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.
CITATION STYLE
Quintana, J. M., Arboleda, D., Hu, H., Scott, E., Luthria, G., Pai, S., … Miller, M. A. (2022). Radiation Cleaved Drug-Conjugate Linkers Enable Local Payload Release. Bioconjugate Chemistry, 33(8), 1474–1484. https://doi.org/10.1021/acs.bioconjchem.2c00174
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