Engineered stimuli-responsive drug delivery devices hold vast promise in biological applications for disease treatment due to their maximized therapeutic efficacy In this study a novel, stably cross-linked, and pH-sen...Engineered stimuli-responsive drug delivery devices hold vast promise in biological applications for disease treatment due to their maximized therapeutic efficacy In this study a novel, stably cross-linked, and pH-sensitive biodegradable gel-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 paditaxel （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 tumor targetability. 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 multiple cytosolic enzymes that mainly degraded the remaining hydrophobic stearylamine core. During the in vitro cytotoxicity assay, PTX-loaded TMHS gel-micelles （ct~） revealed anticancer efficacy against human hepatocellular carcinoma HepG2 cells with ICs0 of 1.42 gg/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 CLTMHSFrx gel-micelles hold a great potential for flexible modulation of intracellular delivery of hydrophobic anticancer drugs with maximized antitumor efficacy.展开更多
文摘Engineered stimuli-responsive drug delivery devices hold vast promise in biological applications for disease treatment due to their maximized therapeutic efficacy In this study a novel, stably cross-linked, and pH-sensitive biodegradable gel-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 paditaxel （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 tumor targetability. 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 multiple cytosolic enzymes that mainly degraded the remaining hydrophobic stearylamine core. During the in vitro cytotoxicity assay, PTX-loaded TMHS gel-micelles （ct~） revealed anticancer efficacy against human hepatocellular carcinoma HepG2 cells with ICs0 of 1.42 gg/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 CLTMHSFrx gel-micelles hold a great potential for flexible modulation of intracellular delivery of hydrophobic anticancer drugs with maximized antitumor efficacy.
