Carrier-Free Nanoagent Interfering with Cancer-Associated Fibroblasts’ Metabolism to Promote Tumor Penetration for Boosted Chemotherapy

IF 9.6 1区材料科学 Q1 CHEMISTRY, MULTIDISCIPLINARY

Nano Letters Pub Date : 2024-09-13 DOI:10.1021/acs.nanolett.4c03433

Lili Yu, Xiaocheng Zhou, Zhenan Liu, Hanzhe Liu, Xian-Zheng Zhang, Guo-Feng Luo, Zhengjun Shang

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Abstract

Elevated production of extracellular matrix (ECM) in tumor stroma is a critical obstacle for drug penetration. Here we demonstrate that ATP-citrate lyase (ACLY) is significantly upregulated in cancer-associated fibroblasts (CAFs) to produce tumor ECM. Using a self-assembling nanoparticle-design approach, a carrier-free nanoagent (CFNA) is fabricated by simply assembling NDI-091143, a specific ACLY inhibitor, and doxorubicin (DOX) or paclitaxel (PTX), the first-line chemotherapeutic drug, via multiple noncovalent interactions. After arriving at the CAFs-rich tumor site, NDI-091143-mediated ACLY inhibition in CAFs can block the de novo synthesis of fatty acid, thereby dampening the fatty acid-involved energy metabolic process. As the lack of enough energy, the energetic CAFs will be in a dispirited state that is unable to produce abundant ECM, thereby significantly improving drug perfusion in tumors and enhancing the efficacy of chemotherapy. Such a simple drug assembling strategy aimed at CAFs’ ACLY-mediated metabolism pathway presents the feasibility of stromal matrix reduction to potentiate chemotherapy.

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无载体纳米试剂干扰癌症相关成纤维细胞的新陈代谢，促进肿瘤穿透以增强化疗效果

肿瘤基质中细胞外基质（ECM）的生成增加是药物渗透的关键障碍。在这里，我们证明了ATP-柠檬酸裂解酶（ACLY）在癌症相关成纤维细胞（CAFs）中显著上调，从而产生肿瘤ECM。我们采用自组装纳米粒子设计方法，将特异性 ACLY 抑制剂 NDI-091143 和一线化疗药物多柔比星（DOX）或紫杉醇（PTX）通过多种非共价相互作用组装在一起，制成了一种无载体纳米试剂（CFNA）。NDI-091143介导的ACLY抑制剂到达富含CAFs的肿瘤部位后，可阻断CAFs中脂肪酸的从头合成，从而抑制脂肪酸参与的能量代谢过程。由于缺乏足够的能量，精力充沛的CAFs将处于萎靡状态，无法产生丰富的ECM，从而显著改善肿瘤内的药物灌注，提高化疗的疗效。这种针对 CAFs ACLY 介导的新陈代谢途径的简单药物组装策略，展示了基质减少以增强化疗效果的可行性。

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来源期刊

Nano Letters 工程技术-材料科学：综合

CiteScore

16.80

自引率

2.80%

发文量

1182

审稿时长

1.4 months

期刊介绍： Nano Letters serves as a dynamic platform for promptly disseminating original results in fundamental, applied, and emerging research across all facets of nanoscience and nanotechnology. A pivotal criterion for inclusion within Nano Letters is the convergence of at least two different areas or disciplines, ensuring a rich interdisciplinary scope. The journal is dedicated to fostering exploration in diverse areas, including: - Experimental and theoretical findings on physical, chemical, and biological phenomena at the nanoscale - Synthesis, characterization, and processing of organic, inorganic, polymer, and hybrid nanomaterials through physical, chemical, and biological methodologies - Modeling and simulation of synthetic, assembly, and interaction processes - Realization of integrated nanostructures and nano-engineered devices exhibiting advanced performance - Applications of nanoscale materials in living and environmental systems Nano Letters is committed to advancing and showcasing groundbreaking research that intersects various domains, fostering innovation and collaboration in the ever-evolving field of nanoscience and nanotechnology.