دورية أكاديمية
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: | Gayle S; Cybrexa Therapeutics, New Haven, CT 06511, USA., Aiello R; Cybrexa Therapeutics, New Haven, CT 06511, USA., Leelatian N; Department of Pathology, Yale University School of Medicine, New Haven, CT 06520, USA., Beckta JM; Department of Therapeutic Radiology, Yale University School of Medicine, New Haven, CT 06520, USA., Bechtold J; Cybrexa Therapeutics, New Haven, CT 06511, USA., Bourassa P; Cybrexa Therapeutics, New Haven, CT 06511, USA., Csengery J; Cybrexa Therapeutics, New Haven, CT 06511, USA., Maguire RJ; Cybrexa Therapeutics, New Haven, CT 06511, USA., Marshall D; Cybrexa Therapeutics, New Haven, CT 06511, USA., Sundaram RK; Department of Therapeutic Radiology, Yale University School of Medicine, New Haven, CT 06520, USA., Van Doorn J; Department of Therapeutic Radiology, Yale University School of Medicine, New Haven, CT 06520, USA., Jones K; Cybrexa Therapeutics, New Haven, CT 06511, USA., Moore H; Cybrexa Therapeutics, New Haven, CT 06511, USA., Lopresti-Morrow L; Cybrexa Therapeutics, New Haven, CT 06511, USA., Paradis T; Cybrexa Therapeutics, New Haven, CT 06511, USA., Tylaska L; Cybrexa Therapeutics, New Haven, CT 06511, USA., Zhang Q; Cybrexa Therapeutics, New Haven, CT 06511, USA., Visca H; Physics Department, University of Rhode Island, Kingston, RI 02881, USA., Reshetnyak YK; Physics Department, University of Rhode Island, Kingston, RI 02881, USA., Andreev OA; Physics Department, University of Rhode Island, Kingston, RI 02881, USA., Engelman DM; Department of Molecular Biophysics and Biochemistry, Yale University, New Haven, CT 06511, USA., Glazer PM; Department of Therapeutic Radiology, Yale University School of Medicine, New Haven, CT 06520, USA., Bindra RS; Department of Pathology, Yale University School of Medicine, New Haven, CT 06520, USA., Paralkar VM; Cybrexa Therapeutics, New Haven, CT 06511, USA. |
| المصدر: | NAR cancer [NAR Cancer] 2021 Jun 04; Vol. 3 (2), pp. zcab021. Date of Electronic Publication: 2021 Jun 04 (Print Publication: 2021). |
| نوع المنشور: | Journal Article |
| اللغة: | English |
| بيانات الدورية: | Publisher: Oxford University Press Country of Publication: England NLM ID: 101769553 Publication Model: eCollection Cited Medium: Internet ISSN: 2632-8674 (Electronic) Linking ISSN: 26328674 NLM ISO Abbreviation: NAR Cancer Subsets: PubMed not MEDLINE |
| أسماء مطبوعة: | Original Publication: Oxford : Oxford University Press, [2019]- |
| مستخلص: | 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. (© The Author(s) 2021. Published by Oxford University Press on behalf of NAR Cancer.) |
| التعليقات: | Erratum in: NAR Cancer. 2021 Dec 07;3(4):zcab047. (PMID: 34888524) |
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| معلومات مُعتمدة: | R01 CA215453 United States CA NCI NIH HHS; R01 GM073857 United States GM NIGMS NIH HHS; R35 CA197574 United States CA NCI NIH HHS; R44 CA236107 United States CA NCI NIH HHS |
| تواريخ الأحداث: | Date Created: 20210728 Latest Revision: 20220329 |
| رمز التحديث: | 20221213 |
| مُعرف محوري في PubMed: | PMC8210154 |
| DOI: | 10.1093/narcan/zcab021 |
| PMID: | 34316708 |
| قاعدة البيانات: | MEDLINE |
Full Text Finder | تدمد: | 2632-8674 |
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| DOI: | 10.1093/narcan/zcab021 |