Alginate/poly-L-lysine microparticles for the intestinal delivery of antisense oligonucleotides
Alginate/poly-L-lysine microparticles for the intestinal delivery of antisense oligonucleotides
复制标题
DOI：
10.1023/a:1016188312399
复制
发表时间：
2002-06-01
影响因子：
3.7
通讯作者：
Bodmeier, R
中科院分区：
文献类型：
--
作者：
Ferreiro, MG;Tillman, LG;Bodmeier, R
目的。研制了一种基于海藻酸盐和多聚L赖氨酸的微粒载体，并对其在肠道部位的反义寡核苷酸递送进行了评价。不同载体相对分子质量和组成的寡核苷酸微球制剂的体外和体内表征。将海藻酸盐与钙离子和聚L赖氨酸进行离子凝胶化和交联反应，制得聚合物微球。反义寡核苷酸的负载是通过在水介质中的吸附实现的。对微粒的缔合能力、负载量和粒径进行了表征。在大鼠和犬模型上研究了不同剂型空肠给药后的体内表现。微粒呈海绵状结构，寡核苷酸负载量为27-35%。介质的组成影响微球的颗粒大小和体外释放曲线。在有渗透促进剂存在的情况下，大鼠空肠内给药后，寡核苷酸的生物利用度对大多数受试系统都是好的。与同等的混悬液相比，粉末状微粒的应用提高了寡核苷酸在大鼠空肠内的生物利用度(分别为25%和10%)。相反，犬空肠内给药导致寡核苷酸生物利用度较低(0.42%)。在海藻酸盐和多聚L赖氨酸微粒中构建反义寡核苷酸是一种很有前途的口服应用策略。
Purpose. A microparticle carrier based on alginate and poly-L-lysine was developed and evaluated for the delivery of antisense oligonucleotides at the intestinal site. Formulations of oligonucleotide-loaded microparticles having differences in the carrier molecular weight and composition were characterized in vitro and in vivo.Methods. Polymeric microparticles were prepared by ionotropic gelation and crosslinking of alginate with calcium ions and poly-L-lysine. The loading of the antisense oligonucleotide into the microparticles was achieved by absorption in aqueous medium. The association capacity, loading and particle size of the microparticles were characterized. The in vivo performances of various formulations after intrajejunal administration were studied in rat and in dog models.Results. Microparticles had a sponge-like structure and an oligonucleotide loading of 27-35%. The composition of the medium affected the particle size and the in vitro release profiles. The oligonucleotide bioavailability after intrajejunal administration to rats in the presence of permeation enhancers was good for most of the tested systems. The application of microparticles in powder form compared to an equivalent suspension improved the intrajejunal bioavailability of the oligonucleotide (25% and 10% respectively) in rats. On the contrary, the intrajejunal administration to dogs resulted in poor oligonucleotide bioavailability (0.42%).Conclusions. The formulation of antisense oligonucleotides within alginate and poly-L-lysine microparticles is a promising strategy for the oral application.