Bortezomib (BTZ)
is a first-in-class boronate proteasome inhibitor
used for cancer therapy, but its therapeutic efficacy is usually inhibited
by dietary polyphenols due to boronate-catechol complexation. Benefiting
from such dynamic covalent chemistry, herein we describe a novel class
of supramolecular nanomedicines by rationally converting natural polyphenols
from foe to friend through polyphenol-mediated BTZ assembly strategy.
The simple conjugation of BTZ to catechol-containing natural polyphenols
via boronate ester bond allows the facile formation of dynamic drug
amphiphiles, with pH-dependent assembly/disassembly behaviors under
different physiological conditions. Ferric ion was also incorporated
into the supramolecular system via metal-phenolic coordination interaction
to both introduce bioimaging function and facilitate stability of
the supramolecular nanomedicines. Our investigation revealed that
the supramolecular nanomedicine consisting of natural polyphenol,
BTZ and ferric ion dramatically induced apoptosis on cancer cells
and suppressed tumor growth in both subcutaneous and bone tumor models
with limited adverse effects. Such natural polyphenol-mediated small
drug assembly strategy enables the robust fabrication of supramolecular
nanomedicines for efficient delivery and controlled release of BTZ
in targeted tumor sites, which could be further employed in other
types of boronic acid-containing supramolecular therapeutics toward
a wide range of diseases.
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