Bioreducible polymers with cell penetrating and endosome buffering functionality for gene delivery systems.
Bioreducible polymers with cell penetrating and endosome buffering functionality for gene delivery systems.
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DOI：
10.1016/j.jconrel.2011.02.013
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发表时间：
2011-05-30
期刊：
影响因子：
--
通讯作者：
Kim SW
中科院分区：
文献类型：
--
作者：
Kim TI;Rothmund T;Kissel T;Kim SW
以N，N '-胱胺双丙烯酰胺（CBA）为原料，通过Michael加成反应，合成了不同比例（a：B = 2：1，1：1，1：2）的甘氨酸接枝己二胺（DAH-R）和1-（3-氨丙基）咪唑（API）单体组成的生物可还原阳离子聚合物（p（DAHa-R/APIb）s），研究了内体缓冲基团对甘氨酸接枝生物可还原聚合物基因载体的影响。几个实验显示出p（DAH-R/API）的单体组成比与聚合物特征之间的明显相关性。由于API的咪唑基（PKa=6），评价了p（DAH-R/API）的内体缓冲能力与API部分成比例增加。在生理pH下非离子化的API部分的增加和精氨酸残基的最终减少也降低了聚合物的细胞毒性，这是由于细胞区室与带较少正电荷的聚合物的相互作用较少，但也降低了pDNA凝聚能力、Zeta电位值、聚合复合物的细胞摄取以及最终的转染效率。因此，关于p（DAH-R/API）的有效基因递送，揭示了精氨酸残基相对于内体缓冲部分的优势。从氯喹或尼日利亚菌素的转染结果可以推断，p（DAH-R/API）复合物的内体逃逸是通过精氨酸部分的直接端体膜穿透以及细胞摄取后聚合物的内体缓冲能力发生的，这强调了精氨酸部分对于聚合物基因递送系统的重要性。
Bioreducible cationic polymers (p(DAHa-R/APIb)s) composed of different ratios (a:b = 2:1, 1:1, 1:2) between arginine-grafted diaminohexane (DAH-R) (cell penetrating functionality) and 1-(3-aminopropyl) imidazole (API) (endosome buffering functionality) monomers were synthesized by Michael reaction of N,N’-cystaminebisacrylamide (CBA) with them, in order to study the effect of endosome buffering moiety on arginine-grafted bioreducible polymeric gene carriers. Several experiments displayed a distinct correlation between monomer composition ratios of p(DAH-R/API)s and the polymer features. Increased endosome buffering capacities proportional to API portions was evaluated for p(DAH-R/API)s due to the imidazole group (pKa=6) of API. Increased portions of API non-ionized at physiological pH and resultant decrease of arginine residues also reduced cytotoxicities of the polymers due to less interaction of cellular compartments with less positively charged polymers, but decreased pDNA condensing abilities, Zeta-potential values, cellular uptakes of polyplexes, and finally transfection efficiencies as well. Thus, the predominance of arginine residues over endosome buffering moieties was revealed regarding efficient gene delivery for p(DAH-R/API)s. From transfection results with chloroquine or nigericin, it can be deduced that the endosomal escape of p(DAH-R/API) polyplexes occurs by direct endsome membrane penetration of arginine moieties as well as endosome buffering abilities of the polymers after cellular uptake, which emphasizes the importance of arginine moieties for polymeric gene delivery systems.
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