Self-immolative nanoparticles for simultaneous delivery of microRNA and targeting of polyamine metabolism in combination cancer therapy.
Self-immolative nanoparticles for simultaneous delivery of microRNA and targeting of polyamine metabolism in combination cancer therapy.
复制标题
在联合癌症治疗中同时递送microRNA和靶向多胺代谢的自动耐纳米颗粒。
DOI：
10.1016/j.jconrel.2016.12.017
复制
发表时间：
2017-01-28
期刊：
影响因子：
--
通讯作者：
Oupický D
中科院分区：
文献类型：
--
作者：
Xie Y;Murray-Stewart T;Wang Y;Yu F;Li J;Marton LJ;Casero RA Jr;Oupický D
将抗癌药物与治疗性miRNA相结合已成为一种很有前途的抗癌策略。然而，由于缺乏理想的交付系统，这一承诺受到了阻碍。我们报道了能够同时传递miR-34a模拟物和靶向癌症中失调的多胺代谢的自焚纳米粒的开发。这些纳米粒是由可生物降解的聚阳离子前药DSS-BEN制备的，DSS-BEN是由多胺类似物N1，N11-二乙基去甲精胺(BENSpm)合成的。这些纳米颗粒被选择性地分解在细胞质中，在那里它们释放了miRNA。谷胱甘肽(GSH)诱导的自焚连接体的降解从DSS-BEN聚合物中释放BENSpm。MiR-34a模拟物被有效地输送到癌细胞，细胞内miR-34a表达上调，而作为miR-34a下游靶点之一的Bcl-2表达下调。降解的纳米颗粒产生的胞内BENSpm诱导多胺分解代谢限速酶(SMOX，SSAT)和耗竭的细胞天然多胺的表达。DSS-BEN/miR-34a同时调节多胺代谢和miR-34a的表达，不仅增强了培养的人结肠癌细胞的杀伤作用，而且提高了体内的抗肿瘤活性。报道的结果验证了自焚纳米颗粒作为治疗性miRNA的载体，能够同时靶向癌症中调节失调的多胺代谢，从而为组合纳米药物提供了一种优雅而有效的方法。
Combination of anticancer drugs with therapeutic miRNA has emerged as a promising anticancer strategy. However, the promise is hampered by a lack of desirable delivery systems. We report on the development of self-immolative nanoparticles capable of simultaneously delivering miR-34a mimic and targeting dysregulated polyamine metabolism in cancer. The nanoparticles were prepared from a biodegradable polycationic prodrug, named DSS-BEN, which was synthesized from a polyamine analog N1,N11-bisethylnorspermine (BENSpm). The nanoparticles were selectively disassembled in the cytoplasm where they released miRNA. Glutathione (GSH)-induced degradation of self-immolative linkers released BENSpm from the DSS-BEN polymers. MiR-34a mimic was effectively delivered to cancer cells as evidenced by upregulation of intracellular miR-34a and downregulation of Bcl-2 as one of the downstream targets of miR-34a. Intracellular BENSpm generated from the degraded nanoparticles induced the expression of rate-limiting enzymes in polyamine catabolism (SMOX, SSAT) and depleted cellular natural polyamines. Simultaneous regulation of polyamine metabolism and miR-34a expression by DSS-BEN/miR-34a not only enhanced cancer cell killing in cultured human colon cancer cells, but also improved antitumor activity in vivo. The reported findings validate the self-immolative nanoparticles as delivery vectors of therapeutic miRNA capable of simultaneously targeting dysregulated polyamine metabolism in cancer, thereby providing an elegant and efficient approach to combination nanomedicines.