Hepatobiliary and Pancreatic Surgery Department, General Surgery Center, First Hospital of Jilin University, Changchun, China.
Department of General Surgery, Xuanwu Hospital, Capital Medical University, Beijing, China.
Sci Rep. 2024 Nov 9;14(1):27395. doi: 10.1038/s41598-024-79069-9.
Although there have been remarkable advances in the treatment of hepatocellular carcinoma (HCC), the prognosis remains poor in those with advanced stage and more effective therapeutic options are urgently needed. Lenvatinib (Len), a multiple receptor tyrosine kinase inhibitor, is an emerging molecular targeted agent for HCC, whose immunomodulatory activities have been investigated. However, Len utilization is limited because of its low metabolic stability, poor bioavailability and dose-dependent toxicity, rendering its direct use insufficient for immune modulation. Stimuli-responsive nanoparticles, which are drug-targeted delivery platforms for on-demand drug release, facilitate deeper and uniform tumour penetration, providing alternative solutions to overcome current limitations. Ultrasound (US) exhibits superior tissue penetration abilities and can produce reactive oxygen species (ROS) at the tumour site to treat deeper tumours. In addition, US serves as an excellent and selective drug delivery mediator for tumour treatment. Herein, we designed US-triggered lenvatinib nanoparticles (Len-RNPs) for selective drug delivery that utilize US-triggered ROS to induce in situ oxidation reactions, resulting in nanoparticle disintegration. Len-RNPs mitigate the toxicity of Len and effectively trigger robust systemic anti-tumour immune responses in a H22 tumour model, resulting in a tumour suppression rate of 95.7%, with 60% of mice being cured. Our study elucidates a novel and precise strategy of combining Len and US therapy for enhanced HCC immunotherapy.
尽管肝细胞癌（HCC）的治疗取得了显著进展，但晚期患者的预后仍然较差，因此迫切需要更有效的治疗选择。仑伐替尼（Len）是一种多受体酪氨酸激酶抑制剂，是一种新兴的 HCC 分子靶向药物，其免疫调节活性已得到研究。然而，由于其代谢稳定性低、生物利用度差和剂量依赖性毒性，限制了其使用，其直接使用不足以进行免疫调节。刺激响应性纳米颗粒是一种药物靶向递药平台，可实现按需药物释放，有利于更深和更均匀的肿瘤渗透，为克服当前限制提供了替代解决方案。超声（US）具有优越的组织穿透能力，并可在肿瘤部位产生活性氧（ROS）来治疗更深的肿瘤。此外，超声还是一种用于肿瘤治疗的优秀和选择性药物输送介质。在此，我们设计了超声触发的仑伐替尼纳米颗粒（Len-RNPs）用于选择性药物输送，利用超声触发的 ROS 诱导原位氧化反应，导致纳米颗粒解体。Len-RNPs 减轻了 Len 的毒性，并在 H22 肿瘤模型中有效触发了强大的全身抗肿瘤免疫反应，肿瘤抑制率为 95.7%，有 60%的小鼠被治愈。我们的研究阐明了一种将 Len 和 US 治疗相结合以增强 HCC 免疫治疗的新的精确策略。
