Radiation Cleaved Drug-Conjugate Linkers Enable Local Payload Release.
Journal
Bioconjugate chemistry
ISSN: 1520-4812
Titre abrégé: Bioconjug Chem
Pays: United States
ID NLM: 9010319
Informations de publication
Date de publication:
17 08 2022
17 08 2022
Historique:
pubmed:
15
7
2022
medline:
19
8
2022
entrez:
14
7
2022
Statut:
ppublish
Résumé
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 achieve >2000-fold enhanced MMAE cytotoxicity upon irradiation. Overall, this work establishes ionizing radiation as a strategy for spatially localized cancer drug delivery.
Identifiants
pubmed: 35833631
doi: 10.1021/acs.bioconjchem.2c00174
pmc: PMC9390333
doi:
Substances chimiques
Albumins
0
Antineoplastic Agents
0
Immunoconjugates
0
Pharmaceutical Preparations
0
Doxorubicin
80168379AG
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Research Support, N.I.H., Extramural
Langues
eng
Sous-ensembles de citation
IM
Pagination
1474-1484Subventions
Organisme : NCI NIH HHS
ID : DP2 CA259675
Pays : United States
Organisme : NCI NIH HHS
ID : T32 CA079443
Pays : United States
Organisme : NHGRI NIH HHS
ID : T32 HG002295
Pays : United States
Organisme : NCI NIH HHS
ID : U01 CA206997
Pays : United States
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