Rerouting Native HDL to Predetermined Receptors for Improved Tumor-Targeted Gene Silencing Therapy
Rerouting Native HDL to Predetermined Receptors for Improved Tumor-Targeted Gene Silencing Therapy
复制标题
将天然 HDL 重新路由至预定受体以改善肿瘤靶向基因沉默疗法
DOI：
10.1021/acsami.7b10047
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发表时间：
2017-09-13
影响因子：
9.5
通讯作者：
Zhou, Jianping
中科院分区：
文献类型：
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作者：
Ding, Yang;Han, Yue;Zhou, Jianping
高密度脂蛋白（HDL）是一种出色的生物相容性纳米载体，可用于肿瘤靶向递送多模型药物。然而，这种看似有希望的给药平台在肝脏和肾上腺中表现出不利的积累，这是由于天然靶清道夫受体B类I型（SR-BI）的主要表达，该受体在恶性细胞中也过表达。因此，我们赋予天然hdl重定向能力，即使hdl能够脱离天然受体（SR-BI），选择性地替代富含肿瘤的受体。α v β(3)-整合素特异性环rgdyk肽与hdl蛋白组分载脂蛋白A-I （apoA-I）偶联，取代度高达26.2%。随后，引入rgd修饰的apoA-I，制备装载胆固醇sirna的HDL纳米颗粒（RGD-HDL/Ch-siRNA），与肿瘤血管生成和肿瘤表面的α v β(3)整合素具有特异性亲和力。制备后，RGD-HDL/Ch-siRNA具有理想的粒径，在血液循环中具有有效的siRNA保护作用，具有良好的质子海绵效应。在体外和体内均证实了α v β(3)整合素相关的优越重传能力、内吞途径和快速内溶酶体逃逸。在靶向基因沉默治疗中，引入了pokemon特异性siRNA （siPokemon）作为RNA干扰候选物；通过抑制肿瘤生长、延长生存期和western blot分析，证实了抗肿瘤效果的增强和Pokemon表达水平的降低。总的来说，周期- rgdyk修饰赋予了天然HDL重定向到特异性α v β(3)整合素受体的能力，这为将天然HDL的恶性靶向潜力扩展到更广泛的范围提供了一个有希望的策略。
High-density lipoprotein (HDL) is an outstanding biocompatible nanovector for tumor-targeted delivery of multimodel drugs in cancer therapy. However, this seemingly promising delivery platform demonstrates an adverse accumulation in liver and adrenal due to the primary expression of natural target scavenger receptor class B type I (SR-BI), which overexpressed in malignant cells as well. Therefore, we endowed native HDLs with rerouting capacity, that is, enabling HDLs to get away from natural receptors (SR-BI) to selectively alternate tumor-rich receptors. The alpha v beta(3)-integrin specific cyclic-RGDyk peptide was conjugated with HDL-protein component apolipoprotein A-I (apoA-I), demonstrating high substitution degree of 26.2%. Afterward, RGD-modified apoA-I was introduced to fabricate cholesterol siRNA-loaded HDL nanoparticles (RGD-HDL/Ch-siRNA) for specific affinity with tumor angiogenesis and alpha v beta(3) integrin on tumor surface. After preparation, RGD-HDL/Ch-siRNA shared desirable particle size, efficient siRNA protection during blood circulation, and favorable proton sponge effect. alpha v beta(3) integrin-associated superior rerouting capacity, endocytosis pathway, and rapid endolysosome escape were confirmed both in vitro and in vivo. For targeted gene silencing therapy, Pokemon-specific siRNA (siPokemon) was introduced as RNA interference candidate; the enhanced antitumor efficacy and decreased Pokemon expression level were commendably confirmed by tumor growth inhibition, survival period extension, and western blot analysis. Collectively, cyclic-RGDyk modification endows native HDLs with rerouting capacity to specific alpha v beta(3) integrin receptor, which provides a promising strategy to extend malignancy targeting potential of native HDL to a broader purview.