Surface-Confinement Effect Enables Bioorthogonal Drug Release in Tumors

Area of Science:

• Materials Science
• Nanotechnology
• Drug Delivery

Background:

• Controlled drug release faces challenges in biological systems.
• Radiotherapy-mediated drug release is often inefficient due to reactive intermediate quenching.

Purpose of the Study:

• To develop a platform for bioorthogonal-like drug release.
• To overcome limitations in radiotherapy-mediated prodrug activation.

Main Methods:

• Engineered a hafnium-based nanoscale metal-organic layer (Hf-nMOLs) platform.
• Covalently tethered prodrugs to the Hf-nMOLs surface to create nanoreactors.
• Utilized a surface-confinement effect to localize prodrug activation.

Main Results:

• Hf-nMOLs demonstrated efficient payload release across increasing biological complexity.
• Exatecan-loaded Hf-nMOLs achieved significant radiosensitization and tumor suppression.
• Achieved an intratumoral drug-release G-value of 568 nM·Gy-1.

Conclusions:

• The Hf-nMOLs platform offers a versatile strategy for robust radio-chemotherapeutic combinations.
• Nanoscale surface confinement can confer bioorthogonality to labile activation reactions.
• This approach enhances drug release efficiency in complex biological environments.