posted on 2021-10-11, 17:35authored byBabak Mamnoon, Li Feng, Jamie Froberg, Yongki Choi, Venkatachalem Sathish, Oleh Taratula, Olena Taratula, Sanku Mallik
Endoxifen is the
primary active metabolite of tamoxifen, a nonsteroidal-selective
estrogen receptor modulator (SERM) and widely used medication to treat
estrogen receptor-positive (ER+) breast cancer. In this study, endoxifen
was conjugated to the surface of polymeric nanoparticles (polymersomes)
for targeted delivery of doxorubicin (DOX) to estrogen receptor-positive
breast cancer cells (MCF7). Rapid cell growth and insufficient blood
supply result in low oxygen concentration (hypoxia) within the solid
breast tumors. The polymersomes developed here are prepared from amphiphilic
copolymers of polylactic acid (PLA) and poly(ethylene glycol) (PEG)
containing diazobenzene as the hypoxia-responsive linker. We prepared
two nanoparticle formulations: DOX-encapsulated hypoxia-responsive
polymersomes (DOX-HRPs) and endoxifen-conjugated, DOX-encapsulated
hypoxia-responsive polymersomes (END-DOX-HRPs). Cellular internalization
studies demonstrated eight times higher cytosolic and nuclear localization
after incubating breast cancer cells with END-DOX-HRPs (targeted polymersomes)
in contrast to DOX-HRPs (nontargeted polymersomes). Cytotoxicity studies
on monolayer cell cultures exhibited that END-DOX-HRPs were three
times more toxic to ER+ MCF7 cells than DOX-HRPs and free DOX in hypoxia.
The cell viability studies on three-dimensional hypoxic cultures also
demonstrated twice as much toxicity when the spheroids were treated
with targeted polymersomes instead of nontargeted counterparts. This
is the first report of surface-decorated polymeric nanoparticles with
endoxifen ligands for targeted drug delivery to ER+ breast cancer
microtumors. The newly designed endoxifen-conjugated, hypoxia-responsive
polymersomes might have translational potential for ER+ breast cancer
treatment.