Yueh Po-Fu, Chiang Chih-Sheng, Tsai I-Jung, Tseng Yun-Long, Chen He-Ru, Lan Keng-Li, Hsu Fei-Ting
Institute of Traditional Medicine, National Yang Ming Chiao Tung University, 6th Floor, Shouren Building, No. 155, Section 2, Linong Street, Beitou District, Taipei, 112, Taiwan, ROC.
Graduate Institute of Biomedical Sciences, China Medical University, Taichung, Taiwan, ROC.
J Nanobiotechnology. 2024 Jul 31;22(1):459. doi: 10.1186/s12951-024-02664-5.
Sunitinib is a multikinase inhibitor used to treat patients with advanced renal cell carcinoma (RCC). However, sunitinib toxicity makes it a double-edged sword. Potent immune modulation by sunitinib extends to nuclear interactions. To address these issues, there is an urgent need for delivery vectors suitable for sunitinib treatment.
We developed PEGylated liposomes as delivery vectors to precisely target sunitinib (lipo-sunitinib) to RCC tumors. Further investigations, including RNA sequencing (RNA-seq), were performed to evaluate transcriptomic changes in these pathways. DiI/DiR-labeled lipo-sunitinib was used for the biodistribution analysis. Flow cytometry and immunofluorescence (IF) were used to examine immune modulation in orthotopic RCC models.
The evaluation of results indicated that lipo-sunitinib precisely targeted the tumor site to induce autophagy and was readily taken up by RCC tumor cells. In addition, transcriptomic assays revealed that following lipo-sunitinib treatment, autophagy, antigen presentation, cytokine, and chemokine production pathways were upregulated, whereas the epithelial-mesenchymal transition (EMT) pathway was downregulated. In vivo data provided evidence supporting the inhibitory effect of lipo-sunitinib on RCC tumor progression and metastasis. Flow cytometry further demonstrated that liposunitinib increased the infiltration of effector T cells (Teffs) and conventional type 1 dendritic cells (cDC1s) into the tumor. Furthermore, systemic immune organs such as the tumor-draining lymph nodes, spleen, and bone marrow exhibited upregulated anticancer immunity following lipo-sunitinib treatment.
Our findings demonstrated that lipo-sunitinib is distributed at the RCC tumor site, concurrently inducing potent autophagy, elevating antigen presentation, activating cytokine and chemokine production pathways, and downregulating EMT in RCC cells. This comprehensive approach significantly enhanced tumor inhibition and promoted anticancer immune modulation.
舒尼替尼是一种用于治疗晚期肾细胞癌（RCC）患者的多激酶抑制剂。然而，舒尼替尼的毒性使其成为一把双刃剑。舒尼替尼强大的免疫调节作用延伸至核相互作用。为解决这些问题，迫切需要适合舒尼替尼治疗的递送载体。
我们开发了聚乙二醇化脂质体作为递送载体，以将舒尼替尼（脂质体-舒尼替尼）精确靶向RCC肿瘤。进行了包括RNA测序（RNA-seq）在内的进一步研究，以评估这些途径中的转录组变化。使用DiI/DiR标记的脂质体-舒尼替尼进行生物分布分析。采用流式细胞术和免疫荧光（IF）检测原位RCC模型中的免疫调节。
结果评估表明，脂质体-舒尼替尼精确靶向肿瘤部位以诱导自噬，并易于被RCC肿瘤细胞摄取。此外，转录组分析显示，脂质体-舒尼替尼治疗后，自噬、抗原呈递、细胞因子和趋化因子产生途径上调，而上皮-间质转化（EMT）途径下调。体内数据提供了支持脂质体-舒尼替尼对RCC肿瘤进展和转移具有抑制作用的证据。流式细胞术进一步证明，脂质体-舒尼替尼增加了效应T细胞（Teffs）和常规1型树突状细胞（cDC1s）向肿瘤的浸润。此外，脂质体-舒尼替尼治疗后，肿瘤引流淋巴结、脾脏和骨髓等全身免疫器官的抗癌免疫力上调。
我们的研究结果表明，脂质体-舒尼替尼分布于RCC肿瘤部位，同时诱导强效自噬，提高抗原呈递，激活细胞因子和趋化因子产生途径，并下调RCC细胞中的EMT。这种综合方法显著增强了肿瘤抑制作用并促进了抗癌免疫调节。
