Tumor-selective, antigen-independent delivery of a pH sensitive peptide-topoisomerase inhibitor conjugate suppresses tumor growth without systemic toxicity
| العنوان: | Tumor-selective, antigen-independent delivery of a pH sensitive peptide-topoisomerase inhibitor conjugate suppresses tumor growth without systemic toxicity |
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| المؤلفون: | Daniel Richard Marshall, Timothy Joseph Paradis, Ranjit S. Bindra, Vishwas M. Paralkar, Johanna Marie Csengery, Qing Zhang, Hannah M. Visca, Nalin Leelatian, Hunter Moore, Laurie Tylaska, Donald M. Engelman, Jane Bechtold, Jason M. Beckta, Sophia Gayle, Yana K. Reshetnyak, Peter M. Glazer, Patricia Bourassa, Oleg A. Andreev, Kelli Jones, Robert John Maguire, Lori Lopresti-Morrow, Robert J. Aiello, Jinny Van Doorn, Ranjini K. Sundaram |
| المصدر: | NAR Cancer |
| بيانات النشر: | Oxford University Press, 2021. |
| سنة النشر: | 2021 |
| مصطلحات موضوعية: | 0301 basic medicine, AcademicSubjects/SCI01140, AcademicSubjects/SCI01060, medicine.drug_class, DNA repair, Poly ADP ribose polymerase, AcademicSubjects/SCI00030, Standard Article, AcademicSubjects/SCI01180, 03 medical and health sciences, 0302 clinical medicine, Therapeutic index, medicine, Chemistry, Cancer, General Medicine, medicine.disease, Warburg effect, 030104 developmental biology, 030220 oncology & carcinogenesis, PARP inhibitor, Cancer research, AcademicSubjects/SCI00980, Corrigendum, Topoisomerase inhibitor, Conjugate |
| الوصف: | Topoisomerase inhibitors are potent DNA damaging agents which are widely used in oncology, and they demonstrate robust synergistic tumor cell killing in combination with DNA repair inhibitors, including poly(ADP)-ribose polymerase (PARP) inhibitors. However, their use has been severely limited by the inability to achieve a favorable therapeutic index due to severe systemic toxicities. Antibody-drug conjugates address this issue via antigen-dependent targeting and delivery of their payloads, but this approach requires specific antigens and yet still suffers from off-target toxicities. There is a high unmet need for a more universal tumor targeting technology to broaden the application of cytotoxic payloads. Acidification of the extracellular milieu arises from metabolic adaptions associated with the Warburg effect in cancer. Here we report the development of a pH-sensitive peptide-drug conjugate to deliver the topoisomerase inhibitor, exatecan, selectively to tumors in an antigen-independent manner. Using this approach, we demonstrate potent in vivo cytotoxicity, complete suppression of tumor growth across multiple human tumor models, and synergistic interactions with a PARP inhibitor. These data highlight the identification of a peptide-topoisomerase inhibitor conjugate for cancer therapy that provides a high therapeutic index, and is applicable to all types of human solid tumors in an antigen-independent manner. Graphical Abstract Graphical AbstractCBX-12 is a pH-sensitive peptide-drug conjugate that selectively delivers the TOP1 inhibitor exatecan into tumor cells in an antigen agnostic manner. The peptide forms an alpha helix only in the low pH tumor microenvironment, allowing directional insertion of the peptide across the tumor membrane, cleavage of the linker within the cytosol, and release of free exatecan within the tumor cell. This pH-based delivery approach results in a high therapeutic index universally across solid tumors. |
| اللغة: | English |
| تدمد: | 2632-8674 |
| الوصول الحر: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::641a346869b65a66c91c777023c8a97bTest http://europepmc.org/articles/PMC8210154Test |
| حقوق: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....641a346869b65a66c91c777023c8a97b |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 26328674 |
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