TY - JOUR
T1 - Stimuli-responsive gel-micelles with flexible modulation of drug release for maximized antitumor efficacy
AU - Aouameur, Djamila
AU - Cheng, Hao
AU - Opoku-Damoah, Yaw
AU - Sun, Bo
AU - Dong, Qiuling
AU - Han, Yue
AU - Zhou, Jianping
AU - Ding, Yang
N1 - Funding Information:
The authors gratefully acknowledge the financial support from the National Natural Science Foundation of China (Nos. 81501582 and 81573379), the National Key Research and Development Program (No. 2017YFD0501403), and Natural Science Foundation of Jiangsu Province (No. BK20171390). This study was also supported by the National Science and Technology Major Project (Nos. 2017ZX09101001005 and 2017ZX09101001006022), Development Funds for Priority Academic Programs in Jiangsu Higher Education Institutions, and Fostering Plan of University Scientific and Technology Innovation Team of Jiangsu Qing Lan Project (2014).
Publisher Copyright:
© 2018, Tsinghua University Press and Springer-Verlag GmbH Germany, part of Springer Nature.
PY - 2018/8/1
Y1 - 2018/8/1
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85044389816&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85044389816&partnerID=8YFLogxK
U2 - 10.1007/s12274-018-2012-1
DO - 10.1007/s12274-018-2012-1
M3 - Article
AN - SCOPUS:85044389816
SN - 1998-0124
VL - 11
SP - 4245
EP - 4264
JO - Nano Research
JF - Nano Research
IS - 8
ER -