2 NANOTHERANOSTICS FOR CUPROPTOSIS-BASED CANCER THERAPY
Since the concept was proposed, increasing evidence has demonstrated the anti-cancer promise of cuproptosis induction, and much effort has been devoted to the design and development of various cuproptosis-based nanomaterials for the eradication of malignancies. For example, Heet al . reported a copper-based nanomedicine (CuET NP) including the copper (II) bis(diethyldithiocarbamate) (CuET) encapsulated by the bovine serum albumin (BSA) shell to replace drug-resistant cisplatin for the treatment of non-small-cell lung cancer.38Cisplatin resistance was attributed to the high concentration of GSH, and CuET could be candidate for alternative treatment because of its GSH-resistant performance endowed by the chelating geometry of CuET and the strong bonding of Cu–S. After intravenous injection, the CuET was found to accumulate obviously in tumor cells due to the EPR effect. CuET not only reduced the expression of FDX1 to induce cuproptosis, but also bound to the P97 segregase adaptor NPL4 and induced cytotoxicity, thus demonstrating excellent tumor inhibition ability (tumor inhibition rate: 56%). These results illustrated that nanosystem induced cuproptosis of tumor cells may be a promising cancer treatment strategy.
Due to the heterogeneity of tumor cells, chemotherapy alone may be less efficient and less comfortable in the treatment of some cancers, so it is necessary to deliver combination therapies in a number of ways for improving the treatment effect.39,40 For example, Panet al . prepared a glucose oxidase (GOx)-engineered nonporous copper(I) 1,2,4-triazolate ([Cu(tz)]) coordination polymer (CP) nanocomposite (GOx@[Cu(tz)]) consisting of GSH-responsive nonporous [Cu(tz)] as a shell and GOx as a core for starvation-augmented cuproptosis and photodynamic synergistic cancer therapy (Figure 3A ).41 After intravenous administration, GSH-responsive nonporous GOx@[Cu(tz)] not only achieved on-demand release of Cu2+ and GOx at the GSH-enriched tumor site, but also consumed the content of GSH, which contributed to Cu2+-induced cuproptosis. Moreover, the released GOx oxidized glucose to yield gluconic acid and H2O2, which cut off the energy supply of cancer cells, resulting in inhibition of glycolysis, thus exacerbating cuproptosis. After incubation with two cuproptosis inhibitors UK 5099 and Antimycin A, cancer cells treated with GOx@[Cu(tz)] showed higher cell viability than those treated with [Cu(tz)] and GOx, indicating that cuproptosis inhibitors effectively reversed GOx@[Cu(tz)]-induced cell death (Figure 3B ). Moreover, the treatment of copper chelating agent BCS restored 79.7% cell vitality of the GOx@[Cu(tz)]-treated cancer cells, showing that GOx@[Cu(tz)]-mediated cell death was related to cuproptosis (Figure 3C ). Furthermore, GOx@[Cu(tz)]-treated cells consistently exhibited lipoacylated DLAT oligomerization similar to that of elesclomol-treated cells, further confirming that GOx@[Cu(tz)] induced cell death through cuproptosis (Figure 3D ). In addition to cuproptosis, GOx@[Cu(tz)] can also be used as a photosensitizer for photodynamic therapy (PDT). Therefore, benefiting from the synergistic therapeutic effects of cuproptosis and PDT, after 21 days of GOx@[Cu(tz)] treatment of tumor-bearing mice, tumor growth in the GOx@[Cu(tz)]/laser group was suppressed by 92.4% compared to the PBS group, indicating the excellent anti-cancer effect of GOx@[Cu(tz)] (Figure 3E ). These results illustrated that the cuproptosis via consuming intracellular glucose and GSH concentrations is a promising cancer therapeutic strategy.