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Enzyme-Triggered Disassembly of Polymeric Micelles by Controlled Depolymerization via Cascade Cyclization for Anticancer Drug Delivery
journal contribution
posted on 2021-02-12, 11:13 authored by Jaehyun Park, Seokhee Jo, Yeong Mi Lee, Gurusamy Saravanakumar, Junseok Lee, Dongsik Park, Won Jong KimThe high activity of specific enzymes
in cancer has been utilized
in cancer diagnosis, as well as tumor-targeted drug delivery. NAD(P)H:quinone
oxidoreductase-1 (NQO1), an overexpressed enzyme in certain tumor
types, maintains homeostasis and inhibits oxidative stress caused
by elevated reactive oxygen species (ROS) in tumor cells. The activity
of NQO1 in lung and liver cancer cells is increased compared to that
in normal cells. Interestingly, NQO1 reacts with trimethyl-locked
quinone propionic acid (QPA) and produces a lactone-based group via
intramolecular cyclization. Toward this objective, we synthesized
an amphiphilic block copolymer (QPA-P) composed of NQO1 enzyme-triggered
depolymerizable QPA-locked polycaprolactone (PCL) and poly(ethylene
glycol) (PEG) as hydrophobic and hydrophilic constituents, respectively.
This QPA-P formed self-assembled micelles in aqueous conditions. It
was observed that NQO1 catalyzed the depolymerization of QPA-locked
PCL via a cascade two-step cyclization process, which eventually induced
the dissociation of micellar structure and triggered the release of
loaded drugs at the target cancer cells. Compared to the control group,
the NQO1-responsive micelle showed NQO1-triggered intracellular drug
release and enhanced anticancer effects. These results indicate that
the NQO1-responsive polymeric micelles present a promising potential
for improving therapeutic efficacy of an anticancer drug delivery
system.
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NADtarget cancer cellstumor-targeted drug deliveryQPA-PPCLROSreactive oxygen speciesNQO 1NQO 1-responsive micellePEGtrimethyl-locked quinone propionic acidNQO 1 enzyme-triggered depolymeriza...anticancer drug delivery systemNQO 1-triggered intracellular drug ...liver cancer cellsamphiphilic block copolymerAnticancer Drug Delivery