posted on 2021-08-10, 11:34authored byJi Hyeon Kim, Peter Verwilst, Miae Won, Junhyoung Lee, Jonathan L. Sessler, Jiyou Han, Jong Seung Kim
Breast
cancer consists of heterogenic subpopulations, which determine
the prognosis and response to chemotherapy. Among these subpopulations,
a very limited number of cancer cells are particularly problematic.
These cells, known as breast cancer stem cells (BCSCs), are thought
responsible for metastasis and recurrence. They are thus major contributor
to the unfavorable outcomes seen for many breast cancer patients.
BCSCs are more prevalent in the hypoxic niche. This is an oxygen-deprived
environment that is considered crucial to their proliferation, stemness,
and self-renewal but also one that makes BCSCs highly refractory to
traditional chemotherapeutic regimens. Here we report a small molecule
construct, AzCDF, that allows the therapeutic targeting
of BCSCs and which is effective in normally refractory hypoxic tumor
environments. A related system, AzNap, has been developed
that permits CSC imaging. Several design elements are incorporated
into AzCDF, including the CAIX inhibitor acetazolamide
(Az) to promote localization in MDA-MB-231 CSCs, a dimethylnitrothiophene
subunit as a hypoxia trigger, and a 3,4-difluorobenzylidene
curcumin (CDF) as a readily released therapeutic payload. This allows AzCDF to serve as a hypoxia-liable molecular platform that
targets BCSCs selectively which decreases CSC migration, retards tumor
growth, and lowers tumorigenesis rates as evidenced by a combination
of in vitro and in vivo studies. To the best of our knowledge, this
is the first time a CSC-targeting small molecule has been shown to
prevent tumorigenesis in an animal model.