Targeted embolization and chemotherapy for solid tumors by microenvironment-responsive poly(amino acid)s

Abstract

Transcatheter arterial embolization (TAE) has been used to treat advanced and unresectable tumors, whose treatment is complex and may involve other risks. Here, inspired by the acid and reductive microenvironment of the solid tumors, a new approach for noninvasive and targeted intravenous embolization and chemotherapy is developed. The method was based on a series of acid microenvironment-responsive polypeptides poly[(L-Glutamic acid -ran-L-Tyrosine) -b-L-Threonine-b-L-Cysteines]s, PGTTCs.) to construct the reduction-responsive chemoembolic agent by grafting modified paclitaxel (HS-PTX) to sulfhydryl side groups on PGTTCs for noncatheter targeted-embolization, which effectively improved the solubility of paclitaxel. HS-PTX could release in the presence of glutathione (GSH) due to disulfide bond disruption in vitro, and the results of tumor-bearing mice experiments showed that these polypeptides could effectively target to the tumor, embolize the tumor supply vessels rapidly and release paclitaxel in tumor sites. By comparing the therapeutic effect of embolization therapy only with that of embolization combined with chemotherapy, the chemoembolization agent showed excellent effect of embolization chemotherapy in subcutaneous tumor models, and cured tumor in mice within 20 days. Therefore, this polypeptide is expected to be a favorable candidate for effective catheterless inteavenous embolization combined with chemotherapy.

GRAPHICAL ABSTRACT

Keywords:

• polypeptides
• non-interventional embolization
• paclitaxel
• chemotherapy
• solid tumors

Acknowledgments

We also thank Key Laboratory of Eco-functional Polymer Materials of the Ministry of Education, Key Laboratory of Eco-environmental Polymer Materials of Gansu Province, for financial support.

Author contributions

Y.H. and Z.C. synthesized most of the copolymers, participated in most of the relevant experimental work, and wrote the article. Y.J. and J.W. participated in data processing. Y.Z. established the experimental animal models and participated in toxicity tests and tissue histological analysis. M.M. participated in animal experiments and fluorescence imaging. H.M., Z.Y. and Z.L. gave advice in experimental design and article writing work. D.L. designed and supervised the whole work, as well as overall controlled and modified the article.

Ethical statement

All tests including animal procedures were constructed as prescribed by the agreements on animal use permitted by The Cancer Hospital of Gansu Province and the Southeast University.

Disclosure statement

No potential conflict of interest was reported by the authors.

Additional information

Funding

This work was supported in part by the National Natural Science Foundation of China (No. 21865029, 22265028), West Light Foundation of the Chinese Academy of Sciences (2018[99]).