Zhang Lei, Wang Duo, Zhang Lin-Zhu, Yang Wei-Hao, Yu Chao, Qin Juan, Feng Liang-Zhu, Liu Zhuang, Teng Gao-Jun
Center of Interventional Radiology and Vascular Surgery, Nurturing Center of Jiangsu Province for State Laboratory of AI Imaging & Interventional Radiology (Southeast University), Department of Radiology, Zhongda Hospital, Medical School, Southeast University, 87 Dingjiaqiao Road, Nanjing, 210009, China; National Innovation Platform for Integration of Medical Engineering Education (NMEE) (Southeast University), Nanjing, 210009, China; Basic Medicine Research and Innovation Center of Ministry of Education, Zhongda Hospital, Southeast University, Nanjing, 210009, China; State Key Laboratory of Digital Medical Engineering, Southeast University, Nanjing, 210009, China.
Department of Interventional Radiology, The First Affiliated Hospital of Soochow University, Suzhou, 215006, China.
Biomaterials. 2025 May;316:123018. doi: 10.1016/j.biomaterials.2024.123018. Epub 2024 Dec 18.
In the clinic, Lipiodol chemotherapeutic emulsions remain a main choice for patients diagnosed with hepatocellular carcinoma (HCC) via the mini-invasive transarterial chemoembolization (TACE) therapy. However, the poor stability of conventional Lipiodol chemotherapeutic emulsions would result in the fast drug diffusion and incomplete embolization, inducing systemic toxicity and impairing the efficacy of TACE therapy. Therefore, it is of great importance to construct alternative formulations based on commercial Lipiodol to achieve the improved efficacy and safety of HCC treatment. Herein, calcium phosphate (CaP) nanoparticles-stabilized Lipiodol Pickering emulsion (CaP-LPE) with improved stability and pH-responsiveness is prepared and utilized for the encapsulation of combretastatin A4-phosphate (CA4P), a clinically approved vascular disrupting agent. The obtained CA4P-loaded CaP-LPE (CCaP-LPE) was shown to be enhanced stability compared to conventional Lipiodol emulsion and pH-responsive release of the encapsulated drugs. On one hand, the released CA4P could disrupt tumor vascular and cut off the blood supplying of tumor cells, thus starving cancer cells. Moreover, it was revealed that CCaP-LPE could reverse immunosuppressive tumor microenvironment (TME) by neutralizing tumor acidity, leading to the increased infiltration of CD8 T cells and the decreased percentages of immunosuppressive cells. As the result, such CCaP-LPE could effectively shrink orthotopic N1S1 HCC tumors in rats by eliciting a potent antitumor immune response. Therefore, this study highlights a simple strategy to construct a novel LPE with the potencies of tumor vascular disruption and TME modulation, holding a great promise for TAE therapy of HCC.
在临床上，碘油化疗乳剂仍然是通过微创经动脉化疗栓塞（TACE）疗法诊断为肝细胞癌（HCC）患者的主要选择。然而，传统碘油化疗乳剂稳定性差会导致药物快速扩散和栓塞不完全，引发全身毒性并损害TACE疗法的疗效。因此，基于市售碘油构建替代制剂以提高HCC治疗的疗效和安全性具有重要意义。在此，制备了具有改善稳定性和pH响应性的磷酸钙（CaP）纳米颗粒稳定的碘油皮克林乳液（CaP-LPE），并用于包裹临床上已批准的血管破坏剂磷酸柯里拉京（CA4P）。与传统碘油乳剂相比，所获得的负载CA4P的CaP-LPE（CCaP-LPE）显示出增强的稳定性和包封药物的pH响应释放。一方面，释放的CA4P可破坏肿瘤血管并切断肿瘤细胞的血液供应，从而使癌细胞饥饿。此外，研究表明CCaP-LPE可通过中和肿瘤酸度来逆转免疫抑制性肿瘤微环境（TME），导致CD8 T细胞浸润增加和免疫抑制细胞百分比降低。结果，这种CCaP-LPE可通过引发有效的抗肿瘤免疫反应有效缩小大鼠原位N1S1 HCC肿瘤。因此，本研究突出了一种构建具有肿瘤血管破坏和TME调节能力的新型LPE的简单策略，为HCC的TAE治疗带来了巨大希望。
