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.