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Biomaterials. 2017 Feb;116:82-94. doi: 10.1016/j.biomaterials.2016.11.030. Epub 2016 Nov 23.

Targeted hydroxyethyl starch prodrug for inhibiting the growth and metastasis of prostate cancer.

Author information

1
Department of Urology, The First Hospital of Jilin University, Changchun, 130041, People's Republic of China; Key Laboratory of Polymer Ecomaterials, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun, 130022, People's Republic of China; Department of Urology, General Hospital of Benxi Iron and Steel Co., Ltd., Benxi, 117000, People's Republic of China.
2
Key Laboratory of Polymer Ecomaterials, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun, 130022, People's Republic of China.
3
Key Laboratory of Polymer Ecomaterials, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun, 130022, People's Republic of China. Electronic address: jxding@ciac.ac.cn.
4
Department of Biomedical Engineering, Columbia University, New York, NY, 10027, United States.
5
Key Laboratory of Polymer Ecomaterials, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun, 130022, People's Republic of China. Electronic address: ml3777@columbia.edu.
6
Department of Urology, The First Hospital of Jilin University, Changchun, 130041, People's Republic of China. Electronic address: chunxi_wang@126.com.

Abstract

Prostate cancer is one of the most prevalent malignancies among men. Although chemotherapy has been an effective therapeutic approach for treating metastatic prostate cancer, serious undesired side effects have hampered its wide application clinically. In this work, a pH-responsive LHRH-conjugated hydroxyethyl starch-doxorubicin (HES-DOX/LHRH) prodrug was facilely synthesized by conjugating oxidized HES (HES-CHO) with DOX and LHRH through an acid-sensitive Schiff base bond. The resulting prodrug spontaneously self-assembled into nanoscopic micelle with a radius of about 55 nm in an aqueous environment. HES-DOX/LHRH significantly improved the in vivo tissue distribution of the drug. Compared to its non-targeted counterpart, targeted HES-DOX/LHRH demonstrated a greater in vitro anti-proliferative capability toward mouse RM-1 prostate cells. More importantly, targeted HES-DOX/LHRH exhibited higher levels of anti-tumor and anti-metastasis activities against an RM-1-xenografted mouse model, with lower systemic toxicity compared to free DOX·HCl and non-targeted HES-DOX. Hence, these results revealed that targeted HES-DOX/LHRH possesses great potential application in clinical chemotherapy of metastatic prostate cancer.

KEYWORDS:

Chemotherapy; Hydroxyethyl starch prodrug; Prostate cancer therapy; Schiff base bond; Targeted drug delivery

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