Enzyme-Responsive Metallopeptide Hydrogel Enables Cancer Cell-Selective Prodrug Activation via Bioorthogonal...

Area of Science:

• Biomaterials Science
• Nanotechnology
• Cancer Therapy

Background:

• Systemic toxicity and poor selectivity limit chemotherapy effectiveness.
• Targeted drug delivery is crucial for improving cancer treatment outcomes.
• Enzyme-responsive materials offer potential for site-specific drug activation.

Purpose of the Study:

• To develop an enzyme-responsive metallopeptide hydrogel for targeted prodrug activation.
• To integrate enzyme-instructed self-assembly (EISA) with bioorthogonal catalysis.
• To address the efficacy versus safety challenges in chemotherapy.

Main Methods:

• Development of H2Yp-Pd, an enzyme-responsive metallopeptide hydrogel.
• Utilizing alkaline phosphatase (ALP) overexpression in osteosarcoma cells (Saos-2) for targeted activation.
• Employing palladium catalysis for in situ activation of a caged doxorubicin prodrug (Alloc-Dox).

Main Results:

• H2Yp-Pd self-assembles into catalytic nanofibers upon ALP exposure.
• Achieved nearly 90% in vitro prodrug conversion with potent cancer cell cytotoxicity.
• Demonstrated significant suppression of cancer cell migration and invasion, comparable to free doxorubicin.
• Hydrogel showed injectability and biocompatibility, suitable for localized drug delivery.

Conclusions:

• The enzyme-responsive hydrogel system enables spatiotemporally controlled prodrug activation.
• This approach offers a promising solution to enhance chemotherapy efficacy while minimizing toxicity.
• The integrated EISA and bioorthogonal catalysis paradigm advances targeted cancer therapy.