Stimuli-responsive gel-micelles with flexible modulation of drug release for maximized antitumor efficacy

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 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 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 (CLTMHSPTX) revealed anticancer efficacy against human hepatocellular carcinoma HepG2 cells with IC₅₀ of 1.42 μg/mL (PTX concentration), significantly lower than other groups. In parallel, the in vivo anti-tumor efficacy of ^CLTMHS_PTX 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 ^CLTMHS_PTX gel-micelles hold a great potential for flexible modulation of intracellular delivery of hydrophobic anticancer drugs with maximized antitumor efficacy.