Multistage Nanovehicle Delivery System Based on Stepwise Size Reduction and Charge Reversal for Programmed Nuclear Targeting of Systemically Administered Anticancer Drugs
Multistage Nanovehicle Delivery System Based on Stepwise Size Reduction and Charge Reversal for Programmed Nuclear Targeting of Systemically Administered Anticancer Drugs
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DOI：
10.1002/adfm.201501248
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发表时间：
2015-07-08
影响因子：
19
通讯作者：
Huang, Yuan
中科院分区：
文献类型：
--
作者：
Li, Lian;Sun, Wei;Huang, Yuan
细胞核是许多一线化疗药物的最终靶点，但克服多种生理障碍的需要对全身给药的药物递送系统的尺寸和电荷提出了相互矛盾的要求。在此，描述了一种基于N-（2-羟丙基）甲基丙烯酰胺（HPMA）聚合物的纳米载体（PNV），其由具有电荷反转能力的阴离子HPMA共聚物和具有细胞内可分离亚基（IDS）的阳离子HPMA共聚物自组装。IDS带有抗癌药物和核归巢细胞穿透肽（R8 NLS配体），通过腙键接枝到HPMA共聚物上。大的、带中性电荷的、自组装的PNV（约55 nm）显示出良好的血液持久性和优先的肿瘤积累。到达肿瘤后，细胞外环境促使PNV分解为线性缀合物（约10 nm/39 kDa）。这种第一阶段的尺寸减小暴露了R8 NLS，并允许更深的组织渗透和更大的细胞内化。内吞作用后，当酸性更强的内溶酶体pH将约2.4 kDa的IDS从HPMA共聚物主链上切割下来，并通过核定位信号辅助确保成功进入核时，发生第二阶段的尺寸减小。基于逐步减小尺寸和按需R8 NLS暴露，PNV抑制裸鼠中HeLa肿瘤的生长达75%。这项工作提供了重要的见解，通过多级尺寸/电荷变化的方式设计系统的核靶向输送。
The nucleus is the final target of many first-line chemotherapeutics, but the need to overcome multiple physiological barriers imposes conflicting requirements for size and charge on systemically administered drug delivery systems. Here, an N-(2-hydroxypropyl) methacrylamide (HPMA) polymer-based nanovehicle (PNV) that self-assembles from anionic HPMA copolymers with charge-reversal ability and cationic HPMA copolymers with intracellularly detachable subgroups (IDS) is described. The IDS, bearing an anticancer drug and nuclear-homing cell-penetrating peptide (R8NLS ligand), is grafted onto the HPMA copolymer via hydrazone linkage. The large, neutrally charged, self-assembled PNV (approximate to 55 nm) shows good blood persistence and preferential tumor accumulation. After tumoral arrival, the extracellular milieu actuates the disassembly of PNV to linear conjugates (approximate to 10 nm/39 kDa). This first-stage size reduction exposes R8NLS and allows for deeper tissue penetration and greater cellular internalization. After endocytosis, a second-stage size reduction occurs when the more acidic endolysosomal pH cleaved the approximate to 2.4 kDa IDS off the HPMA copolymer backbone and guaranteed the successful nuclear entry via nuclear localization signal assistance. Based on the stepwise size reduction and on-demand R8NLS exposure, the PNV inhibits growth of HeLa tumors in nude mice by 75%. This work gives important insights into the design of systemic nuclear-targeted delivery via a multistage size/charge changing way.