Department of Radiology, Pingtung Christian Hospital, Pingtung, Taiwan.
Institute of Biomedical Sciences, National Sun Yat-Sen University, Kaohsiung, Taiwan.
Int J Nanomedicine. 2021 Feb 5;16:867-879. doi: 10.2147/IJN.S282172. eCollection 2021.
Transcatheter arterial chemoembolization (TACE) is a common clinical treatment for hepatocellular carcinoma (HCC). However, hypoxia induction after treatment might trigger tumor invasiveness and metastasis. Although pterostilbene (PTS) has antitumor effects, its chemoprevention in HepG2 cells under hypoxia has not been investigated yet. In addition, the poor water solubility of raw PTS limits its clinical application. Here, we prepared nanoparticles of PTS (PSN) and compared their antihepatoma activities with those of raw PTS in HepG2 under hypoxic conditions.
The PTS nanoparticle formulation was prepared by nanoprecipitation, using Eudragit e100 (EE) and polyvinyl alcohol (PVA) as carriers. We analyzed the physicochemical properties of raw PTS and PSN, including yield, encapsulation efficiency, water-solubility, particle size, morphology, crystalline-to-amorphous transformation, and molecular interaction between PTS and carriers. We also evaluated their antihepatoma activities under hypoxia treatment in HepG2 cells, including cell viability, hypoxia, and apoptosis.
The yield and encapsulation efficiency of PSN were 86.33% and >99%, respectively. The water solubility and drug release of PTS were effectively improved after nanoprecipitation corresponding to the reduction in particle size, amorphous transformation, and formation of hydrogen bonding with carriers. PSN had a better cytotoxic effect than raw PTS in HepG2 under pre- and post-hypoxia conditions. In addition, hypoxia- and apoptosis-related proteins in HepG2 cells under two different hypoxic conditions were significantly inhibited by PSN compared with the control group with hypoxia only, except for HIF-1α in the post-hypoxia group. PSN was also significantly better in inhibiting these proteins, except for Bcl2, under pre-hypoxic conditions.
Our results suggested that PSN could improve the water solubility and drug release of PTS and enhance the efficacy of HCC treatment under hypoxic conditions.
经导管动脉化疗栓塞术（TACE）是治疗肝细胞癌（HCC）的常用临床治疗方法。然而，治疗后缺氧的诱导可能会引发肿瘤侵袭和转移。虽然紫檀芪（PTS）具有抗肿瘤作用，但尚未研究其在缺氧下对 HepG2 细胞的化学预防作用。此外，原始 PTS 的水溶性差限制了其临床应用。在这里，我们制备了 PTS 的纳米粒子（PSN），并在缺氧条件下比较了其在 HepG2 中的抗肝癌活性与原始 PTS 的活性。
采用纳米沉淀法制备 PTS 纳米粒制剂，以 Eudragit e100（EE）和聚乙烯醇（PVA）为载体。我们分析了原始 PTS 和 PSN 的理化性质，包括产率、包封效率、水溶性、粒径、形态、晶型到无定形转变以及 PTS 与载体之间的分子相互作用。我们还评估了它们在 HepG2 细胞缺氧处理下的抗肝癌活性，包括细胞活力、缺氧和细胞凋亡。
PSN 的产率和包封效率分别为 86.33%和>99%。纳米沉淀后，PTS 的水溶性和药物释放得到有效改善，相应的粒径减小、无定形转变以及与载体形成氢键。PSN 在缺氧和后缺氧条件下对 HepG2 的细胞毒性作用均优于原始 PTS。此外，与仅缺氧的对照组相比，PSN 显著抑制了两种不同缺氧条件下 HepG2 细胞中的缺氧和凋亡相关蛋白，后缺氧组的 HIF-1α 除外。PSN 在抑制这些蛋白方面也明显优于前缺氧组，除了 Bcl2 之外。
我们的结果表明，PSN 可以提高 PTS 的水溶性和药物释放，增强缺氧条件下 HCC 治疗的疗效。
