A Dual-Mechanism Targeted Bioorthogonal Prodrug Therapy

Area of Science:

• Biomedical Engineering
• Oncology
• Drug Delivery Systems

Background:

• Bioorthogonal prodrug therapies offer controlled drug activation but often face limitations in tumor targeting and efficacy.
• Current monomechanism strategies struggle with solid tumor heterogeneity, impacting both drug and activator delivery.
• A dual-targeting approach is needed to overcome these limitations and improve therapeutic outcomes.

Purpose of the Study:

• To develop a dual-mechanism targeted bioorthogonal prodrug therapy for enhanced anticancer efficacy and safety.
• To integrate two orthogonal, receptor-independent tumor-targeting strategies for simultaneous delivery of prodrug and activator.
• To optimize administration sequence based on pharmacokinetics for spatiotemporally controlled drug activation.

Main Methods:

• Utilized the endogenous albumin transport system for *in situ* albumin-bound, bioorthogonal-caged doxorubicin prodrug formation.
• Employed enzyme-instructed self-assembly (EISA) for selective enrichment of bioorthogonal activators within tumor cells.
• Optimized the administration sequence of prodrug and activator based on their distinct pharmacokinetic profiles.

Main Results:

• Achieved extended plasma circulation and selective tumor accumulation of the doxorubicin prodrug via albumin binding.
• Demonstrated specific enrichment of bioorthogonal activators in tumor cells through EISA.
• Enabled spatiotemporally controlled, on-target, and on-demand prodrug activation through optimized administration sequencing.

Conclusions:

• Orchestrating two discrete, receptor-independent targeting strategies provides a robust platform for bioorthogonal prodrug therapies.
• The developed all-small-molecule system maximizes therapeutic efficacy by improving drug delivery and activation.
• This dual-mechanism approach significantly minimizes adverse drug reactions, enhancing the safety profile of chemotherapeutic agents.