Delivery of antisense oligonucleotides using poly(alkylene oxide)-poly(propylacrylic acid) graft copolymers in conjunction with cationic liposomes.
Delivery of antisense oligonucleotides using poly(alkylene oxide)-poly(propylacrylic acid) graft copolymers in conjunction with cationic liposomes.
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DOI：
10.1016/j.jconrel.2014.08.023
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发表时间：
2014-11-28
期刊：
影响因子：
--
通讯作者：
Roth CM
中科院分区：
文献类型：
--
作者：
Peddada LY;Garbuzenko OB;Devore DI;Minko T;Roth CM
裸寡核苷酸稳定性差、递送效率低，阻碍了基因沉默的临床应用。在这里，我们提出了一个合理设计的，三元的，自组装的纳米粒子复合物，由阴离子共聚物，阳离子DOTAP脂质体，和反义寡核苷酸（AON）的体外和体内的行为。多功能共聚物是基于主链聚（丙基丙烯酸）（PPAA），pH敏感的疏水聚合物，与接枝聚（环氧烷）（PAO）的接枝程度和PAO化学变化。具有PPAA-g-PAO共聚物的纳米颗粒复合物增强A2780人卵巢癌细胞中的反义基因沉默效应。在小鼠腹膜内注射后，与二元DOTAP/AON复合物相比，使用三元共聚物稳定的递送系统将更大量的AON递送至卵巢肿瘤异种移植物。此外，肿瘤内注射含有1摩尔%接枝PAO的纳米颗粒复合物使肿瘤bcl-2表达降低高达60%。跨PAO聚合物组的复合物的数据支持接枝共聚物的亲油-亲脂平衡在实现血清稳定性和细胞摄取中的强作用。基于这些结果，我们预期这种新型纳米颗粒递送系统可以扩展到临床前和临床开发的质粒DNA、siRNA或适体的递送。
The clinical application of gene silencing is hindered by poor stability and low delivery efficiency of naked oligonucleotides. Here, we present the in vitro and in vivo behavior of a rationally designed, ternary, self-assembled nanoparticle complex, consisting of an anionic copolymer, cationic DOTAP liposome, and antisense oligonucleotide (AON). The multifunctional copolymers are based on backbone poly (propylacrylic acid) (PPAA), a pH-sensitive hydrophobic polymer, with grafted poly (alkylene oxides) (PAOs) varying in extent of grafting and PAO chemistry. The nanoparticle complexes with PPAA-g-PAO copolymers enhance antisense gene silencing effects in A2780 human ovarian cancer cells. A greater amount of AON is delivered to ovarian tumor xenografts using the ternary copolymer-stabilized delivery system, compared to a binary DOTAP/AON complex, following intraperitoneal injection in mice. Further, intratumoral injection of the nanoparticle complexes containing 1 mol% grafted PAO reduced tumoral bcl-2 expression by up to 60%. The data for complexes across the set of PAO polymers support a strong role for the hydrophilic-lipophilic balance of the graft copolymer in achieving serum stability and cellular uptake. Based upon these results, we anticipate that this novel nanoparticle delivery system can be extended to the delivery of plasmid DNA, siRNA, or aptamers for preclinical and clinical development.
反义活性动力学中聚乙烯亚胺的分子量和寡核苷酸骨架化学的相互作用。
影响因子：
14.9
作者：
Sundaram, Sumati;Lee, Li Kim;Roth, Charles M
通讯作者：
Roth, Charles M