Ye Zirui, Yan Bin, Li Hugang, Tang Qianqian, Yuan Kexin, Hou Jingjing, Xu Lexuan, Yuan Jianlan, Wang Siyao, Jiao Wangbo, Fan Haiming, Lyu Yi, Wang Bo, Liu Xiaoli
National Local Joint Engineering Research Center for Precision Surgery & Regenerative Medicine, Shaanxi Province Center for Regenerative Medicine and Surgery Engineering Research, Shaanxi Provincial Key Laboratory of Magnetic Medicine, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi 710061, China; Institute of Regenerative and Reconstructive Medicine, Med-X Institute, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi 710049, China.
School of Future Technology, Xi'an Jiaotong University, Xi'an, Shaanxi 710049, China.
Acta Biomater. 2025 May 15;198:389-400. doi: 10.1016/j.actbio.2025.04.014. Epub 2025 Apr 11.
Hepatocellular carcinoma (HCC) presents significant treatment challenges, primarily due to its ability to suppress immune responses. Lenvatinib (LT), approved as a first-line therapy for HCC, modulates the immune microenvironment by reducing PD-L1 expression and decreasing the infiltration of regulatory T cells (T) within the tumor. However, the low immunogenicity of HCC and high toxicity of LT often undermine its effectiveness. To address these challenges, polydopamine (PDA)-coated ferrimagnetic vortex-domain iron oxide nanorings (FVIO@PDA) were engineered to respond to both acidic conditions and magnetic fields, facilitating the simultaneous delivery of the drug (LT) and a physio-therapeutic heat modality. The dual-responsive nature of FVIO@PDA ensures a controlled and synergistic release of LT, activated by acidic tumor microenvironments and the heat produced by an alternating magnetic field (AMF). In a subcutaneous Hepa1-6 HCC model, LT-loaded FVIO@PDA-PEG (denoted as LT-loaded FPP)-mediated magnetic hyperthermia significantly increased the levels of cytotoxic T lymphocytes, showing an approximate 3.86-fold increase compared to the control groups. This combination of LT and magnetic hyperthermia also reduced Treg populations to 1.4 %, synergistically triggering a robust antitumor immune response. Additionally, it altered cytokine profiles, reducing the secretion of the immunosuppressive cytokine IL-10 to 0.41 times that of control levels, while increasing the secretion of pro-inflammatory cytokines IFN-γ and TNF-α by 3.25 and 4.34 times, respectively. Furthermore, LT-loaded FPP-mediated magnetic hyperthermia exhibits superior anti-tumor activity compared to either treatment alone. These results highlight the promise of combining LT with FPP-mediated immunogenic magnetic hyperthermia as a potent therapeutic strategy for HCC, offering a more effective approach to modulate the immune environment and enhance antitumor efficacy. STATEMENT OF SIGNIFICANCE: Lenvatinib (LT) is a selective multi-targeted tyrosine kinase inhibitor used for patients with unresectable HCC who have not previously undergone systemic therapy. LT's immunomodulatory effects alone are often insufficient to induce an effective immune response, and treatment outcomes continue to be unsatisfactory. We developed FVIO@PDA for the delivery of LT and localized heat. FVIO@PDA allowed for controlled release of LT, triggered by the acidic tumor microenvironment and the heat generated under an AMF. LT combined with magnetic hyperthermia increased CTLs, reduced T, decreased immunosuppressive cytokines, and elevated pro-inflammatory ones, collectively initiating a strong antitumor immune response. LT combined with magnetic hyperthermia showed superior antitumor effect compared to either treatment alone.
肝细胞癌(HCC)带来了重大的治疗挑战,主要是因为它能够抑制免疫反应。乐伐替尼(LT)被批准作为HCC的一线治疗药物,通过降低PD-L1表达和减少肿瘤内调节性T细胞(Tregs)的浸润来调节免疫微环境。然而,HCC的低免疫原性和LT的高毒性常常削弱其疗效。为了应对这些挑战,设计了聚多巴胺(PDA)包覆的亚铁磁性涡旋域氧化铁纳米环(FVIO@PDA),使其对酸性条件和磁场都有响应,便于同时递送药物(LT)和物理治疗热疗方式。FVIO@PDA的双重响应特性确保了LT的可控和协同释放,由酸性肿瘤微环境和交变磁场(AMF)产生的热量激活。在皮下Hepa1-6 HCC模型中,负载LT的FVIO@PDA-PEG(表示为负载LT的FPP)介导的磁热疗显著增加了细胞毒性T淋巴细胞的水平,与对照组相比增加了约3.86倍。LT与磁热疗的这种组合还将Tregs群体减少到1.4%,协同触发强大的抗肿瘤免疫反应。此外,它改变了细胞因子谱,将免疫抑制细胞因子IL-10的分泌减少到对照水平的0.41倍,同时将促炎细胞因子IFN-γ和TNF-α的分泌分别增加了3.25倍和4.34倍。此外,负载LT的FPP介导的磁热疗与单独的任何一种治疗相比都表现出 superior抗肿瘤活性。这些结果突出了将LT与FPP介导的免疫原性磁热疗相结合作为HCC有效治疗策略的前景,提供了一种更有效的方法来调节免疫环境并增强抗肿瘤疗效。
重要性声明:乐伐替尼(LT)是一种选择性多靶点酪氨酸激酶抑制剂,用于未曾接受过全身治疗的不可切除HCC患者。单独使用LT的免疫调节作用往往不足以诱导有效的免疫反应,治疗结果仍然不尽人意。我们开发了FVIO@PDA用于递送LT和局部加热。FVIO@PDA允许LT在酸性肿瘤微环境和AMF下产生的热量触发下进行可控释放。LT与磁热疗相结合增加了CTLs,减少了Tregs,降低了免疫抑制细胞因子,并提高了促炎细胞因子,共同引发了强烈的抗肿瘤免疫反应。LT与磁热疗相结合与单独的任何一种治疗相比都显示出 superior抗肿瘤效果。
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