Proteolysis-targeting chimeras (PROTACs) have rapidly developed. However, issues such as poor water solubility and low cell permeability limit the therapeutic application of PROTACs. This calls for appropriate delivery systems to improve these shortcomings. BOC Sciences provides PROTAC delivery services, offering solutions for our clients in various aspects, including delivery system selection and development, PROTAC design and synthesis, linker optimization, PROTAC encapsulation, and PROTAC conjugation, to facilitate PROTAC project development.
Why PROTAC Delivery?
PROTAC is a heterobifunctional molecule composed of two ligands connected by a flexible chemical linker, enabling them to simultaneously bind to E3 ubiquitin ligases and the target protein (POI). Unlike traditional small molecule inhibitors, PROTACs catalyze and irreversibly remove disease-causing target proteins.
Issues to consider and address in PROTAC design include:
- PROTAC structures consist of at least two protein ligands, resulting in a large molecular weight exceeding 700 Da. Additionally, they contain many polar chemical bonds, contributing to an increased topological polar surface area (TPSA) leading to decreased cell permeability and increased efflux by membrane transporters.
- PROTACs have poor water solubility, leading to instability in biological media. Low serum stability and cell permeability of PROTACs affect their pharmacokinetics (PK) and bioavailability, resulting in adverse distribution in normal tissues.
Chemical optimization of PROTAC structures can partially improve their performance, but it is often time-consuming and less applicable. Moreover, most modification methods only focus on adjusting their cell permeability rather than their biodistribution. Therefore, developing various delivery systems to enhance PROTAC performance is a favorable strategy.
PROTAC Delivery Development
PROTACs can be transported through a variety of delivery systems, such as lipid nanoparticles and inorganic nanoparticles, small-molecule targeting moieties, and antibodies. By passive or active targeting techniques, they can modify PROTACs' poor water solubility and cell permeability, control their PK characteristics, and encourage their preferential localisation in tumor tissues.
Nanoparticle-Based PROTAC Delivery
Nanoparticles are used to modulate the poor water solubility and PK properties of drugs. Typically, nanoparticles have much larger sizes than drug molecules, so once the drug is encapsulated into nanoparticles, its solubility is entirely dependent on the solubility of the nanoparticles. Additionally, nanoparticles can provide drugs with a longer circulation time. BOC Sciences provides nanoparticle-based PROTAC delivery services.
- Lipid nanoparticles (LNP): Lipid nanoparticles facilitate the internalization of PROTACs into cancer cells, escaping from lysosomes and functioning smoothly in the cytoplasm.
- Inorganic nanoparticles: Such as silica, gold, iron oxide, and quantum dots. The morphology and size distribution of inorganic nanoparticles can be precisely controlled, and their rigid structure reduces the risk of off-target drug leakage.
Active Targeting PROTAC Delivery
Active targeting strategies mainly rely on the specific binding affinity between targeting ligands and overexpressed membrane receptors. By using targeting moieties for PROTAC delivery, the poor cell permeability of PROTACs can be regulated, as they are internalized through receptor-mediated endocytosis rather than simple transmembrane diffusion. Internalized PROTACs distribute in the cytoplasm, catalyzing the degradation of the target protein. BOC Sciences provides PROTAC conjugation services with various targeting molecules, including small molecules, antibodies, aptamers, and functionalized nanoparticles. This strategy promotes the selective enrichment of PROTAC conjugates, reducing systemic toxicity caused by off-target delivery.
Our Services:
Why Choose BOC Sciences?
With a powerful PROTAC technology platform and comprehensive PROTAC services, BOC Sciences provides PROTAC delivery system development, optimizes the physicochemical properties of PROTACs, promotes intracellular accumulation, and enhances their degrading potency. We are able to assist our clients in overcoming PROTAC molecule development challenges and deliver satisfactory results in the shortest possible timeframe.
* PROTAC® is a registered trademark of Arvinas Operations, Inc., and is used under license.
