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

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Abstract

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.

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    Authors and Affiliations

    1. State Key Laboratory of Natural Medicines, Department of Pharmaceutics, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing, 210009, China

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

    2. Department of Radiation Oncology, Lineberger Comprehensive Cancer Center, Carolina Center for Cancer Nanotechnology Excellence, Carolina Institute of Nanomedicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599, USA

      Bo Sun

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    1. Djamila Aouameur
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    Correspondence to Jianping Zhou or Yang Ding.

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    Aouameur, D., Cheng, H., Opoku-Damoah, Y. et al. Stimuli-responsive gel-micelles with flexible modulation of drug release for maximized antitumor efficacy. Nano Res. 11, 4245–4264 (2018). https://doi.org/10.1007/s12274-018-2012-1

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