Highly potent monomethyl auristatin E prodrug activated by caspase-3 for the chemoradiotherapy of triple-negative breast cancer.

Abstract

Despite the emergence of advanced therapeutics such as targeted therapy and immunotherapy in the modern oncology, cytotoxic chemotherapy still remains as the first-line treatment option in a wide range of cancers attributing to its potency. Many endeavors have been made to overcome the toxicity issues of cytotoxic chemotherapy by improving the specific delivery to the tumor, with active tumor targeting being one of the most popular approaches. However, such an approach has been challenged by the intratumor heterogeneity and the lack of valid molecular target in many types of cancer. Here, we introduce a novel albumin-binding prodrug MPD02 that could specifically deliver highly potent cytotoxin monomethyl auristatin E (MMAE) to the tumor as an important component of chemoradiotherapy for the treatment of triple-negative breast cancer (TNBC). MPD02 was synthesized by conjugating MMAE to the C-terminus of the KGDEVD peptide via self-eliminating linker and introducing a maleimide group to the Lys side chain of the peptide. MPD02 was able to bind albumin after administration via maleimide group for an extended circulation time and metabolized into MMAE in tumor-specific manner by reacting with the caspase-3 upregulated in tumor by radiotherapy, exerting a highly potent anticancer effect with good safety profile in two different TNBC xenograft models.

• Authors: Seung Woo Chung, Young Seok Cho, Jeong Uk Choi, Ha Rin Kim, Tae Hyung Won, Sang Yoon Kim, Youngro Byun
• Journal: Biomaterials (Biomaterials) Vol. 192 Pg. 109-117 (02 2019) ISSN: 1878-5905 [Electronic] Netherlands
• PMID: 30447398 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2018 Elsevier Ltd. All rights reserved.

Chemical References

• Oligopeptides
• Prodrugs
• Caspase 3
• monomethyl auristatin E

Topics

• Animals
• Caspase 3 (metabolism)
• Cell Line, Tumor
• Chemoradiotherapy
• Female
• Humans
• Mice, Inbred BALB C
• Oligopeptides (therapeutic use)
• Prodrugs (therapeutic use)
• Triple Negative Breast Neoplasms (drug therapy, metabolism, radiotherapy)