期刊
BIOMATERIALS
卷 192, 期 -, 页码 109-117出版社
ELSEVIER SCI LTD
DOI: 10.1016/j.biomaterials.2018.11.001
关键词
Chemoradiotherapy; Radiotherapy; Prodrug; Monomethyl auristatin E; Triple-negative breast cancer; Caspase
资金
- National Research Foundation of Korea (NRF) through the Ministry of Science, ICT and Future planning [NRF-2018R1A2A1A05020064, NRF-2017R1A5A1070259, NRF-2017M3A9F5029655, NRF-2016M3A9B5941836, NRF-2016M3A9B6903426]
- National Research Foundation of Korea [2016M3A9B6903426] Funding Source: Korea Institute of Science & Technology Information (KISTI), National Science & Technology Information Service (NTIS)
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.
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