2. Academic Validation
  3. Radiation Cleaved Drug-Conjugate Linkers Enable Local Payload Release

Radiation Cleaved Drug-Conjugate Linkers Enable Local Payload Release

  • Bioconjug Chem. 2022 Aug 17;33(8):1474-1484. doi: 10.1021/acs.bioconjchem.2c00174.
Jeremy M Quintana 1,  David Arboleda 1,  Huiyu Hu 1 2,  Ella Scott 1,  Gaurav Luthria 1,  Sara Pai 1 2,  Sareh Parangi 2,  Ralph Weissleder 1 3 4,  Miles A Miller 1 3
Affiliations

Affiliations

  • 1 Center for Systems Biology, Massachusetts General Hospital Research Institute, Boston, Massachusetts 02114, United States.
  • 2 Department of Surgery, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts 02114, United States.
  • 3 Department of Radiology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts 02114, United States.
  • 4 Department of Systems Biology, Harvard Medical School, Boston, Massachusetts 02115, United States.
PMID: 35833631 DOI: 10.1021/acs.bioconjchem.2c00174
Abstract

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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