Radiation Cleaved Drug-Conjugate Linkers Enable Local Payload Release

Autor:	Jeremy M. Quintana, David Arboleda, Huiyu Hu, Ella Scott, Gaurav Luthria, Sara Pai, Sareh Parangi, Ralph Weissleder, Miles A. Miller
Rok vydání:	2022
Předmět:	Pharmacology Immunoconjugates Pharmaceutical Preparations Doxorubicin Albumins Cell Line Tumor Organic Chemistry Biomedical Engineering Pharmaceutical Science Antineoplastic Agents Bioengineering Biotechnology
Zdroj:	Bioconjugate Chemistry. 33:1474-1484
ISSN:	1520-4812 1043-1802
DOI:	10.1021/acs.bioconjchem.2c00174
Popis:	Conjugation of therapeutic payloads to biologics including antibodies and albumin can enhance the selectively of drug delivery to solid tumors. However, achieving activity in tumors while avoiding healthy tissues remains a challenge, and payload activity in off-target tissues can cause toxicity for many such drug-conjugates. Here, we address this issue by presenting a drug-conjugate linker strategy that releases an active therapeutic payload upon exposure to ionizing radiation. Localized X-ray irradiation at clinically relevant doses (8 Gy) yields 50% drug (doxorubicin or monomethyl auristatin E, MMAE) release under hypoxic conditions that are traditionally associated with radiotherapy resistance. As proof-of-principle, we apply the approach to antibody- and albumin-drug conjugates and achieve2000-fold enhanced MMAE cytotoxicity upon irradiation. Overall, this work establishes ionizing radiation as a strategy for spatially localized cancer drug delivery.
Databáze:	OpenAIRE
Externí odkaz:	https://explore.openaire.eu/search/publication?articleId=doi_dedup___::02521df61787f76f6a38f703cc08750e https://doi.org/10.1021/acs.bioconjchem.2c00174 Zobrazit plný text záznamu