Author(s): Yan, Jiahui ; Chen, Haoyu ; Guimarães, Carlos Ferreira ; Reis, R. L. ; Zhu, Zhihua ; Wang, Tianyi ; Zhang, Fenglan ; Zhou, Qihui ; Kong, Xiaoying ; Shi, Jinsheng ; Lv, Yaqian
Date: 2024
Persistent ID: https://hdl.handle.net/1822/94773
Origin: RepositóriUM - Universidade do Minho
Subject(s): Cu+/Ca2+ dual-overload; Metabolic symbiosis; Tumor Apoptosis; Tumor Immune Activation; Cu /Ca dual-overload + 2+; disruption of metabolic symbiosis
Ion interference including copper (Cu+)/calcium (Ca2+) overload activate cell-specific death channels, damage mitochondria and disrupt cellular homeostasis, showing great potential in anti-tumor therapy. However, the complex metabolic environment and the powerful self-protection of tumors cause clinical failure of ion interference. Thus, metabolic disruption is expected an innovative strategy for the enhancement of ion interference. Herein, CuS-α-CHCA&penthiopyrad@CaCO3-RGD nanoparticles (CCPCR NPs) are prepared to provide a Cu+/Ca2+ dual-overload anti-tumor therapy assisted by metabolic-symbiosis-destruction strategy, realizing the collapse of tumor self-protection. Specifically, precise CuS and CaCO3 delivery triggered irreversible Cu+/Ca2+ dual-overload and reactive oxygen species (ROS) attack toward 4T1 cells. Meanwhile, α-CHCA and penthiopyrad disturbed the metabolic symbiotic environment by disrupting the TCA cycle and preventing lactate efflux to aggravate intracellular acidosis and promote Fenton-like reaction of Cu+, enhancing the sensitivity of tumor cells to copper death and Ca2+ overload. Further, aided by the metabolism of symbiosis, the destroyed tumor cells further activate the polarization of M1 macrophages and the maturation and antigen cross-presentation of dendritic cells (DCs), which further eliminate tumor cells. In summary, an amplified anti-tumor dual-ion interference strategy assisted by metabolic symbiotic destruction is established, which is of great significance in improving the clinical effect of ion therapy for tumors.
