Dual-Function Polymeric HPMA Prodrugs for the Delivery of miRNA.
Dual-Function Polymeric HPMA Prodrugs for the Delivery of miRNA.
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DOI：
10.1021/acs.molpharmaceut.6b00999
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发表时间：
2017-05-01
影响因子：
4.9
通讯作者：
Oupický D
中科院分区：
文献类型：
--
作者：
Peng ZH;Xie Y;Wang Y;Li J;Oupický D
CXCR 4拮抗剂的基于HPMA的聚合物前药AMD 3465（P-SS-AMD）被开发为治疗性miRNA的双功能载体。P-SS-AMD是通过HPMA与甲基丙烯酰胺单体的共聚反应合成的，其中AMD 3465通过自分解的二硫键连接。P-SS-AMD显示在用细胞内水平的谷胱甘肽（GSH）处理后母体AMD 3465药物有效释放。AMD 3465在细胞中释放，并表现出功能性CXCR 4拮抗作用，表现为抑制CXCR 4介导的癌细胞侵袭。由于其阳离子特性，P-SS-AMD可以与miRNA形成复合物，并介导miR-200 c模拟物的有效转染，以下调癌细胞中下游靶ZEB-1的表达。与单独治疗相比，组合的P-SS-AMD/miR-200 c聚合复合物显示出改善的抑制癌细胞迁移的能力。所报道的发现验证了P-SS-AMD作为双功能递送载体，其可以同时递送治疗性miRNA和作为CXCR 4拮抗剂的聚合物前药。
An HPMA-based polymeric prodrug of a CXCR4 antagonist, AMD3465 (P-SS-AMD), was developed as a dual-function carrier of therapeutic miRNA. P-SS-AMD was synthesized by a copolymerization of HPMA with a methacrylamide monomer in which the AMD3465 was attached via a self-immolative disulfide linker. P-SS-AMD showed effective release of the parent AMD3465 drug following treatment with intracellular levels of glutathione (GSH). The AMD3465 was released in the cells and exhibited functional CXCR4 antagonism, demonstrated by inhibition of the CXCR4-mediated cancer cell invasion. Due to its cationic character, P-SS-AMD could form polyplexes with miRNA and mediate efficient transfection of miR-200c mimics to downregulate expression of a downstream target ZEB-1 in cancer cells. The combined P-SS-AMD/miR-200c polyplexes showed improved ability to inhibit cancer cell migration when compared with individual treatments. The reported findings validate P-SS-AMD as a dual-function delivery vector that can simultaneously deliver a therapeutic miRNA and function as a polymeric prodrug of CXCR4 antagonist.