The preparation and study on drug release of a triply-responsive (redox/thermo/pH) cross-linked polymeric micelle as anti-cancer drug carrier_Journal of Biomedical Engineering

Authors：

QU Jing ¹ , CHEN Kanglong ¹ , WANG Qiuyue ¹ , LIN Juan ² ,  ZHOU Qinghan ¹

1. School of Chemical & Environmental Protection Engineering, Southwest Minzu University, Chengdu 610041, P.R.China;
2. School of Biomedical Science, Chengdu Medical College, Chengdu 610083, P.R.China;

Corresponding author：

ZHOU Qinghan, Email: zhqinghan@163.com

Keywords：

cross-linked polymeric micelle; redox-sensitivity; pH-sensitivity; temperature-sensitivity; drug release

DOI：

10.7507/1001-5515.201708038

Video：

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Abstract Full text Figures/Tables Video References Cited by

A multiple-stimuli-responsive drug-conjugated cross-linked micelles was prepared by radical copolymerization. The chemical structure, morphology, and size of the cross-linked micelles were characterized, and the drug loading of the micelle was calculated. The experimental results indicated that the hydrodynamic size of the drug-loaded micelles were about 100 nm, and the as prepared micelles could be degraded and swelled in presence of reducing glutathione (GSH). The low critical solution temperature (LCST) of the micelle was around 39.4℃. According to the experimental results, the micelles will shrink at temperature above the LCST. Subsequently, the accumulative drug release rate was up to 91.78% under acidic (pH 5.0), reductive (GSH 10 mmol/L) and high temperature (42.0℃) conditions mimicking the tumor microenvironment, while a relatively low release rate of 1.12% was observed without stimulation. The drug-conjugated cross-linked micelles showed a strong cell uptake behavior. In the cytotoxicity assay, the micelles exhibited effective anti-cancer activity and excellent biocompatibility. In brief, the experimental results show that the as-prepared drug-conjugated cross-linked micelle exhibits multiple stimuli-responsiveness, which holds great promise for anti-cancer drug delivery.

Citation： QU Jing, CHEN Kanglong, WANG Qiuyue, LIN Juan, ZHOU Qinghan. The preparation and study on drug release of a triply-responsive (redox/thermo/pH) cross-linked polymeric micelle as anti-cancer drug carrier. Journal of Biomedical Engineering, 2018, 35(1): 70-80. doi: 10.7507/1001-5515.201708038 Copy

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5.	Zhou Qinghan, Lin Juan, Li Lidong, et al. Biodegradable micelles self-assembled from miktoarm star block copolymers for MTX delivery. Colloid Polym Sci, 2015, 293(8): 2291-2300.
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11.	Li W W, Kong H, Gao C, et al. pH-responsive poly(2-diethylaminoethylmethacrylate)– functionalized multi walled Carbon nanotubes. Chinese Science Bulletin, 2005, 50(20): 2276-2280.
12.	Gong Chu, Shan Meng, Li Bingqiang, et al. A pH and redox dual stimuli-responsive poly(amino acid) derivative for controlled drug release. Colloids Surf B Biointerfaces, 2016, 146: 396-405.
13.	Wu Can, Yang Jinlong, Xu Xiubin, et al. Redox-responsive core-cross-linked mPEGylated starch micelles as nanocarriers for intracellular anticancer drug release. Eur Polym J, 2016, 83: 230-243.
14.	Pan Yuanjia, Chen Yuanyuan, Wang Dongrui, et al. Redox/pH dual stimuli-responsive biodegradable nanohydrogels with varying responses to dithiothreitol and glutathione for controlled drug release. Biomaterials, 2012, 33(27): 6570-6579.
15.	Gamcsik M P, Kasibhatla M S, Teeter S D, et al. Glutathione levels in human tumors. Biomarkers, 2012, 17(8): 671-691.
16.	Liu Fei, Kozlovskaya V, Medipelli S, et al. Temperature-Sensitive polymersomes for controlled delivery of anticancer drugs. Chem Mater, 2015, 27(23): 7945-7956.
17.	韩雪, 曹蒋永荃, 周江玲, 等. 基于壳聚糖的 pH 响应双重药物释放系统研究. 高分子学报, 2015(12): 1471-1476.
18.	Lin Weifeng, Ma Guanglong, Kampf N, et al. Development of Long-Circulating zwitterionic Cross-Linked micelles for Active-Targeted drug delivery. Biomacromolecules, 2016, 17(6): 2010-2018.
19.	Gao Yuanfeng, Dong Changming. Reduction- and thermo-sensitive core-cross-linked polypeptide hybrid micelles for triggered and intracellular drug release. Polym Chem, 2017, 8(7): 1223-1232.

1. Agut W, Brûlet A, Schatz C, et al. pH and temperature responsive polymeric micelles and polymersomes by self-assembly of poly[2-(dimethylamino)ethyl methacrylate]-b- poly(glutamic acid) double hydrophilic block copolymers. Langmuir, 2010, 26(13): 10546-10554.
2. Thambi T, Yoon H Y, Kim K, et al. Bioreducible block copolymers based on poly(ethylene glycol) and poly(gamma-Benzyl L-Glutamate) for intracellular delivery of camptothecin. Bioconjug Chem, 2011, 22(10): 1924-1931.
3. Chen Wei, Zhong Ping, Meng Fenghua, et al. Redox and pH-responsive degradable micelles for dually activated intracellular anticancer drug release. J Control Release, 2013, 169(3): 171-179.
4. Huang Lumei, Li Lidong, Shang Le, et al. Preparation of pH-sensitive micelles from miktoarm star block copolymers by ATRP and their application as drug nanocarriers. React Funct Polym, 2016, 107: 28-34.
5. Zhou Qinghan, Lin Juan, Li Lidong, et al. Biodegradable micelles self-assembled from miktoarm star block copolymers for MTX delivery. Colloid Polym Sci, 2015, 293(8): 2291-2300.
6. Li Lidong, Shang Le, Chen Kanglong, et al. Redox-Sensitive core Cross-Linked polyethylene Glycol-Polypeptide hybrid micelles for anticancer drug delivery. J Nanosci Nanotechnol, 2017, 17(7): 4532-4541.
7. Page S M, Henchey E, Chen X A, et al. Efficacy of PolyMPC-DOX prodrugs in 4T1 Tumor-Bearing mice. Mol Pharm, 2014, 11(5): 1715-1720.
8. Remant B K C, Thapa B, Xu P. pH and redox dual responsive nanoparticle for nuclear targeted drug delivery. Mol Pharm, 2012, 9(9): 2719-2729.
9. Wu Luyan, Ni Caihua, Zhang Liping, et al. Preparation of pH-sensitive zwitterionic nano micelles and drug controlled release for enhancing cellular uptake. J Biomater Sci Polym Ed, 2016, 27(7): 643-656.
10. Jassal M, Boominathan V P, Ferreira T A, et al. pH-responsive drug release from functionalized electrospun poly(caprolactone) scaffolds under simulated in vivo environment. J Biomater Sci Polym Ed, 2016, 27(13): 1380-1395.
11. Li W W, Kong H, Gao C, et al. pH-responsive poly(2-diethylaminoethylmethacrylate)– functionalized multi walled Carbon nanotubes. Chinese Science Bulletin, 2005, 50(20): 2276-2280.
12. Gong Chu, Shan Meng, Li Bingqiang, et al. A pH and redox dual stimuli-responsive poly(amino acid) derivative for controlled drug release. Colloids Surf B Biointerfaces, 2016, 146: 396-405.
13. Wu Can, Yang Jinlong, Xu Xiubin, et al. Redox-responsive core-cross-linked mPEGylated starch micelles as nanocarriers for intracellular anticancer drug release. Eur Polym J, 2016, 83: 230-243.
14. Pan Yuanjia, Chen Yuanyuan, Wang Dongrui, et al. Redox/pH dual stimuli-responsive biodegradable nanohydrogels with varying responses to dithiothreitol and glutathione for controlled drug release. Biomaterials, 2012, 33(27): 6570-6579.
15. Gamcsik M P, Kasibhatla M S, Teeter S D, et al. Glutathione levels in human tumors. Biomarkers, 2012, 17(8): 671-691.
16. Liu Fei, Kozlovskaya V, Medipelli S, et al. Temperature-Sensitive polymersomes for controlled delivery of anticancer drugs. Chem Mater, 2015, 27(23): 7945-7956.
17. 韩雪, 曹蒋永荃, 周江玲, 等. 基于壳聚糖的 pH 响应双重药物释放系统研究. 高分子学报, 2015(12): 1471-1476.
18. Lin Weifeng, Ma Guanglong, Kampf N, et al. Development of Long-Circulating zwitterionic Cross-Linked micelles for Active-Targeted drug delivery. Biomacromolecules, 2016, 17(6): 2010-2018.
19. Gao Yuanfeng, Dong Changming. Reduction- and thermo-sensitive core-cross-linked polypeptide hybrid micelles for triggered and intracellular drug release. Polym Chem, 2017, 8(7): 1223-1232.

Journal of Biomedical Engineering

The preparation and study on drug release of a triply-responsive (redox/thermo/pH) cross-linked polymeric micelle as anti-cancer drug carrier

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