Radiation Cleaved Drug-Conjugate Linkers Enable Local Payload Release

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.

Bioorthogonal chemistry for prodrug activation in vivo

“…In 2022, Miller and coworkers expanded the above work by designing two prodrugs using 3,5-dimethylbenzyl alcohol (DMBA) as the caging moiety, which enables the conjugation of the prodrugs with antibody or albumin to enhance tumor accumulation. 138 Detectable drug release can be achieved by administering localized X-ray irradiation at low doses ranging from 1 to 2 Gy. However, when higher doses of 8 to 16 Gy are applied, commonly used in hypofractionated treatment regimens, approximately 66 AE 6% and 69 AE 8% of MMAE and Dox are released.…”

Radiotherapy-Triggered Proteolysis Targeting Chimera Prodrug Activation in Tumors

“…The ionizing radiation of X-ray has been widely used in radiotherapy, which is a first-line treatment strategy for cancer. − The local radiation results in DNA damage, cell apoptosis, and tumor necrosis. , In addition, the hydrogen radical (·H), hydroxyl radical (·OH), and hydrated electron (e – aq ) produced by X-ray radiation can trigger a series of chemical reactions. − Recently, several prodrug activation strategies have been proposed to use clinically relevant doses of X-ray radiation to control the release of the chemical-modified cages on chemotherapeutic prodrugs. ,− Owing to the excellent precision and deep tissue penetration of X-ray radiation, these strategies provide an avenue to achieve spatiotemporal activation of prodrugs at the tumor site.…”

Nanoscale Metal–Organic Framework with an X-ray Triggerable Prodrug for Synergistic Radiotherapy and Chemotherapy

“…We established subcutaneous CT26 and 4T1 tumor models to assess the in vivo anticancer efficacy of Hf-TP-SN(+). CT26 or 4T1 tumor-bearing mice were intratumorally injected with PBS, irinotecan (a prodrug of SN38, 0.047 μmol), 34 Hf-TP-OH (0.5 μmol Hf), or Hf-TP-SN (0.5 μmol Hf and 0.047 μmol SN38). Six to eight hours later, the tumors were irradiated with 2 Gy X-ray.…”

“…Metal–organic frameworks (MOFs) have recently been exploited for biomedical applications due to their tunable compositions, large porosity, ease of surface functionalization, and biodegradability. − In particular, MOFs have been widely used as drug carriers, − via direct encapsulation of drugs in the pores, , coordination of drugs to metal-cluster secondary building units (SBUs), and covalent conjugation of drugs to the ligands . While the first two methods can have premature drug release due to weak interactions between MOFs and drug molecules, the third method requires an actionable trigger to release the conjugated drug from the MOF. , Among many potential triggers, − X-ray stands out as a great external stimulus due to its deep tissue penetration, image-guided precise dosing, , and radiotherapeutic effects through direct DNA damage or indirect cytotoxic effects via generating reactive oxygen species (ROS). − …”