Radiotherapy activates picolinium prodrugs in tumours.
Nat Chem
; 16(8): 1348-1356, 2024 Aug.
Article
in En
| MEDLINE
| ID: mdl-38561425
ABSTRACT
Radiotherapy-induced prodrug activation provides an ideal solution to reduce the systemic toxicity of chemotherapy in cancer therapy, but the scope of the radiation-activated protecting groups is limited. Here we present that the well-established photoinduced electron transfer chemistry may pave the way for developing versatile radiation-removable protecting groups. Using a functional reporter assay, N-alkyl-4-picolinium (NAP) was identified as a caging group that efficiently responds to radiation by releasing a client molecule. When evaluated in a competition experiment, the NAP moiety is more efficient than other radiation-removable protecting groups discovered so far. Leveraging this property, we developed a NAP-derived carbamate linker that releases fluorophores and toxins on radiation, which we incorporated into antibody-drug conjugates (ADCs). These designed ADCs were active in living cells and tumour-bearing mice, highlighting the potential to use such a radiation-removable protecting group for the development of next-generation ADCs with improved stability and therapeutic effects.
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Prodrugs
Limits:
Animals
/
Female
/
Humans
Language:
En
Journal:
Nat Chem
/
Nat. chem. (Online)
/
Nature chemistry (Online)
Journal subject:
QUIMICA
Year:
2024
Document type:
Article
Affiliation country:
China
Country of publication:
United kingdom