Extended Pharmacokinetics Improve Site-Specific Prodrug Activation Using Radiation.

Autor:	Quintana JM; Center for Systems Biology, Massachusetts General Hospital Research Institute, Boston, Massachusetts 02114, United States.; Department of Radiology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts 02114, United States., Kang M; Center for Systems Biology, Massachusetts General Hospital Research Institute, Boston, Massachusetts 02114, United States.; Department of Radiology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts 02114, United States., Hu H; Center for Systems Biology, Massachusetts General Hospital Research Institute, Boston, Massachusetts 02114, United States.; Department of Surgery, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts 02114, United States., Ng TSC; Center for Systems Biology, Massachusetts General Hospital Research Institute, Boston, Massachusetts 02114, United States.; Department of Radiology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts 02114, United States., Wojtkiewicz GR; Center for Systems Biology, Massachusetts General Hospital Research Institute, Boston, Massachusetts 02114, United States., Scott E; Center for Systems Biology, Massachusetts General Hospital Research Institute, Boston, Massachusetts 02114, United States., Parangi S; Department of Surgery, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts 02114, United States., Schuemann J; Department of Radiation Oncology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts 02114, United States., Weissleder R; Center for Systems Biology, Massachusetts General Hospital Research Institute, Boston, Massachusetts 02114, United States.; Department of Radiology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts 02114, United States.; Department of Systems Biology, Harvard Medical School, Boston, Massachusetts 02115, United States., Miller MA; Center for Systems Biology, Massachusetts General Hospital Research Institute, Boston, Massachusetts 02114, United States.; Department of Radiology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts 02114, United States.
Jazyk:	angličtina
Zdroj:	ACS central science [ACS Cent Sci] 2024 Jun 21; Vol. 10 (7), pp. 1371-1382. Date of Electronic Publication: 2024 Jun 21 (Print Publication: 2024).
DOI:	10.1021/acscentsci.4c00354
Abstrakt:	Radiotherapy is commonly used to treat cancer, and localized energy deposited by radiotherapy has the potential to chemically uncage prodrugs; however, it has been challenging to demonstrate prodrug activation that is both sustained in vivo and truly localized to tumors without affecting off-target tissues. To address this, we developed a series of novel phenyl-azide-caged, radiation-activated chemotherapy drug-conjugates alongside a computational framework for understanding corresponding pharmacokinetic and pharmacodynamic (PK/PD) behaviors. We especially focused on an albumin-bound prodrug of monomethyl auristatin E (MMAE) and found it blocked tumor growth in mice, delivered a 130-fold greater amount of activated drug to irradiated tumor versus unirradiated tissue, was 7.5-fold more efficient than a non albumin-bound prodrug, and showed no appreciable toxicity compared to free or cathepsin-activatable drugs. These data guided computational modeling of drug action, which indicated that extended pharmacokinetics can improve localized and cumulative drug activation, especially for payloads with low vascular permeability and diffusivity and particularly in patients receiving daily treatments of conventional radiotherapy for weeks. This work thus offers a quantitative PK/PD framework and proof-of-principle experimental demonstration of how extending prodrug circulation can improve its localized activity in vivo . Competing Interests: The authors declare the following competing financial interest(s): M.A.M. has received unrelated support from Genentech/Roche and Pfizer and research funding from Ionis Pharmaceuticals. R.W. has consulted for Boston Scientific, ModeRNA, Earli, and Accure Health, none of whom contributed to or were involved in this research. Patents are pending and/or awarded with the authors and Massachusetts General Hospital. (© 2024 The Authors. Published by American Chemical Society.)
Databáze:	MEDLINE
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