The antisense oligonucleotides are promising agents for application in anti-HIV therapies. The antiretroviral nucleoside analogues administrated into circulatory system are vulnerable to nuclease degradation and require a vehicle which would not only facilitate therapeutic nucleotides into host cells, but would also provide protection against enzymatic degradation. Such potential is exhibited by poly(propylene imine) dendrimers - the branched cationic polymers easily interacting with oligonucleotides to form complexes called "dendriplexes". The aim of the present study was to evaluate the abilities of the fourth generation poly(propylene imine) dendrimers partially modified with maltose (PPI-Mal G4) or maltotriose (PPI-Mal-III G4) to protect anti-HIV antisense oligonucleotides (ODNs) from nucleolytic degradation. The ODNs (AT, GEM91, SREV) were complexed with dendrimers and subjected to cleavage by serum nucleases or endonuclease S1. The results showed that all examined dendrimers protected ODNs against nucleases contained in FBS. Both PPI-Mal G4 and PPI-Mal-III G4 dendrimers completely prevented ODNs digestion by nuclease S1 at neutral pH. The protective capabilities of investigated dendrimers were significantly weaker in acidic environment. The time stability assay showed that the dendriplexes formed by AT, GEM91, SREV and carbohydrate-modified PPI G4 dendrimers still existed after 12h incubation both in low and at neutral pH buffers. The conformational change of dendriplexes in acidic environment was proposed as possible phenomenon leading to exposition of ODNs to nuclease attack and significantly diminishing dendriplexes' resistance to nucleolitic digestion.

译文

反义寡核苷酸是有前途的抗HIV疗法药物。循环系统中施用的抗逆转录病毒核苷类似物易受核酸酶降解的影响,并且需要一种载体,该载体不仅将促进治疗性核苷酸进入宿主细胞,而且还将提供针对酶降解的保护。聚 (丙烯亚胺) 树枝状大分子表现出这种潜力-支化的阳离子聚合物很容易与寡核苷酸相互作用以形成称为 “树枝状复合物” 的络合物。本研究的目的是评估用麦芽糖 (PPI-Mal G4) 或麦芽三糖 (PPI-Mal-III G4) 部分修饰的第四代聚 (丙烯亚胺) 树状大分子保护抗HIV反义寡核苷酸的能力 (odn) 从核分解降解。将odn (AT,GEM91,SREV) 与树枝状聚合物复合,并通过血清核酸酶或核酸内切酶s1进行切割。结果表明,所有检查过的树状大分子都保护odn免受FBS中所含核酸酶的侵害。PPI-Mal G4和PPI-Mal-III G4树状大分子都完全阻止了中性pH下核酸酶S1消化ODNs。在酸性环境中,所研究的树状大分子的保护能力明显较弱。时间稳定性测定表明,在低pH和中性pH缓冲液中孵育12小时后,由AT,GEM91,SREV和碳水化合物修饰的PPI G4树状大分子形成的树枝状体仍然存在。提出了在酸性环境中树突状体的构象变化,这是可能导致odn暴露于核酸酶攻击并显着降低树突状体对核仁消化的抵抗力的现象。

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