School of Medicine, South China University of Technology, Guangzhou, 510006, China.
Department of Radiology, The Second Affiliated Hospital, School of Medicine, South China University of Technology, Guangzhou, 510180, China.
J Mater Chem B. 2024 Oct 9;12(39):9963-9978. doi: 10.1039/d4tb00081a.
The combination therapy of targeted treatments and immune checkpoint blockade (ICB) holds great promise for hepatocellular carcinoma (HCC) treatment. However, challenges such as immunogenicity, off-target toxicity of ICB antibodies, low drug co-delivery efficiency, and lack of effective biomarkers to monitor treatment response limit the efficacy of existing targeted immunotherapies. Herein, we synthesized iRGD-modified pH-sensitive liposomal nanoparticles co-encapsulating lenvatinib (Len) and the small molecule PD-1/PD-L1 inhibitor BMS-202 (iRGD-lip@Len/BMS-202) to address issues related to inadequate tumor enrichment and distinct pharmacokinetics of these drugs. Furthermore, intravoxel incoherent motion-magnetic resonance imaging (IVIM-MRI), which is calculated using a biexponential model, can simultaneously reflect both the diffusion of water molecules within the tissue and the microcirculatory perfusion of capillaries. Consequently, we further assessed the feasibility of using IVIM-MRI to monitor the cancer treatment response in nanodrug therapy. These results demonstrated that the iRGD-targeted liposomal nanodrug effectively accumulated in tumors and released in acidic microenvironments. The sustained release of Len facilitated tumor vascular normalization, decreased the presence of Tregs and MDSCs and activated the IFN-γ signaling pathway. This led to increased PD-L1 expression in tumor cells, enhancing the sensitivity of BMS-202. Consequently, there was a synergistic amplification of antitumor immune therapy, resulting in the shrinkage of subcutaneous and orthotopic HCC and inhibition of lung metastasis. Furthermore, IVIM-MRI technology facilitated the non-invasive monitoring of the tumor microenvironment (TME), revealing critical therapeutic response indicators such as the normalization of tumor blood vessels and the degree of hypoxia. Collectively, the combination of Food and Drug Administration (FDA)-approved drugs with iRGD-modified liposomes presents a promising strategy for HCC treatment. Simultaneously, IVIM-MRI provides a non-invasive method to accurately predict the response to this nanodrug.
联合靶向治疗和免疫检查点阻断（ICB）为肝细胞癌（HCC）的治疗带来了巨大的希望。然而，免疫原性、ICB 抗体的脱靶毒性、低药物共递效率以及缺乏有效的生物标志物来监测治疗反应等挑战限制了现有靶向免疫疗法的疗效。在这里，我们合成了 iRGD 修饰的 pH 敏感脂质体纳米粒，共包封仑伐替尼（Len）和小分子 PD-1/PD-L1 抑制剂 BMS-202（iRGD-lip@Len/BMS-202），以解决这些药物肿瘤富集不足和药代动力学差异的问题。此外，体素内不相干运动磁共振成像（IVIM-MRI），它是使用双指数模型计算的，可以同时反映组织内水分子的扩散和毛细血管的微循环灌注。因此，我们进一步评估了使用 IVIM-MRI 监测纳米药物治疗癌症反应的可行性。这些结果表明，iRGD 靶向脂质体纳米药物有效地在肿瘤中积累并在酸性微环境中释放。Len 的持续释放促进了肿瘤血管正常化，减少了 Tregs 和 MDSCs 的存在，并激活了 IFN-γ 信号通路。这导致肿瘤细胞中 PD-L1 的表达增加，增强了 BMS-202 的敏感性。因此，增强了抗肿瘤免疫治疗的协同作用，导致皮下和原位 HCC 的缩小以及肺转移的抑制。此外，IVIM-MRI 技术促进了肿瘤微环境（TME）的无创监测，揭示了关键的治疗反应指标，如肿瘤血管的正常化和缺氧程度。总之，将 FDA 批准的药物与 iRGD 修饰的脂质体结合为 HCC 的治疗提供了一种很有前途的策略。同时，IVIM-MRI 提供了一种无创方法，可以准确预测这种纳米药物的反应。
