Recent advances in copper homeostasis-involved tumor theranostics

Abstract

As the third essential trace element in the human body, copper plays a crucial role in various physiological processes, which lays the foundation for its broad applications in cancer treatments. The overview of copper, including pharmacokinetics, signaling pathways, and homeostasis dysregulation, is hereby discussed. Additionally, cuproptosis, as a newly proposed cell death mechanism associated with copper accumulation, is analyzed and further developed for efficient cancer treatment. Different forms of Cu-based nanoparticles and their advantages, as well as limiting factors, are introduced. Moreover, the unique characteristics of Cu-based nanoparticles give rise to their applications in various imaging modalities. In addition, Cu-based nanomaterials are featured by their excellent photothermal property and ROS-associated tumor-killing potential, which are widely explored in diverse cancer therapies and combined therapies. Reducing the concentration of Cu²⁺/Cu⁺ is another cancer-killing method, and chelators can meet this need. More importantly, challenges and future prospects are identified for further research.

Keywords: Chelators; Copper homeostasis; Cu-based nanoparticles; Cuproptosis; Tumor theranostics.

Graphical abstract

Fig. 1

Schematic illustration of regulating Cu homeostasis and Cu-based nanoparticles for tumor theranostics. The mechanisms of cuproptosis and Cu chelation, classification of Cu-based NPs, and application are involved.

Fig. 2

Mechanism and application of cuproptosis. (A) Mechanism illustration of cuproptosis [44]. Copyright 2022, Science. (B) The preparation process of Au @ MSN-Cu/polyethylene glycol /DSF and its cuproptosis and other functions in tumor treatment [54]. Copyright 2022, Wiley. (C) The synthesis of nonporous GOx@[Cu(tz)] and starvation enhanced cuproptosis and photodynamic therapy [55]. Copyright 2022, Wiley. (D) The synthetic process and anticancer mechanism of CuET NPs [56]. Copyright 2022, the Royal Society of Chemistry.

Fig. 3

Cu-based nanoparticles for PTT. (A) Application of CuFe₂S₃ nanoplates in synergistic NIR-II PTT and CDT [124]. Copyright 2021 Elsevier. (B) Application of Cu-BTC in the treatment of melanoma by enhancing the PTT and CDT characteristics of PDA [125]. Copyright 2023 Elsevier. (C) Application of BP@Cu in PET-guided PTT cancer treatment [126]. Copyright 2020 Nature Communications.

Fig. 4

Cu-based nanoparticles for CDT. (A) Mechanism of Cu-OCNP/Lap's abundant H₂O₂ supply enhancing CDT [136]. Copyright 2021, Elsevier. (B) Schematic illustration of tumor-specific therapeutic mechanism of GOD/CuFe-LDHs [137]. Copyright 2021, the Royal Society of Chemistry. (C) Application of Cu-SeC nanoparticles in strengthening CDT [139]. Copyright 2023, American Chemical Society. (D) Schematic illustration of BCHN's synergistic therapy combined with CDT and RT [140]. Copyright 2021, Elsevier.

Fig. 5

Cu-based nanoparticles for PDT. (A) Application of CuCy NPs to enhance PDT of type I photosensitizer NS-STPA with AIE activity [150]. Copyright 2022, American Chemical Society. (B) Application of mCMSNs with GSH depletion and hypoxia relief in the synergetic therapy of PDT and CDT [151]. Copyright 2019, American Chemical Society. (C) Application of J-MOPs in enhancing environmental stability and PDT efficiency [152]. Copyright 2019, the Royal Society of Chemistry.

Fig. 6

Cu-based nanoparticles for SDT. (A) Schematic illustration of anti-tumor SDT mediated by FA–L–CuPP [155]. Copyright 2022, Multidisciplinary Digital Publishing Institute. (B) Schematic illustration of synergistic SDT and CDT of 2D Ti₃C₂/CuO₂@BSA nanosheets under ultrasound [156]. Copyright 2022, American Chemical Society. (C) Schematic illustration of SonoCu's effective combination of SDT and cuproptosis in the treatment of cancer [157]. Copyright 2023, American Chemical Society. (D) Schematic illustration of H-Cu₉S₈@CCM NPs synergistic PTT-SDT [158]. Copyright 2023, Elsevier. (E) Schematic illustration of antitumor mechanism of PCPT [159]. Copyright 2019, American Chemical Society.

Fig. 7

Cu-based nanoparticles for immunotherapy. (A) Schematic illustration of CuS-OMVs cooperating with PTT and immunotherapy for cancer [163]. Copyright 2022, Elsevier. (B) Schematic illustration of the preparation of Cu-COF and ICD induced by enhanced Fenton-like effect [164]. Copyright 2023, Wiley. (C) Schematic illustration of the preparation of BMS-SNAP-MOF and synergistic enhancement of anti-tumor immunotherapy by IDO inhibition and NO combination therapy [165]. Copyright 2022, Wiley. (D) schematic illustration of the preparation of NP@ESCu and inducing Cu death for enhancing cancer immunotherapy [166]. Copyright 2023, Wiley.

Fig. 8

Cu-based nanoparticles for combined cancer therapy. (A) Schematic illustration of GOx@CMPB-HN NPs for in-situ amplification of PTT, CDT and hunger therapy [169]. Copyright 2023, American Chemical Society. (B) Schematic illustration of O2-Cu/ZIF-8 @ Ce6/ZIF-8 @ F127 for synergistic therapy of PDT and CDT [170]. Copyright 2019, American Chemical Society. (C) Schematic illustration of synthesis process of CuPP nanoenzyme and its application in PTT, CDT and immunotherapy [172]. Copyright 2022, Wiley.

Fig. 9

Cu-based nanoparticles involved in cancer imaging. (A) PEG-coated ⁶⁴CuS NPs for PET imaging of U87 xenograft tumor [176]. Copyright 2016, American Chemical Society. (B) In vivo CT imaging of mice using Cu_2-xS:Pt(0.3)/PVP NPs [179]. Copyright 2018, the Royal Society of Chemistry. (C) Application of RGD-CuS-Cy5.5 NPs in fluorescence and CT dual-mode cancer imaging in vivo [183]. Copyright 2018, Elsevier. (D) Application of CuCD NSs in photoacoustic and fluorescence dual-mode cancer imaging [184]. Copyright 2018, American Chemical Society.

Fig. 10

Cu chelation for killing cancer. (A) Schematic illustration of PSP-2 chelating Cu ions in tumor, which leads to the obvious decrease of blood vessel density in tumor and tumor [186]. Copyright 2022, Multidisciplinary Digital Publishing Institute. (B) Schematic illustration of PY-TBDP chelates Cu ions and shows high photothermal properties [187]. Copyright 2022, the Royal Society of Chemistry. (C) Schematic illustration of a proposed model of the important role of Nedd4l-CTR 1- Cu -PDK1-AKT signaling pathway in tumorigenesis [188]. Copyright 2021, Wiley. (D) Schematic illustration of the preparation of targeted micelles assembled by CPLP/PLP/ probe X/DOX and tumor therapeutic diagnostic mechanism of targeted drug delivery [189]. Copyright 2022, Elsevier.