Department of Radiology, Stanford University, School of Medicine, Stanford, CA, USA.
Department of Comparative Medicine, Stanford University, Stanford, CA, USA.
J Control Release. 2018 Jul 10;281:19-28. doi: 10.1016/j.jconrel.2018.05.009. Epub 2018 May 24.
Hepatocellular carcinoma (HCC) is the second-leading cause of cancer related deaths worldwide and new strategies to efficiently treat HCC are critically needed. The aim of this study was to assess the longitudinal treatment effects of two complementary miRNAs (miRNA-122 and antimiR-21) encapsulated in biodegradable poly lactic-co-glycolic acid (PLGA) - poly ethylene glycol (PEG) nanoparticles (PLGA-PEG-NPs), administered by an ultrasound-guided and microbubble-mediated delivery approach in doxorubicin-resistant and non-resistant human HCC xenografts. Using in vitro assays, we show that repeated miRNA treatments resulted in gradual reduction of HCC cell proliferation and reversal of doxorubicin resistance. Optimized US parameters resulted in a 9-16 fold increase (p = 0.03) in miRNA delivery in vivo in HCC tumors after two US treatments compared to tumors without US treatment. Furthermore, when combined with doxorubicin (10 mg/kg), longitudinal miRNA delivery showed a significant inhibition of tumor growth in both resistant and non-resistant tumors compared to non-treated, and doxorubicin treated controls. We also found that ultrasound-guided miRNA therapy was not only effective in inhibiting HCC tumor growth but also allowed lowering the dose of doxorubicin needed to induce apoptosis. In conclusion, the results of this study suggest that ultrasound-guided and MB-mediated delivery of miRNA-122 and antimiR-21, when combined with doxorubicin, is a highly effective approach to treat resistant HCC while reducing doxorubicin doses needed for treating non-resistant HCC in longitudinal treatment experiments. Further refinement of this strategy could potentially lead to better treatment outcomes for patients with HCC.
肝细胞癌（HCC）是全球癌症相关死亡的第二大原因，迫切需要新的策略来有效治疗 HCC。本研究旨在评估两种互补 miRNA（miRNA-122 和 antimiR-21）封装在可生物降解的聚乳酸-共-羟基乙酸（PLGA）-聚乙二醇（PEG）纳米颗粒（PLGA-PEG-NPs）中，通过超声引导和微泡介导的给药方法在多柔比星耐药和非耐药人 HCC 异种移植瘤中的纵向治疗效果。通过体外实验，我们表明重复 miRNA 治疗导致 HCC 细胞增殖逐渐减少，并逆转多柔比星耐药性。优化的超声参数导致两次超声治疗后 HCC 肿瘤内 miRNA 递送增加 9-16 倍（p=0.03），而未经超声治疗的肿瘤则没有增加。此外，当与多柔比星（10mg/kg）联合使用时，与未治疗组和多柔比星治疗组相比，纵向 miRNA 递送在耐药和非耐药肿瘤中均显著抑制肿瘤生长。我们还发现，超声引导的 miRNA 治疗不仅有效抑制 HCC 肿瘤生长，还允许降低诱导细胞凋亡所需的多柔比星剂量。总之，这项研究的结果表明，超声引导和 MB 介导的 miRNA-122 和 antimiR-21 递送与多柔比星联合使用，是治疗耐药 HCC 的一种非常有效的方法，同时在纵向治疗实验中降低了治疗非耐药 HCC 所需的多柔比星剂量。这种策略的进一步改进可能为 HCC 患者带来更好的治疗效果。
