Journal
BIOCONJUGATE CHEMISTRY
Volume 33, Issue 8, Pages 1474-1484Publisher
AMER CHEMICAL SOC
DOI: 10.1021/acs.bioconjchem.2c00174
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Funding
- NIH [T32CA079443, DP2CA259675, U01CA206997]
- China Scholarship Council [201906370164]
- National Natural Science Foundation of China [81974423]
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Conjugating therapeutic payloads to biologics can improve drug delivery to tumors, but also poses a risk of toxicity in off-target tissues. This study presents a novel drug-conjugate linker strategy that releases active drugs upon exposure to ionizing radiation, resulting in localized cancer drug delivery.
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.
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