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Tumor microenvironment-targeted PROTAC nanoparticle self-assembly broadly predicted by structural descriptors
Kristen C Vogt1,2,3, Magdalini Panagiotakopoulou1, Mandana T Manzari Honu1
1Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
Abstract:
Proteolysis-targeting chimeras (PROTACs) are catalytic protein degraders with promising preclinical activity. The clinical translation of PROTACs has been limited by poor pharmacologic properties and toxicities, in part due to their "non-druglike" characteristics, including large molecular weights. We found that the vast majority of PROTACs can self-assemble into nanoparticles, yielding nanoparticle PROTACs (nanoPROTACs) with ultrahigh drug loadings. While PROTAC molecular features can be deleterious to their pharmacokinetic properties, we found that they can drive nanoencapsulation more efficiently than FDA-approved small-molecule drugs. Using structure-based prediction algorithms, we identified spatial autocorrelation molecular descriptors that defined nanoPROTAC formation with 96% sensitivity at 100% specificity. NanoPROTACs, targeted to the tumor microenvironment via P-selectin, led to significantly enhanced tumor drug uptake, target degradation, tumor growth inhibition, and overall survival in solid tumor xenografts. These findings offer a broad strategy to improve the pharmacologic properties and therapeutic index of PROTACs and potentially other non-druglike experimental therapeutics.
Insights
Proteolysis-targeting chimeras (PROTACs) self-assemble into nanoparticles (nanoPROTACs), improving drug delivery and efficacy. This strategy enhances tumor targeting, drug uptake, and survival in preclinical models.
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.
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