Stimuli-responsive gel-micelles with flexible modulationof drug release for maximized antitumor efficacy
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Engineered stimuli-responsive drug delivery devices hold vast promise inbiological applications for disease treatment due to their maximized therapeuticefficacy. In this study, a novel, stably cross-linked, and pH-sensitive biodegradablegel-micelle was constructed with amphiphilic conjugates of trimethylene dipiperidine-methacrylic anhydride-hyaluronic acid-stearylamine (TMDP-MA-HA-SA, TMHS) to improve tumor-targeting with flexible intracellular delivery of paclitaxel (PTX).The cross-linked methacrylate bonds significantly improved the biostability of TMHS gel-micelle (~ 200 nm) over the non-cross-linked under physiological conditions, while hyaluronic acid plays an important role in active tumortargetability. The gradual degradation of cross-linked hyaluronic acid shell was triggered by the concentrated hyaluronidase. Meanwhile, under acidic conditions(pH < 6.5), the tertiary amines of pH-sensitive TMDP moieties were protonated and thereby solubilized the gel-micellar core-portions. The resultant pH-triggered inner-core spaces rapidly prompted PTX release in the presence of multiplecytosolic enzymes that mainly degraded the remaining hydrophobic stearylaminecore. During the in vitro cytotoxicity assay, PTX-loaded TMHS gel-micelles (CLTMHSPTX) revealed anticancer efficacy against human hepatocellular carcinomaHepG2 cells with IC50 of 1.42 μg/mL(PTX concentration), significantly lower than other groups. In parallel, the in vivo anti-tumor efficacy of CLTMHSPTX gel-micelles against BALB/c xenograft tumor animal model demonstrated the greater tumor growth inhibition capacity of 72.06%, compared to other treatment groups at a safe concentration. Consequently, the cross-linked and stimuli-responsive CLTMHSPTX gel-micelles hold a great potential for flexible modulation of intracellular delivery of hydrophobic anticancer drugs withmaximized antitumor efficacy.
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