Abstract
In this report, disulfide-crosslinked paclitaxel (PTX) prodrug micelles were developed through covalently conjugating PTX onto water soluble poly(ethylene glycol)-dihydrolipoic acid (MeO-PEG2k-DHLA) via a disulfide linkage and studied their perspectives for chemotherapic antitumor capacity. The polymer-PTX prodrug (MeO-PEG2k-SS-PTX), structurally determined by 1H NMR, possessed high PTX content up to 26 wt% and exhibited sharp reduction-responsive behavior. MeO-PEG2k-SS-PTX micelles were then subjected to crosslinking by oxidization of thiol (-SH) groups in the core of micellar particles after self-assembly of the amphimictic prodrug. The resultant crosslinked micelles were stable with spherical morphology having the uniform size of 87.67 nm in phosphate buffer (PBS, pH 7.4), as confirmed by transmission electron microscope (TEM) and dynamic light scattering (DLS). The cross-linked micelles based on the redox-sensitive MeO-PEG2k-SS-PTX prodrug exhibited an obvious glutathione (GSH)-dependant manner of fast PTX release with appropriate 65.6% in 12 h and 92.6% in 72 h after incubation in PBS medium containing 10 mM GSH. MTT assay together with apoptosis analysis showed that cross-linked MeO-PEG2k-SS-PTX micelles worked the higher antitumor activity against MCF-7, A549, BEL-7402 and 4T1 cells, using free PTX as a positive control. More importantly, such micelles were found to hold a longer circulation time in bloodstream and be able to passively targeting accumulate in tumor sites of 4T1-transplanted BALB/c mice model.
Published Version
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