Absorption of antisense oligonucleotides in rat intestine: Effect of chemistry and length
Absorption of antisense oligonucleotides in rat intestine: Effect of chemistry and length
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DOI：
10.1089/oli.1.2000.10.35
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发表时间：
2000-02-01
期刊：
影响因子：
--
通讯作者：
Geary, RS
中科院分区：
文献类型：
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作者：
Khatsenko, O;Morgan, R;Geary, RS
采用原位单次灌流模型，观察化学修饰和长度对不同寡核苷酸在大鼠肠内通透性和吸收的影响。将磷硫代寡脱氧核苷酸（PS-ODN）与2'-甲氧基乙基（MOE）或2'- o -甲基（OMe）修饰的寡核苷酸进行了比较。在该模型中，25-mer ps - omer修饰寡核苷酸的渗透性相对较差，未修饰的20-mer PS-ODN也是如此（渗透系数[P-eff] = 2-8 × 10(-6)cm/sec）。用脱氧核糖上的2′-MOE基团和胞嘧啶的5′-甲基化修饰部分或全部寡核苷酸显著增加了寡核苷酸的肠通透性，部分修饰和完全修饰的PS-MOE寡核苷酸的通透性都比未修饰的PS-ODN增加了2-4倍，在moe修饰的化合物中存在磷酸二酯主链导致肠道通透性进一步增加，PS-MOE由6、8、10、12、14、16、18、20组成。对22个核苷酸进行了检测，发现这些寡核苷酸的通透性随长度的减小而线性增加。
An in situ single-pass perfusion model was used to assess the effect of chemical modification and length on permeability and absorption of various oligonucleotides in rat intestine. Phosphorothioate oligodeoxynucleotides (PS-ODN) were compared with oligoribonucleotides with 2'-methoxyethyl (MOE) or 2'-O-methyl (OMe) modifications. A 25-mer PS-OMe-modified oligonucleotide showed relatively poor permeability in this model, as did unmodified 20-mer PS-ODN (permeability coefficient [P-eff] = 2-8 x 10(-6)cm/sec). Modifying some or all of the oligonucleotides with 2'-MOE groups on deoxyribose and 5'-methylation of the cytosines substantially increased intestinal permeability of oligonucleotides, Both partially and fully modified PS-MOE oligonucleotides showed a 2-4-fold increase in permeability as compared with unmodified PS-ODN, The presence of a phosphodiester backbone in MOE-modified compounds led to further increases in intestinal permeability, PS-MOE composed of 6, 8, 10, 12, 14, 16, 18, 20, and 22 nucleotides were also examined, It was found that the permeability of these oligonucleotides increased linearly with decreasing length.