Carrier-Free Nanoagent Interfering with Cancer-Associated Fibroblasts’ Metabolism to Promote Tumor Penetration for Boosted Chemotherapy
Lili Yu, Xiaocheng Zhou, Zhenan Liu, Hanzhe Liu, Xian‐Zheng Zhang, Guo‐Feng Luo, Z. J. Shang
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.