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Natural Particulates Inspired Specific-Targeted Codelivery of siRNA and Paclitaxel for Collaborative Antitumor Therapy
Molecular Pharmaceutics ( IF 4.5 ) Pub Date : 2017-08-14 00:00:00 , DOI: 10.1021/acs.molpharmaceut.7b00192 Ruoning Wang 1 , Ziqiang Zhao 1 , Yue Han 1 , Shihao Hu 1 , Yaw Opoku-Damoah 1 , Jianping Zhou 1 , Lifang Yin 1 , Yang Ding 1
Molecular Pharmaceutics ( IF 4.5 ) Pub Date : 2017-08-14 00:00:00 , DOI: 10.1021/acs.molpharmaceut.7b00192 Ruoning Wang 1 , Ziqiang Zhao 1 , Yue Han 1 , Shihao Hu 1 , Yaw Opoku-Damoah 1 , Jianping Zhou 1 , Lifang Yin 1 , Yang Ding 1
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The effective combination of drugs promoting antiangiogenesis and apoptosis effects has proven to be a promising collaborative tumor antidote; and the codelivery of small interfering RNA (siRNA) and chemotherapy agents within one efficient vehicle has gained more attention over single regimen administration. Herein, vascular endothelial growth factor specific siRNA (siVEGF) and paclitaxel (PTX) were introduced as therapeutic companions and coencapsulated into naturally mimic high-density lipoproteins (rHDL/siVEGF-PTX), so that various mechanisms of treatment can occur simultaneously. The terminal nanoparticles share capacity of specific-targeting to tumor cells overexpressed scavenger receptor class B type I (SR-BI) and deliver siVEGF and PTX into cytoplasm by a nonendocytosis mechanism. By exchanging HDL core lipids with hydrophobic therapeutics, rHDL/siVEGF-PTX possessed particle size of ∼160 nm, surface potential of ∼−20 mV, and desirable long-term storage stability. In vitro results confirmed that the parallel activity of siVEGF and PTX displayed enhanced anticancer efficacy. The half-maximal inhibitory concentration (IC50) of rHDL/siVEGF-PTX toward human breast cancer MCF-7 cell is 0.26 μg/mL (PTX concentration), which presents a 14.96-fold increase in cytotoxicity by taking Taxol as comparison. Moreover, in vivo results further demonstrated that rHDL/siVEGF-PTX performed enhanced tumor growth inhibition via natural targeting pathway, accompanied by remarkable inhibition of neovascularization in situ caused by siVEGF silencing in down-regulation of VEGF proteins. On the premise of effective drug codelivery, rHDL/siVEGF-PTX demonstrated high tumor targeting for collaborative antitumor efficacy without side effects after systemic administration, and this bioinspired strategy could open an avenue for exploration of combined anticancer therapy.
中文翻译：
天然颗粒激发了针对siRNA和紫杉醇的特异性靶向共代传递，以用于协同抗肿瘤治疗
促进抗血管生成和凋亡作用的药物的有效结合已被证明是一种有前途的协同肿瘤解毒剂。而且，在一种有效的载体中，小干扰RNA（siRNA）和化学治疗剂的代码传递已比单一方案给药引起了更多关注。在此，引入血管内皮生长因子特异性siRNA（siVEGF）和紫杉醇（PTX）作为治疗伴侣，并共封装在天然模拟的高密度脂蛋白（rHDL / siVEGF-PTX）中，从而可以同时发生多种治疗机制。末端纳米颗粒共享特异性靶向过表达的I类清道夫受体B型（SR-BI）的肿瘤细胞的能力，并通过非内吞作用机制将siVEGF和PTX传递到细胞质中。通过将HDL核心脂质与疏水性治疗剂进行交换，体外结果证实，siVEGF和PTX的平行活性显示出增强的抗癌功效。rHDL / siVEGF-PTX对人乳腺癌MCF-7细胞的半数最大抑制浓度（IC 50）为0.26μg/ mL（PTX浓度），以紫杉醇为对照，其细胞毒性增加了14.96倍。此外，体内结果进一步证明，rHDL / siVEGF-PTX通过天然靶向途径增强了对肿瘤生长的抑制，并伴随着对原位新血管形成的显着抑制siVEGF沉默引起的VEGF蛋白下调。在有效的药物传递的前提下，rHDL / siVEGF-PTX表现出高的靶向性，可在全身给药后发挥协同抗肿瘤作用，且无副作用，而这种受生物启发的策略可为探索联合抗癌治疗开辟道路。
更新日期：2017-08-14
中文翻译：
天然颗粒激发了针对siRNA和紫杉醇的特异性靶向共代传递，以用于协同抗肿瘤治疗
促进抗血管生成和凋亡作用的药物的有效结合已被证明是一种有前途的协同肿瘤解毒剂。而且，在一种有效的载体中，小干扰RNA（siRNA）和化学治疗剂的代码传递已比单一方案给药引起了更多关注。在此，引入血管内皮生长因子特异性siRNA（siVEGF）和紫杉醇（PTX）作为治疗伴侣，并共封装在天然模拟的高密度脂蛋白（rHDL / siVEGF-PTX）中，从而可以同时发生多种治疗机制。末端纳米颗粒共享特异性靶向过表达的I类清道夫受体B型（SR-BI）的肿瘤细胞的能力，并通过非内吞作用机制将siVEGF和PTX传递到细胞质中。通过将HDL核心脂质与疏水性治疗剂进行交换，体外结果证实，siVEGF和PTX的平行活性显示出增强的抗癌功效。rHDL / siVEGF-PTX对人乳腺癌MCF-7细胞的半数最大抑制浓度（IC 50）为0.26μg/ mL（PTX浓度），以紫杉醇为对照，其细胞毒性增加了14.96倍。此外，体内结果进一步证明，rHDL / siVEGF-PTX通过天然靶向途径增强了对肿瘤生长的抑制，并伴随着对原位新血管形成的显着抑制siVEGF沉默引起的VEGF蛋白下调。在有效的药物传递的前提下，rHDL / siVEGF-PTX表现出高的靶向性，可在全身给药后发挥协同抗肿瘤作用，且无副作用，而这种受生物启发的策略可为探索联合抗癌治疗开辟道路。
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