Sorafenib (So) is a multi-target kinase inhibitor extensively used in clinic for hepatocellular carcinoma therapy. It demonstrated strong inhibition both in tumor proliferation and tumor angiogenesis, while hampered by associated cutaneous side-effect and drug resistance. The knockdown of miR-21 with antisense oligonucleotides (antimiRNA21) was regarded as an efficient strategy for increasing tumor sensibility to chemotherapy, which could be employed to appreciate the efficacy of So. Herein, we successfully formulated a dual-targeting delivery system for enhanced hepatocellular carcinoma therapy by encapsulating So and antimiRNA21 in RGD pentapeptide-modified reconstituted high-density lipoprotein (RGD-rHDL/So/antimiRNA21). The RGD and apolipoprotein A-Ⅰ (ApoA-Ⅰ) on nanoparticles (NPs) could drive the system simultaneously to tumor neovascular and parenchyma by binding to the overexpressed ανβ3-integrin and SR-B1 receptors, achieving precise delivery of therapeutics to maximize the efficacy. A series in vitro and in vivo experiments revealed that co-delivery of So and antimiRNA21 by RGD-rHDL significantly strengthened the anti-tumor and anti-angiogenic effect of So with negligible toxicity towards major organs, reversed drug-resistance and was capable of remodeling tumor environments. The constructed RGD-rHDL/So/antimiRNA21 with improved efficacy and excellent tumor targeting ability provided new idea for chemo-gene combined therapy in hepatocellular carcinoma.

Statement of Significance

Sorafenib (So) is a multi-target kinase inhibitor which was approved by FDA as first-line drug for hepatocellular carcinoma (HCC) therapy. However, long term application of So in clinic was hampered by serious dermal toxicity and drug resistance. Although numerous researchers were devoted to finding alternatives or therapies as combination treatments with So to reach more desired therapeutic efficacy, the therapeutic options were still limited. The present study prepares RGD pentapeptide decorated biomimic reconstituted high-density lipoprotein (rHDL) loaded with So and antimiRNA21 (RGD-rHDL/So/antimiRNA21) for enhanced HCC therapy. The RGD-rHDL/So/antimiRNA21 NPs offer an effective platform for anti-tumor and anti-angiogenesis therapy in HCC and provide new approach to reverse drug-resistance of So for feasible clinical application

中文翻译：

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利用索拉非尼和antimiRNA21的协同作用的双重靶向重组高密度脂蛋白，可增强肝细胞癌治疗

索拉非尼（Soora）是一种多靶点激酶抑制剂，在临床上广泛用于肝细胞癌治疗。它显示出对肿瘤增殖和肿瘤血管生成的强抑制作用，同时受到相关的皮肤副作用和耐药性的阻碍。用反义寡核苷酸（antimiRNA21）敲低miR-21被认为是增加肿瘤对化疗敏感性的有效策略，可用于评估So的疗效。在这里，我们成功地通过将So和antimiRNA21封装在RGD五肽修饰的重组高密度脂蛋白（RGD-rHDL / So / antimiRNA21）中，成功地制定了用于增强肝细胞癌治疗的双重靶向递送系统。纳米颗粒（NPs）上的RGD和载脂蛋白A-Ⅰ（ApoA-Ⅰ）可以通过与过度表达的ανβ3-整联蛋白和SR-B1受体结合而同时将系统驱动至肿瘤新生血管和实质，从而实现精确的治疗药物传递，从而最大化疗效。一系列的体外和体内实验表明，RGD-rHDL共同递送So和antimiRNA21可以显着增强So的抗肿瘤和抗血管生成作用，对主要器官的毒性可以忽略不计，逆转耐药性并能够重塑肿瘤环境。构建的RGD-rHDL / So / antimiRNA21具有更高的疗效和优异的肿瘤靶向能力，为肝癌化学基因联合治疗提供了新思路。

重要声明

索拉非尼（Soora）是一种多靶点激酶抑制剂，已被FDA批准为肝细胞癌（HCC）治疗的一线药物。但是，严重的皮肤毒性和耐药性阻碍了So在临床上的长期应用。尽管许多研究人员致力于寻找与So的联合治疗的替代方法或疗法，以达到更理想的治疗效果，但治疗选择仍然有限。本研究制备了RGD五肽修饰的仿生重构高密度脂蛋白（rHDL），其中装载了So和antimiRNA21（RGD-rHDL / So / antimiRNA21），用于增强的HCC治疗。RGD-rHDL / So / antimiRNA21 NPs为肝癌的抗肿瘤和抗血管生成治疗提供了一个有效的平台，并为逆转So的耐药性提供了新的方法，以实现可行的临床应用