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Dual pH-Responsive Shell-Cleavable Polycarbonate Micellar Nanoparticles for in Vivo Anticancer Drug Delivery
journal contribution
posted on 2018-05-14, 00:00 authored by Shaoqiong Liu, Robert J. Ono, Chuan Yang, Shujun Gao, Jordan Yong Ming Tan, James L. Hedrick, Yi Yan YangTo
exploit tumor and intracellular microenvironments, pH-responsive diblock
copolymers of poly(ethylene glycol) and catechol-functionalized polycarbonate
with acid-labile acetal bond as the linker are synthesized to prepare
micellar nanoparticles that shed the shell at acidic tumor tissues
and inside cancer cells, hence accelerating drug release at the target.
The pH-dependent cleavage of the shell is demonstrated at pH 5.0 and
6.5 using 1H NMR. Bortezomib (BTZ, an anticancer drug containing
a phenylboronic acid group) is conjugated to the polymers through
formation of pH-responsive boronate ester bond between boronic acid
and catechol in the polymers. Dual pH-responsive bortezomib–polymer
conjugates (BTZ–PC) self-assemble into micellar nanoparticles
of small size (<110 nm) with narrow size distribution and high
drug loading capacity. Acidic pH accelerates BTZ release from BTZ–PC
micelles and enhances intracelluar uptake of the micelles, hence increasing
in vitro cytotoxicity against human breast cancer cells. More importantly,
the BTZ–PC micelles achieve a stronger antitumor effect in
a human breast cancer BT-474 xenograft mouse model than free BTZ and
mitigate in vivo hepatotoxicity of BTZ. These dual pH-responsive shell-cleavable
nanoparticles are a potentially promising carrier for BTZ delivery.
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pH-responsive diblock copolymersDual pH-Responsive Shell-Cleavable Polycarbonate Micellar NanoparticlespH-responsive boronate ester bond1 H NMRdrug loading capacitymicelleBTZbreast cancer cellsVivo Anticancer Drug Deliveryphenylboronic acid groupbreast cancer BT -474 xenograft mouse modelacidic tumor tissuespH-responsive shell-cleavable nanoparticlesmicellar nanoparticlesacid-labile acetal bond
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