Abstract：
The formation of pre-metastatic niche (PMN) in a hospitable organ derived from the primary tumor requires the communication between the tumor cells and the host environment. Pyruvate is a fundamental nutrient by which the tumor cells metabolically reshape the extracellular matrix in the lung to facilitate their own metastatic development. Here we report a combination regimen by integrating the photo-sensitizer and the mitochondrial pyruvate carrier (MPC) inhibitor in a dendritic polycarbonate core-hyaluronic acid shell nano-platform with multivalent reversible crosslinker embedded in it (DOH-NI+L) to reinforce photodynamic therapy (PDT) toward the primary tumor and interrupt PMN formation in the lung via impeding pyruvate uptake. We show that DOH-NI+L mediates tumor-specific MPC inhibitor liberation, inhibiting the aerobic respiration for facilitated PDT and restraining ATP generation for paralyzing cell invasion. Remarkably, DOH-NI+L is demonstrated to block the metabolic crosstalk of tumor cell-host environment by dampening pyruvate metabolism, provoking a series of metabolic responses and resulting in the pulmonary PMN interruption. Consequently, DOH-NI+L realizes a significant primary tumor inhibition and an efficient pulmonary metastasis prevention. Our research extends nano-based anti-metastatic strategies aiming at PMN intervention and such a dendritic core-shell nano-inhibitor provides an innovative paradigm to inhibit tumor growth and prevent metastasis efficiently. STATEMENT OF SIGNIFICANCE: In the progression of cancer metastasis, the formation of a pre-metastatic niche (PMN) in a hospitable organ derived from the primary tumor is one of the rate-limiting stages. The current nano-based anti-metastatic modalities mainly focus on targeted killing of tumor cells and specific inhibition of tumor cell invasion, while nanomedicine-mediated interruption of PMN formation has been rarely reported. Here we report a combination regimen by integrating a photo-sensitizer and an inhibitor of mitochondrial pyruvate carrier in a dendritic core-shell nano-platform with a reversible crosslinker embedded in it to reinforce PDT toward the primary tumor and interrupt PMN formation via impeding the uptake of pyruvate that is a fundamental nutrient facilitating aerobic respiration and PMN formation. Our research proposed a nano-based anti-metastatic strategy aiming at PMN intervention.
摘要：
在源自原发肿瘤的好客器官中形成转移前生态位（PMN）需要肿瘤细胞与宿主环境之间的联系。丙酮酸盐是肿瘤细胞代谢重塑肺细胞外基质以促进其自身转移发展的基本营养素。在这里，我们报告了一种组合方案，通过将光敏剂和线粒体丙酮酸载体（MPC）抑制剂整合到树枝状聚碳酸酯核-透明质酸壳纳米平台中，其中嵌入了多价可逆交联剂（DOH-NIL），以增强光动力疗法（PDT）对原发性肿瘤的作用，并通过阻止丙酮酸摄取来中断肺部PMN的形成。我们显示DOH-NI+L介导肿瘤特异性MPC抑制剂释放，抑制有氧呼吸促进PDT和抑制ATP生成麻痹细胞侵袭。值得注意的是,DOH-NI+L被证明通过抑制丙酮酸代谢来阻断肿瘤细胞-宿主环境的代谢串扰，引起一系列代谢反应，导致肺PMN中断。因此,DOH-NI+L实现了显著的原发肿瘤抑制和有效的肺转移预防。我们的研究扩展了针对PMN干预的基于纳米的抗转移策略，这种树突状核壳纳米抑制剂提供了一种创新的范例，可以有效地抑制肿瘤生长和预防转移。重要性声明：在癌症转移的进展中，在源自原发肿瘤的好客器官中形成转移前生态位（PMN）是限速阶段之一。目前基于纳米的抗转移方式主要集中在靶向杀伤肿瘤细胞和特异性抑制肿瘤细胞侵袭,而纳米医学介导的PMN形成中断的报道很少。在这里，我们报告了一种组合方案，通过将光敏剂和线粒体丙酮酸盐载体抑制剂整合在树突状核壳纳米平台中，其中嵌入了可逆交联剂，以增强对原发性肿瘤的PDT并通过阻止丙酮酸盐的摄取来中断PMN的形成，丙酮酸盐是促进有氧呼吸和PMN形成的基本营养素。我们的研究提出了一种基于纳米的针对PMN干预的抗转移策略。
