Melittin-grafted HPMA-oligolysine based copolymers for gene delivery.
Melittin-grafted HPMA-oligolysine based copolymers for gene delivery.
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DOI：
10.1016/j.biomaterials.2012.09.072
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发表时间：
2013-03
期刊：
影响因子：
14
通讯作者：
Pun, Suzie H.
中科院分区：
文献类型：
--
作者：
Schellinger, Joan G.;Pahang, Joshuel A.;Johnson, Russell N.;Chu, David S. H.;Sellers, Drew L.;Maris, Don O.;Convertine, Anthony J.;Stayton, Patrick S.;Horner, Philip J.;Pun, Suzie H.
能够转染大脑细胞的非病毒基因传递系统对于实现核酸治疗中枢神经系统疾病的潜在影响至关重要。本研究将溶膜肽melittin加入到可逆加成-断裂链转移（RAFT）聚合合成的嵌段共聚物中。第一个区块由N-（2-羟丙基）甲基丙烯酰胺（HPMA）和吡啶二硫基甲基丙烯酰胺（PDSMA）组成，用于蜂毒蛋白偶联；第二个区块由低聚l -赖氨酸（K10）和HPMA组成，用于DNA结合。在c端被半胱氨酸修饰的蜂鸟素通过二硫交换通过吡啶基二硫悬垂基团与聚合物结合。所得的pHgMelbHK10共聚物比不含蜂胶的对照聚合物具有更强的膜裂解性，并能有效地将质粒DNA凝聚成盐稳定的颗粒（~ 100-200 nm）。尽管观察到与蜂毒肽相关的毒性，但与不含蜂毒肽的聚合物相比，修饰的聚合物更有效地转染HeLa和神经元样PC-12细胞。含有荧光素酶报告基因的优化配方通过脑室内注射进入小鼠大脑。含有蜂毒素的多聚体在大脑中产生的荧光素酶活性比不含蜂毒素的多聚体高35倍。因此，在这项工作中描述的含有蜂毒素的嵌段共聚物是很有希望的基因传递到大脑的材料。
Non-viral gene delivery systems capable of transfecting cells in the brain are critical in realizing the potential impact of nucleic acid therapeutics for diseases of the central nervous system. In this study, the membrane-lytic peptide melittin was incorporated into block copolymers synthesized by reversible addition-fragmentation chain transfer (RAFT) polymerization. The first block, designed for melittin conjugation, was composed of N-(2-hydroxypropyl)methacrylamide (HPMA) and pyridyl disulfide methacrylamide (PDSMA) and the second block, designed for DNA binding, was composed of oligo-L-lysine (K10) and HPMA. Melittin modified with cysteine at the C-terminus was conjugated to the polymers through the pyridyl disulfide pendant groups via disulfide exchange. The resulting pHgMelbHK10 copolymers are more membrane-lytic than melittin-free control polymers, and efficiently condensed plasmid DNA into salt-stable particles (~ 100–200 nm). The melittin-modified polymers transfected both HeLa and neuron-like PC-12 cells more efficiently than melittin-free polymers although toxicity associated with the melittin peptide was observed. Optimized formulations containing the luciferase reporter gene were delivered to mouse brain by intraventricular brain injections. Melittin-containing polyplexes produced about 35-fold higher luciferase activity in the brain compared to polyplexes without melittin. Thus, the melittin-containing block copolymers described in this work are promising materials for gene delivery to the brain.
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影响因子：
3.7
作者：
Bergen, Jamie M.;Park, In-Kyu;Horner, Philip J.;Pun, Suzie H.
通讯作者：
Pun, Suzie H.
DOI：
10.1016/j.jconrel.2011.07.009
发表时间：
2011-10-30
期刊：
Journal of controlled release : official journal of the Controlled Release Society
影响因子：
--
作者：
Johnson RN;Chu DS;Shi J;Schellinger JG;Carlson PM;Pun SH
通讯作者：
Pun SH
影响因子：
4.7
作者：
Burke, Rob S.;Pun, Suzie H.
通讯作者：
Pun, Suzie H.
影响因子：
10.8
作者：
Bulmus, V;Woodward, M;Hoffman, A
通讯作者：
Hoffman, A
影响因子：
5.1
作者：
Li, Y;Wang, J;Wang, S
通讯作者：
Wang, S