Background: The combination of BEZ235 with sorafenib (SFB) enhances anti-hepatocellular carcinoma (HCC) efficacy of the two agents. However, pharmacokinetic profiles in vivo and different endocytosis abilities of these two drugs hinder their therapeutic application.Research design and methods: In this work, we developed d-α-tocopheryl polyethylene glycol 1000 succinate - polycaprolactone polymer nanoparticles (NPs) for co-delivery of SFB and BEZ235 (SFB/BEZ235-NPs). Explored the anti-proliferative and pro-apoptotic effects of SFB/BEZ235-NPs through in vitro and in vivo experiments.Results: Stabilized SFB/BEZ235-NPs were prepared with optimized drug ratio, yielding high encapsulation efficiency, low polydispersity, and enhanced cellular internalization in HepG2 cells. Synergistic cytotoxicity and pro-apoptotic ability were documented. In vivo pharmacokinetic results revealed extended circulation and bioavailability of SFB/BEZ235-NPs compared with those of free drugs. SFB/BEZ235-NPs enhanced antitumor effectiveness in SFB-resistant HCC xenograft mouse models.Conclusion: Taken together, the results of this study describe a promising strategy using SFB and BEZ235 in a nanoparticle formulation for treatment of SFB-resistant HCC.

中文翻译：

---

肝细胞癌对索拉非尼的耐药性可以通过在纳米颗粒中共同递送PI3K / mTOR抑制剂BEZ235和索拉非尼来克服。

背景：BEZ235与索拉非尼（SFB）的组合可增强两种药物的抗肝细胞癌（HCC）功效。但是，这两种药物的体内药动学特征和不同的内吞能力阻碍了它们的治疗应用。研究设计和方法：在这项工作中，我们开发了d-α-生育酚聚乙二醇1000琥珀酸酯-聚己内酯聚合物纳米颗粒（NPs）进行共输送SFB和BEZ235（SFB / BEZ235-NP）。通过体外和体内实验探索了SFB / BEZ235-NPs的抗增殖和促凋亡作用。结果：以优化的药物比例制备稳定的SFB / BEZ235-NPs，具有高包封率，低多分散性和增强的细胞活性HepG2细胞内在化。有协同的细胞毒性和促凋亡能力。体内药代动力学结果表明，与游离药物相比，SFB / BEZ235-NPs的循环和生物利用度得到延长。SFB / BEZ235-NPs在耐SFB的HCC异种移植小鼠模型中增强了抗肿瘤效果。结论：综上所述，本研究的结果描述了在纳米颗粒制剂中使用SFB和BEZ235来治疗耐SFB的HCC的有希望的策略。