Theranostics 2019; 9(26):8061-8072. doi:10.7150/thno.37184

Research Paper

Cyclic RGD-Functionalized and Disulfide-Crosslinked Iodine-Rich Polymersomes as a Robust and Smart Theranostic Agent for Targeted CT Imaging and Chemotherapy of Tumor

Yan Zou1,2*, Yaohua Wei1,3*, Yinping Sun1, Jie Bao4, Feirong Yao4, Zekun Li1, Fenghua Meng1✉, Chunhong Hu4, Gert Storm3, Zhiyuan Zhong1✉

1. Biomedical Polymers Laboratory, and Jiangsu Key Laboratory of Advanced Functional Polymer Design and Application, College of Chemistry, Chemical Engineering and Materials Science, and State Key Laboratory of Radiation Medicine and Protection, Soochow University, Suzhou, 215123, P. R. China
2. International Joint Centre for Biomedical Innovation, School of Life Sciences, Henan University, Jin Ming Avenue, Kaifeng, Henan, 475004, P. R. China
3. Department of Targeted Therapeutics, MIRA Institute for Biological Technology and Technical Medicine, University of Twente, PO Box 217, 7500AE, Enschede, The Netherlands
4. Imaging Center, the First Affiliated Hospital of Soochow University, Suzhou, Jiangsu, 215006, P.R. China
*These authors contributed equally to this work

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Citation:
Zou Y, Wei Y, Sun Y, Bao J, Yao F, Li Z, Meng F, Hu C, Storm G, Zhong Z. Cyclic RGD-Functionalized and Disulfide-Crosslinked Iodine-Rich Polymersomes as a Robust and Smart Theranostic Agent for Targeted CT Imaging and Chemotherapy of Tumor. Theranostics 2019; 9(26):8061-8072. doi:10.7150/thno.37184. Available from http://www.thno.org/v09p8061.htm

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Abstract

There is tremendous interest in integrating CT imaging with chemotherapy; however, reported iodine-based nanosystems such as nanogels and nano-emulsions display typically reduced contrast coefficient, low drug loading and stability, and poor targetability. Here, cRGD-functionalized disulfide-crosslinked iodine-rich polymersomes (cRGD-XIPs) were designed as a novel, robust and smart theranostic agent and investigated for targeted CT imaging and chemotherapy of malignant tumors.

Methods: cRGD-XIPs were prepared from co-self-assembly of poly(ethylene glycol)-b-poly(dithiolane trimethylene carbonate-co-iodinated trimethylene carbonate) (PEG-P(DTC-IC)) and cRGD-PEG-P(DTC-IC) block copolymers. In vitro and in vivo CT contrast effect of cRGD-XIPs was studied using αvβ3-overexpressing B16 melanoma as a tumor model in comparison with clinical agent iohexol. The therapeutic efficacy of doxorubicin-loaded cRGD-XIPs (cRGD-XIPs-Dox) to B16 melanoma was investigated and compared with XIPs-Dox (non-targeted), cRGD-IPs-Dox (non-crosslinked) and free Dox.

Results: cRGD-XIPs were formed with 55.5 wt.% iodine and ca. 90 nm in diameter. cRGD-XIPs-Dox with a Dox loading of 15.3 wt.% bared superior colloidal stability and reduction-responsive drug release. Notably, blank cRGD-XIPs showed a maximum-tolerated dose (MTD) > 400 mg iodine equiv./kg while cRGD-XIPs-Dox had an MTD > 150 mg Dox equiv./kg, ca. 15-fold improvement over free Dox. cRGD-XIPs revealed superior CT contrast effect and achieved 46.5- and 24.0-fold better enhancement of CT imaging of B16 melanoma than iohexol at 4 h following intratumoral and intravenous injection, respectively. cRGD-XIPs-Dox displayed an elimination half-life of 6.5 h and an elevated accumulation of 6.68% ID/g in the tumors. Furthermore, cRGD-XIPs-Dox was significantly more effective than XIPs-Dox and cRGD-XPs-Dox in inhibiting growth of B16 melanoma model.

Conclusion: This proof-of-concept study demonstrates that cRGD-XIPs are a robust, non-toxic and smart polymeric theranostic agent that can not only significantly enhance CT imaging of tumors but also mediate efficient tumor-targeted chemotherapy. XIPs offer a unique and safe platform for theranostic polymersomes that pre-select patients using CT imaging prior to targeted chemotherapy with the same system.

Keywords: Targeted delivery, polymersomes, reduction-sensitive, solid tumor, CT imaging