质粒DNA（pDNA）的单离子复合物（MICs）的构效关系。MICs由pDNA与单阳离子聚乙二醇（PEG）大分子形成。作为单阳离子PEG，合成了分别带有稳定酰胺（Am）键和水解酯（Es）键的ω-酰胺-戊基咪唑鎓（APe-Im）末端修饰的PEG，即APe-Im-Am-PEG和APe-Im-Es-PEG。APe-Im-Am-PEG和APe-Im-Es-PEG之间的差异仅在于末端阳离子与PEG链之间的间隔结构。在血清蛋白存在的情况下，电荷比（+/-）为32或64的含APe-Im-Am-PEG的pDNA MICs比含APe-Im-Es-PEG的更稳定。与电荷比为64相比，电荷比（+/-）为32且粒径约为50 nm的APe-Im-Am-PEG/pDNA MIC通过肌肉注射实现了最高的基因表达。因此，与具有水解酯间隔基的单阳离子PEG相比，具有稳定酰胺间隔基的单阳离子PEG的pDNA MIC被认为适合通过肌肉注射实现最高的基因表达。
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