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Synergistically Enhanced Antimetastasis Effects by Honokiol-Loaded pH-Sensitive Polymer–Doxorubicin Conjugate Micelles
journal contribution
posted on 2018-05-11, 00:00 authored by Yang Zou, Yuanhang Zhou, Yao Jin, Chuyu He, Yunqiang Deng, Shidi Han, Chuhang Zhou, Xinru Li, Yanxia Zhou, Yan LiuIn an effort to prevent
metastasis of breast tumor cells- at the
same time of inhibiting tumor growth with less toxic side effects,
honokiol (HNK) was encapsulated into pH-sensitive polymeric micelles
based on the conjugate of poly(2-ethyl-2-oxazoline)-poly(d,l-lactide) (PEOz-PLA) with doxorubicin (DOX), denoted as
PEOz-PLA-imi-DOX. PEOz-PLA-imi-DOX was successfully synthesized by
connecting DOX to the hydrophobic end of PEOz-PLA via acid-cleavable
benzoic imine linker. HNK-loaded conjugate micelles (HNK/PP-DOX-PM)
with a size of 21 nm and homogeneous spherical shape exhibited high
drug-loading capacity. PEOz-PLA-imi-DOX and HNK/PP-DOX-PM displayed
faster release of DOX at pH 5.0 than at pH 7.4. As anticipated, PEOz-PLA-imi-DOX
maintained cytotoxicity of DOX against MDA-MB-231 cells. The synergistically
enhanced in vitro antitumor effect of HNK/PP-DOX-PM was confirmed
by their synergetic inhibition of MDA-MB-231 cell growth. Furthermore,
the efficient prevention of tumor metastasis by HNK/PP-DOX-PM was
testified by in vitro anti-invasion, wound healing and antimigration
assessment in MDA-MB-231 cells, and in vivo bioluminescence imaging
in nude mice. The suppression of growth and metastasis of tumor cells
by HNK/PP-DOX-PM was attributed to the synergistic effect of pH-triggered
drug release and HNK-aroused inhibition of matrix metalloproteinases
and epithelial–mesenchymal transition, respectively. In addition,
HNK/PP-DOX-PM exhibited superior biosafety than physically encapsulated
dual-drug micelles. Consequently, the fabricated HNK/PP-DOX-PM may
have great potential for safe and effective suppression of tumor growth
and metastasis.