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

Djamila Aouameur, Hao Cheng, Yaw Opoku-Damoah, Bo Sun, Qiuling Dong, Yue Han, Jianping Zhou, Yang Ding

Research output: Contribution to journalArticlepeer-review

17 Scopus citations


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 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 with maximized antitumor efficacy.

Original languageEnglish (US)
Pages (from-to)4245-4264
Number of pages20
JournalNano Research
Issue number8
StatePublished - Aug 1 2018
Externally publishedYes

ASJC Scopus subject areas

  • Atomic and Molecular Physics, and Optics
  • Materials Science(all)
  • Condensed Matter Physics
  • Electrical and Electronic Engineering


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