Balancing polymer hydrophobicity for ligand presentation and siRNA delivery in dual function CXCR4 inhibiting polyplexes.
Balancing polymer hydrophobicity for ligand presentation and siRNA delivery in dual function CXCR4 inhibiting polyplexes.
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DOI：
10.1039/c5bm00003c
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发表时间：
2015-07
影响因子：
6.6
通讯作者：
Oupický D
中科院分区：
文献类型：
--
作者：
Wang Y;Li J;Chen Y;Oupický D
在本研究中，通过接枝聚合物Plerixafor/AMD3100 (PAMD)与不同量的胆固醇合成了一系列共聚物(PAMD-Ch)，并研究了胆固醇修饰对siRNA递送的影响。与不含胆固醇的 PAMD/siRNA 复合物相比，PAMD-Ch/siRNA 复合物表现出改善的胶体和酶稳定性。具有低（17 wt%）和中等（25 wt%）胆固醇含量的 PAMD-Ch 表现出与未修饰的 PAMD 相当的 CXCR4 拮抗作用。胆固醇修饰增加了细胞对 siRNA 复合物的摄取，并显着降低了 siRNA 转染对血清存在的敏感性。当用于递送针对 Polo 样激酶 1 (PLK1) 的抗癌 siRNA 时，基于 PAMD-Ch（含 17 wt% 胆固醇）的复合物在无血清和含血清条件下均表现出最高的癌细胞杀伤活性。总体而言，本研究的结果验证了胆固醇修饰的 PAMD 作为双功能递送载体，适用于有效递送抗癌 siRNA 并同时抑制 CXCR4 进行联合抗癌治疗。
In the present study, a series of copolymers (PAMD-Ch) was synthesized by grafting polymeric Plerixafor/AMD3100 (PAMD) with different amounts of cholesterol and the effect of cholesterol modification on siRNA delivery was investigated. PAMD-Ch/siRNA polyplexes exhibited improved colloidal and enzymatic stability when compared with PAMD/siRNA polyplexes containing no cholesterol. PAMD-Ch with low (17 wt%) and medium (25 wt%) cholesterol content exhibited CXCR4 antagonism comparable to unmodified PAMD. Cholesterol modification increased cell uptake of siRNA polyplexes and significantly decreased sensitivity of siRNA transfection to the presence of serum. When used to deliver anticancer siRNA against polo-like kinase 1 (PLK1), polyplexes based on PAMD-Ch with 17 wt% cholesterol exhibited the highest cancer cell killing activity both in serum-free and serum-containing conditions. Overall, the results of this study validate cholesterol modified PAMD as dual-function delivery vectors suitable for efficient delivery of anticancer siRNA and simultaneous CXCR4 inhibition for combined anticancer therapies.