Degradable-brushed pHEMA-pDMAEMA synthesized via ATRP and click chemistry for gene delivery
Degradable-brushed pHEMA-pDMAEMA synthesized via ATRP and click chemistry for gene delivery
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通过 ATRP 和点击化学合成用于基因传递的可降解刷 pHEMA-pDMAEMA
DOI：
10.1021/bc0701186
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发表时间：
2007-11-01
影响因子：
4.7
通讯作者：
Hennink, Wim E.
中科院分区：
文献类型：
--
作者：
Jiang, Xulin;Lok, Martin C.;Hennink, Wim E.
合成了以聚(甲基丙烯酸羟乙酯)(PHEMA)为骨架，以可水解性连接物接枝的聚甲基丙烯酸二甲氨酯-S(PDMAEMA)为骨架的刷状聚合物，并对其作为非病毒基因传递载体进行了评价。采用可控原子转移自由基聚合法(ATRP)合成了相对分子质量可控、分布窄的聚二甲基马来酸乙二酯(PDMAEMA)和聚乙二醇胺(PHEMA)聚合物。叠氮化引发剂用于确保pDMAEMA聚合链的完全和单叠氮化官能化。PHEMA与炔侧基团和pDMAEMA中的叠氮端基之间的点击反应，通过易降解的碳酸酯连接剂，得到了由低分子组分组成的高相对分子质量聚合物。PDMAEMA接枝的长度以及刷毛PHEMA-pDMAEMA的接枝数量可以很容易地改变。在生理条件下(pH 7.4和37℃)，刷状聚合物通过碳酸酯的水解降解，半衰期为96h，形成的降解产物的相对分子质量与起始的pDMAEMA非常接近，很可能低于肾排泄极限(<；30 kDa)。结果表明，可降解的刷状PHEMA-pDMAEMAs能够将DNA凝聚成带正电的纳米粒子。与高分子量的pDMAEMA参照物相比，所有这些可降解的聚合物都显示出较低的细胞毒性。另一方面，用于接枝PHEMA的低相对分子质量的pDMAEMA既不能凝聚DNA的结构，也不能转染细胞。本研究表明，通过可水解性接头将低分子阳离子聚合物接枝到中性亲水性聚合物上是一种有效的调控基因传递聚合物的转染活性和毒性的方法。
Brushed polymers composed of a backbone of poly(hydroxyethyl methacrylate) (pHEMA) onto which poly(2(dimethylamino)ethyl methacrylate)s (pDMAEMAs) was grafted via a hydrolyzable linker were synthesized and evaluated as nonviral gene delivery vectors. Both pDMAEMA and pHEMA polymers with controlled molecular weights and narrow distributions were synthesized by controlled atom transfer radical polymerization (ATRP). The azide initiator was used to ensure complete and monoazide functionalization of the pDMAEMA polymer chains. Click reaction between pHEMA with alkyne side groups and the azide end group in the pDMAEMA resulted in a high-molecular-weight polymer composed of low-molecular-weight constituents via an easily degradable carbonate ester linker. The length of the pDMAEMA grafts as well as the number of grafts of the brushed pHEMA-pDMAEMA can be easily varied. At physiological conditions (pH 7.4 and 37 degrees C, the brushed polymer degraded by hydrolysis of the carbonate ester with a half-life of 96 h. The molecular weights of the formed degradation products was very close to that of the starting pDMAEMA, which is likely below the renal excretion limit (< 30 kDa). It was shown that the degradable brushed pHEMA-pDMAEMAs were able to condense plasmid DNA into positively charged nanosized particles. The resulting polyplexes were able to transfect cells efficiently in the presence of the endosomal membrane disrupting INF-7 peptide, and all these degradable polymers showed lower cellular toxicity compared to a high-molecular-weight pDMAEMA reference. On the other hand, the low-molecular-weight pDMAEMA used for the grafting to pHEMA was neither able to condense the structure of DNA nor able to transfect cells. This study demonstrates that grafting a low-molecular-weight cationic polymer via a hydrolyzable linker to a neutral hydrophilic polymer is an effective approach to modulate the transfection activity and toxicity profile of gene delivery polymers.