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Redox-Responsive Core-Cross-Linked Block Copolymer Micelles for Overcoming Multidrug Resistance in Cancer Cells
journal contribution
posted on 2018-01-22, 00:00 authored by Chiranjit Maiti, Sheetal Parida, Shibayan Kayal, Saikat Maiti, Mahitosh Mandal, Dibakar DharaSuccess of chemotherapy
as a treatment for cancer has been often inhibited by multidrug resistance
(MDR) of the cancer cells. There is a clear need to generate strategies
to overcome this resistance. In this work, we have developed redox-responsive
and core-cross-linked micellar nanocarriers using poly(ethylene glycol)-block-poly(2-(methacryloyloxy)ethyl 5-(1,2-dithiolan-3-yl)pentanoate)
diblock copolymers (PEG-b-PLAHEMA) with tunable swelling
properties for the delivery of drugs toward drug-sensitive MDA-MB-231
and drug-resistant MDA-MB-231 (231R) cancer cells. PEG-b-PLAHEMA containing varying number of 2-(methacryloyloxy)ethyl 5-(1,2-dithiolan-3-yl)pentanoate
(LAHEMA) units were synthesized by employing the reversible addition-fragmentation
chain transfer polymerization technique. The block copolymer self-assembly,
cross-linking induced by reduction, and de-cross-linking triggered
time-dependent controlled swelling of micelles were studied using
dynamic light scattering, fluorescence spectroscopy, and transmission
electron microscopy. In vitro cytotoxicity, cellular uptake efficiency,
and glutathione-responsive anticancer activity of doxorubicin (DOX)
encapsulated in core-cross-linked block copolymer micelles (CCMs)
toward both drug-sensitive and drug-resistant cancer cell lines were
evaluated. Significant reduction in IC50 was observed by
DOX-loaded CCMs toward drug-resistant 231R cancer cell lines, which
was further improved by coencapsulating DOX and verapamil (a P-glycoprotein
inhibitor) in CCMs. Thus, these reduction-sensitive biocompatible
CCMs with tunable swelling property are very promising in overcoming
MDR in cancer cells.
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LAHEMAglutathione-responsive anticancer activitydrug-resistant cancer cell linesreduction-sensitive biocompatible CCMscancer cellsOvercoming Multidrug Resistancedrug-resistant 231 R cancer cell linescore-cross-linked micellar nanocarriersRedox-Responsive Core-Cross-Linked Block Copolymer MicellesDOXPEGICMDRtransmission electron microscopyPLAHEMAblock copolymer self-assemblycore-cross-linked block copolymer micellesaddition-fragmentation chain transfer polymerization techniqueCancer Cells Successdrug-sensitive MDA-MB -231
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