Tumor microenvironment-targeted PROTAC nanoparticle self-assembly broadly predicted by structural descriptors.

Area of Science:

• Biochemistry
• Nanotechnology
• Pharmacology

Background:

• Proteolysis-targeting chimeras (PROTACs) show preclinical promise but face clinical translation challenges due to poor pharmacologic properties and toxicity, often linked to large molecular weights.
• The non-druglike characteristics of PROTACs, including high molecular weight, hinder their clinical application.

Purpose of the Study:

• To investigate the self-assembly of PROTACs into nanoparticles (nanoPROTACs) to overcome pharmacokinetic limitations.
• To identify molecular descriptors predictive of nanoPROTAC formation and evaluate their therapeutic potential.

Main Methods:

• Utilized structure-based prediction algorithms to identify molecular descriptors driving nanoPROTAC formation.
• Developed P-selectin-targeted nanoPROTACs for delivery to the tumor microenvironment.
• Assessed tumor drug uptake, target degradation, tumor growth inhibition, and survival in solid tumor xenografts.

Main Results:

• The majority of PROTACs self-assemble into nanoparticles (nanoPROTACs) with high drug loading capacities.
• Identified specific molecular descriptors that predict nanoPROTAC formation with high accuracy (96% sensitivity, 100% specificity).
• P-selectin-targeted nanoPROTACs demonstrated significantly enhanced tumor drug uptake, target degradation, tumor growth inhibition, and improved survival in preclinical models.

Conclusions:

• PROTACs can self-assemble into nanoparticles, offering a strategy to improve their pharmacologic properties and therapeutic index.
• NanoPROTACs represent a promising approach to enhance the efficacy of PROTACs and other non-druglike therapeutics.
• Targeted nanoPROTAC delivery to the tumor microenvironment significantly improves therapeutic outcomes in solid tumor models.