Surface-Confinement Effect Enables Bioorthogonal Drug Release in Tumors

Area of Science:

• Materials Science
• Nanotechnology
• Biomedical Engineering

Background:

• Controlled drug release faces challenges in biological systems due to decreased efficiency.
• Radiotherapy-mediated drug release is often hindered by the rapid quenching of reactive intermediates in vivo.
• A need exists for drug delivery platforms that maintain stability and efficacy in complex physiological environments.

Purpose of the Study:

• To engineer a hafnium-based nanoscale metal-organic layer (Hf-nMOLs) platform for bioorthogonal drug release.
• To overcome the limitations of radiotherapy-mediated prodrug activation in vivo.
• To develop a versatile strategy for robust radio-chemotherapeutic combinations.

Main Methods:

• Covalently tethering prodrugs to Hf-nMOLs to create 2D nanoreactors.
• Utilizing a surface-confinement effect to spatially localize prodrug activation.
• Loading Hf-nMOLs with the topoisomerase I inhibitor Exatecan for in vivo studies.

Main Results:

• The Hf-nMOLs platform demonstrated efficient payload release across increasing biological complexity.
• Achieved an intratumoral drug-release G-value of 568 nM·Gy-1 with Exatecan.
• Showcased potent radiosensitization and significant tumor-growth suppression under low-dose X-ray irradiation.

Conclusions:

• Engineered nanoscale surface confinement provides a generalizable strategy for bioorthogonal activation reactions.
• The Hf-nMOLs platform offers a versatile approach for combined radio-chemotherapy.
• This strategy enhances drug release efficiency and therapeutic outcomes in complex biological settings.