Original articles
Congcong Lin, Fan Tong, Rui Liu, Rou Xie, Ting Lei, Yuxiu Chen, Zhihang Yang, Huile Gao, Xiangrong Yu. GSH-responsive SN38 dimer-loaded shapetransformable nanoparticles with iRGD for enhancing chemo-photodynamic therapy[J]. Acta Pharmaceutica Sinica B, 2020, 10(12): 2348-2361

GSH-responsive SN38 dimer-loaded shapetransformable nanoparticles with iRGD for enhancing chemo-photodynamic therapy
Congcong Lina,b, Fan Tongc, Rui Liuc, Rou Xiec, Ting Leic, Yuxiu Chenc, Zhihang Yangc, Huile Gaoc, Xiangrong Yua
a Department of Radiology, Zhuhai People's Hospital, Jinan University, Zhuhai 519000, China;
b Department of Medicinal Chemistry and Natural Medicine Chemistry, College of Pharmacy, Harbin Medical University, Harbin 150081, China;
c Key Laboratory of Drug Targeting and Drug Delivery Systems, West China School of Pharmacy, Sichuan University, Sichuan 610041, China
Accurate tumor targeting, deep penetration and superb retention are still the main pursuit of developing excellent nanomedicine. To achieve these requirements, a stepwise stimuli-responsive strategy was developed through co-administration tumor penetration peptide iRGD with shape-transformable and GSH-responsive SN38-dimer (d-SN38)-loaded nanoparticles (d-SN38@NPs/iRGD). Upon intravenous injection, d-SN38@NPs with high drug loading efficiency (33.92±1.33%) could effectively accumulate and penetrate into the deep region of tumor sites with the assistance of iRGD. The gathered nanoparticles simultaneously transformed into nanofibers upon 650 nm laser irradiation at tumor sites so as to promote their retention in the tumor and burst release of reactive oxygen species for photodynamic therapy. The loaded d-SN38 with disulfide bond responded to the high level of GSH in tumor cytoplasm, which consequently resulted in SN38 release and excellent chemo-photodynamic effect on tumor. In vitro, coadministering iRGD with d-SN38@NPs+laser showed higher cellular uptake, apoptosis ratio and multicellular spheroid penetration. In vivo, d-SN38@NPs/iRGD+laser displayed advanced penetration and accumulation in tumor, leading to 60.89% of tumor suppression in 4T1 tumor-bearing mouse model with a favorable toxicity profile. Our new strategy combining iRGD with structural transformable nanoparticles greatly improves tumor targeting, penetrating and retention, and empowers anticancer efficacy.
Key words:    Shape-transformable    SN38 dimer    GSH-responsive    Chemo-photodynamic therapy    iRGD    Co-administration    Ce6    Breast cancer   
Received: 2020-07-26     Revised: 2020-09-12
DOI: 10.1016/j.apsb.2020.10.009
Funds: The authors gratefully acknowledge the financial support from National Natural Science Foundation of China (Nos. 81961138009; 82071915), Research Funds of Sichuan Science and Technology Department (No.19YYJC2250, China), 111 Project (No. B18035, China), Fundamental Research Funds for the Central Universities, and Natural Science Foundation of Heilongjiang Province of China (No. YQ2019H004).
Corresponding author: Huile Gao, gaohuile@scu.edu.cn;Xiangrong Yu, yxr00125040@126.com     Email:gaohuile@scu.edu.cn;yxr00125040@126.com
Author description:
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Congcong Lin
Fan Tong
Rui Liu
Rou Xie
Ting Lei
Yuxiu Chen
Zhihang Yang
Huile Gao
Xiangrong Yu

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