Augmented EPR effect post IRFA to enhance the therapeutic efficacy of arsenic loaded ZIF-8 nanoparticles on residual HCC progression.
Augmented EPR effect post IRFA to enhance the therapeutic efficacy of arsenic loaded ZIF-8 nanoparticles on residual HCC progression.
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IRFA 后增强的 EPR 效果可增强载砷 ZIF-8 纳米颗粒对残留 HCC 进展的治疗效果
DOI：
10.1186/s12951-021-01161-3
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发表时间：
2022-01-15
影响因子：
10.2
通讯作者：
Su Z
中科院分区：
文献类型：
--
作者：
Chen X;Huang Y;Chen H;Chen Z;Chen J;Wang H;Li D;Su Z
背景充分的射频消融（IRFA）可促进残余肝细胞癌（HCC）的局部复发和远端转移，这使得临床治疗极具挑战性。本研究探讨了IRFA后残余肿瘤的恶性转移。然后构建负载砷的沸石咪唑酸框架-8纳米粒子（As@ZIF-8 NPs），并研究其对残余肿瘤的治疗效果。结果IRFA能显著促进残余肿瘤的增殖，诱导肿瘤转移，激活上皮-间质转化（epithelial-mesenchymal transition， EMT），促进肿瘤血管生成。有趣的是，我们首次发现，IRFA后广泛的血管生成可以增强增强的通透性和保留（EPR）效应，并增强ZIF-8纳米载体在残留肿瘤中的富集。在这一独特发现的鼓舞下，我们成功制备了具有良好生物相容性的As@ZIF-8 NPs，并证实其在亚致死热诱导细胞增殖抑制、诱导凋亡、细胞迁移和侵袭抑制以及体外EMT逆转方面比游离三氧化二砷（ATO）更有效。此外，与游离ATO相比，As@ZIF-8 NPs通过抑制体内残余肿瘤的生长和转移，显着提高了治疗效果。结论本研究为肝细胞癌术后残留肝细胞癌的治疗提供了一种新的模式。图形抽象
BackgroundInsufficient radiofrequency ablation (IRFA) can promote the local recurrence and distal metastasis of residual hepatocellular carcinoma (HCC), which makes clinical treatment extremely challenging. In this study, the malignant transition of residual tumors after IRFA was explored. Then, arsenic-loaded zeolitic imidazolate framework-8 nanoparticles (As@ZIF-8 NPs) were constructed, and their therapeutic effect on residual tumors was studied.ResultsOur data showed that IRFA can dramatically promote the proliferation, induce the metastasis, activate the epithelial–mesenchymal transition (EMT) and accelerate the angiogenesis of residual tumors. Interestingly, we found, for the first time, that extensive angiogenesis after IRFA can augment the enhanced permeability and retention (EPR) effect and enhance the enrichment of ZIF-8 nanocarriers in residual tumors. Encouraged by this unique finding, we successfully prepared As@ZIF-8 NPs with good biocompatibility and confirmed that they were more effective than free arsenic trioxide (ATO) in sublethal heat-induced cell proliferation suppression, apoptosis induction, cell migration and invasion inhibition, and EMT reversal in vitro. Furthermore, compared with free ATO, As@ZIF-8 NPs exhibited remarkably increased therapeutic effects by repressing residual tumor growth and metastasis in vivo.ConclusionsThis work provides a new paradigm for the treatment of residual HCC after IRFA.Graphical Abstract
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