Targeted Ovarian Cancer Chemotherapy by EGFR-Specific Peptide-Decorated Polymersomal Doxorubicin

Significance

Ovarian cancer is the world’s most lethal gynecological cancer. This recurrent disease is recalcitrant to various treatment methods, including the commonly used nanomedicine known as pegylated liposomal doxorubicin hydrochloride (Lipo-Dox).

In an attempt to improve the efficacy of Lipo-Dox, researchers have tried to modify liposomes with ligands like folate, antibody, transferrin, and GE11 peptide. GE11 peptide exhibits a high affinity to ovarian cancer cells that overexpress epidermal growth factor receptors (EGFR). Although previous studies have shown that GE11-targeted liposomal doxorubicin displayed fast tumor accumulation and improved the treatment of SMMC-7 human hepatoma compared to non-targeted liposomal doxorubicin, the reduced stability of modified liposome within the body partially contributes to its moderate ability to target tumor cells. Some studies have revealed that polymersomes are a suitable alternative to liposomes due to its stability, ease of modification with various ligands, and stimuli-sensitivity.

Previous research work showed that disulfide-cross linked polymersomes exhibit fast intracellular drug release which results in improved treatment efficacy in different tumor models. Moreover, GE11 peptide-modified reversibly cross-linked polymersomal doxorubicin (GE11-PS-Dox) can be used in the effective treatment of orthotopic SMMC 7721 liver tumor-bearing mice. Based on these findings, it was suggested that GE11-PS-Dox maybe a suitable alternative to clinically used Lipo-Dox for the in vivo treatment of EGFR-overexpressing SKOV3 human ovarian cancers.

In a recent research published in Molecular Pharmaceutics, Soochow University led by Professor Zhiyuan Zhong demonstrated the effect of GE11 peptide-modified reversibly cross-linked polymersomal doxorubicin (GE11-PS-Dox) in the advanced treatment of SKOV3 human ovarian tumors that overexpress epidermal growth factor receptor (EGFR).

The research team observed a higher cellular uptake, accumulation, and retention of GE11-PS-Dox, and a faster delivery of doxorubicin to the nuclei of SKOV3 cancer cells compared to PS-Dox and Lipo-Dox. They also observed that GE11-PS-Dox exhibited higher potency against SKOV3 cancer cells, significantly suppressed the growth and progression of tumors, and prolonged the survival rate of mice. There was no adverse effect such as reduction of body weight in mice treated with GE11-PS-Dox. On the other hand, continuous tumor growth and body weight loss were observed in Lipo-Dox treated mice.

The authors also observed that all the mice treated with GE11-PS-Dox survived over the observation period of 78 days. Moreover, GE11-PS-Dox caused more severe necrosis of tumor tissue and exhibited low toxicity to SKOV3-tumor-bearing mice compared to Lipo-Dox treated mice.

The findings explicated by Professor Zhiyuan Zhong and his research team provide compelling evidence that GE11-PS-Dox formulation exhibits a superior therapeutic efficacy and safety profile compared to the clinically used Lipo-Dox. Their study demonstrated that GE11-PS-Dox actively target and release Dox to SKOV3 cells in vitro and in vivo, significantly inhibits tumor progression and prolongs the survival rate of mice without inducing obvious side effects. These findings will advance further studies on the clinical translation of GE11-PS-Dox for the safe and targeted treatment of ovarian tumors.

 

About the author

Professor Zhiyuan Zhong is a distinguished professor and chair of Soochow University Biomedical Polymers Laboratory. He received his Ph.D. in 2002 from the University of Twente (The Netherlands) under the supervision of Prof. Dr. Jan Feijen. In 2011-2012, he worked as a Vice President of Suzhou BioBay (a top Biomedical Park in China). His research focuses on biomedical polymers, nanomedicine and targeted cancer therapy. He has co-authored more than 200 papers with over 18000 times of citation and an H-Index of 72 (Scholar Google). He has been listed as a Highly Cited Researcher in Pharmacology/Toxicology in 2018 (Clarivate Analytics). He has filed over 50 patents, among which 11 has been licensed to a pharmaceutical company. He has recently co-founded a biomedical company, AK Cell Biopharma Co., Ltd., focusing on clinical translation of proprietary DTC delivery technology.

He has served as an Associate Editor for Biomacromolecules (IF 5.738), a Guest Editor for J. Controlled Release (IF 7.877), an Editorial/Advisory Board Member for over 10 journals including Mater. Today (IF 24.537), J. Controlled Release, Acta Pharmaceutica Sinica B (IF 6.014), Nanotechnology, Nano Futures, J. Mater. Chem. B, PLoS One, J. Gene Med., J. Biomater. Sci. Polym. Ed., and Mater. Today Chem., and an Executive Chair for the 1st-5th Symposium on Innovative Polymers for Controlled Delivery (SIPCD 2010, 2012, 2014, 2016 and 2018) held biennially in Suzhou, China. He has received several awards including Biomacromolecules/Macromolecules Young Investigator Award (ACS), the Friedrich Wilhelm Bessel Research Award (Humboldt Foundation), Award for Breakthrough Technologies in Drug Delivery Systems in Asia from the Japanese Society of Drug Delivery System and Controlled Release Society (2013, Hawaii), National Ten-Thousand Talent Award, and National Outstanding Young Scholar Award. He has recently been elected as a Fellow of the American Institute for Medical and Biological Engineering (AIMBE).  

Reference

Zou, Y., Xia, Y., Meng, F., Zhang, J., and Zhong, Z. GE11-Directed Functional Polymersomal Doxorubicin as an Advanced Alternative to Clinical Liposomal Formulation for Ovarian Cancer Treatment, Molecular Pharmaceutics 15 (2018) 3664−3671

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