Jiahui Yan,Haoyu Chen,Carlos F. Guimarães,Rui L. Reis,Zhihua Zhu,Tianyi Wang,Fenglan Zhang,Yaqian Lv,Qihui Zhou,Xiaoying Kong,Jinsheng Shi
Ion interference including copper (Cu + )/calcium (Ca 2+ ) 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@CaCO 3 -RGD nanoparticles (CCPCR NPs) are prepared to provide a Cu + /Ca 2+ dual-overload anti-tumor therapy assisted by metabolic-symbiosis-destruction strategy, realizing the collapse of tumor self-protection. Specifically, precise CuS and CaCO 3 delivery triggered irreversible Cu + /Ca 2+ 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 Ca 2+ 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.
Single cancer starvation therapy (ST) strategy can’t achieve satisfactory anti-tumor effect, mainly due to the diversified nutritional sources of tumor cells. Herein, [email protected] 2 @2-Deoxy-D-glucose(2-DG)-CaCO 3 -RGD nanoparticles (CADCR NPs) were prepared for three-pathway blocking for efficient starvation therapy as well as reinforced photothermal therapy (PTT) and chemodynamic therapy (CDT). After CADCR NPs were targeted to tumor cells, CaCO 3 was ruptured in the acidic environment, releasing Ca 2+ to chelate glutamine and cutting off the glutamine metabolic pathway of the tumor. 2-DG was also released from mesoporous SiO 2 and restrained the glycolytic pathway of tumor cells. In addition, under the thermal stimulus of near-infrared irradiation, axitinib was released from CuS NPs, which inhibited the proliferation of tumor blood vessels, ultimately inhibiting the aerobic respiratory pathway of tumor cells. Interestingly, CADCR NPs also showed potential to reshape the tumor microenvironment (TME) and promoted the transformation of macrophages from M2 to M1 type, increasing the expression of CD8+ T cells in the tumor site. In conclusion, CADCR NPs achieve severe tumor starvation by simultaneously interfering with three energy metabolic pathways, and further enhance tumor treatment with the aid of PTT, CDT, and TME improvement, which exhibits great potential for clinical cancer therapy.
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