Gao Cheng, Kwong Cheryl H T, Wang Qingfu, Kam Hiotong, Xie Beibei, Lee Simon Ming-Yuen, Chen Guosong, Wang Ruibing
State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Taipa, Macau SAR 999078, China.
MoE Frontiers Science Center for Precision Oncology, University of Macau, Taipa, Macau SAR 999078, China.
ACS Nano. 2023 Feb 28;17(4):4034-4049. doi: 10.1021/acsnano.3c00041. Epub 2023 Feb 5.
Sonodynamic therapy (SDT) is a noninvasive technique for local antitumor treatment; however, its clinical application is often limited by the low tumor accumulation of SDT agents, tumor's hypoxic microenvironment, and cytoprotective effects of autophagy. To address these issues, herein we developed surface-engineered chlorella (Chl, a green algae) as a targeted drug carrier and sustainable oxygen supplier (via photosynthesis) for significantly improved SDT via hypoxia alleviation as well as autophagy inhibition of chloroquine phosphate. In this design, the macrophage membrane was coated onto Chl to form macrophage-mimetic Chl (MChl) to increase its biocompatibility and targeted tumor accumulation driven by the inflammatory-homing effects of macrophage membranes. In addition, the membrane coating on Chl allowed lipid insertion to yield β-cyclodextrin (β-CD) modified MChl (CD-MChl). Subsequently, supramolecular conjugates of MChl-NP were constructed via host-guest interactions between CD-MChl and adamantane (ADA)-modified liposome (ADA-NP), and the anchored liposome went with CD-MChl hand-in-hand to the tumor tissues for co-delivery of Chl, hematoporphyrin, and chloroquine phosphate (loaded in ADA-NP). The synergistic therapy achieved via local oxygenation, SDT, and autophagy inhibition maximally improved the therapeutic efficacy of MChl-CQ-HP-NP against melanoma. Tumor rechallenging results revealed that the changes of tumor microenvironment including hypoxia alleviation, SDT induced immunogenic cell death, and autophagy inhibition collectively induced a strong antitumor immune response and memory.
声动力疗法（SDT）是一种用于局部抗肿瘤治疗的非侵入性技术；然而，其临床应用常常受到声动力治疗剂在肿瘤中低蓄积、肿瘤缺氧微环境以及自噬的细胞保护作用的限制。为了解决这些问题，我们在此开发了表面工程化的小球藻（Chl，一种绿藻）作为靶向药物载体和可持续氧气供应源（通过光合作用），以通过缓解缺氧以及抑制磷酸氯喹的自噬作用显著改善声动力疗法。在这种设计中，将巨噬细胞膜包被在小球藻上以形成模拟巨噬细胞的小球藻（MChl），以提高其生物相容性并通过巨噬细胞膜的炎症归巢效应驱动其靶向肿瘤蓄积。此外，小球藻上的膜包被允许脂质插入，从而产生β-环糊精（β-CD）修饰的MChl（CD-MChl）。随后，通过CD-MChl与金刚烷（ADA）修饰的脂质体（ADA-NP）之间的主客体相互作用构建了MChl-NP的超分子缀合物，并且锚定的脂质体与CD-MChl携手进入肿瘤组织，用于共同递送小球藻、血卟啉和磷酸氯喹（负载于ADA-NP中）。通过局部氧合、声动力疗法和自噬抑制实现的协同治疗最大程度地提高了MChl-CQ-HP-NP对黑色素瘤的治疗效果。肿瘤再激发结果表明，包括缺氧缓解、声动力疗法诱导的免疫原性细胞死亡和自噬抑制在内的肿瘤微环境变化共同诱导了强烈的抗肿瘤免疫反应和记忆。
