ICR Researchers Develop Novel Formulation Strategies to Enable Oral Delivery of VHL-based PROTACs
核心洞察
Researchers at the Institute of Cancer Research are developing innovative formulation and prodrug strategies to overcome the physicochemical limitations that prevent oral delivery of VHL (搜索)-based PROTACs (搜索).
The comprehensive approach includes screening 10-20 PROTAC molecules against diverse formulation types and synthesizing prodrugs to enhance permeability through modulating lipophilicity and blocking hydrogen-bond donor groups.
Advanced delivery platforms including self-emulsifying drug delivery systems, lipid-based carriers, and polymeric nanocarriers will be evaluated to address solubility, permeability and stability challenges.
Researchers at the Institute of Cancer Research (ICR) have launched an ambitious project to overcome one of the most significant barriers facing VHL (搜索)-based PROTACs (搜索): their poor physicochemical properties that limit oral delivery potential. The comprehensive research initiative proposes a rational approach to integrate formulation science into early-stage PROTAC design, with the goal of enabling improved systemic exposure through oral administration.
Multi-Phase Screening Strategy
The research team will begin by selecting 10-20 PROTAC molecules from in-house programs and literature sources, spanning a range of physicochemical properties including molecular weight and polarity, with emphasis on compounds demonstrating low metabolic clearance. Each compound will undergo screening against up to 10 formulation types representing diverse chemistries, with solubility and chemical stability measured in aqueous and biorelevant media including FASSIF and SGF.
This initial screening phase aims to build understanding of which approaches are effective for different compound classes and define a minimum screenable formulation set, enabling rapid identification of appropriate formulations for future PROTAC development.
Innovative Prodrug Design Approach
To address permeability limitations inherent in VHL (搜索)-based PROTACs (搜索), the researchers will synthesize prodrugs designed to enhance permeability through modulating lipophilicity and blocking hydrogen-bond donor groups on the VHL warhead. The team plans to mitigate potential solubility reduction by considering molecular shape factors, such as induction of hydrophobic collapse to reduce exposed lipophilic surface area.
Recognizing that traditional PAMPA assays prove unreliable for PROTACs (搜索), the researchers will explore alternative assessment methods including biomimetic chromatography and modified Caco-2 assay conditions. In-house assays will compare VHL (搜索)-target engagement kinetics in intact versus lysed cells to provide measures of permeability, while LC-MS analysis and plasma stability assays will evaluate prodrug release rates.
Advanced Delivery Platform Development
The project will investigate sophisticated delivery systems including self-emulsifying drug delivery systems (SEDDS), lipid-based carriers, and polymeric nanocarriers. These platforms offer distinct advantages in overcoming the solubility, permeability and stability challenges associated with PROTACs (搜索). Polymeric nanocarriers, for example, can improve solubility while providing encapsulation protection against degradation in the gastrointestinal tract.
Formulations will be prepared using advanced techniques such as microfluidics or high-pressure homogenization and characterized through dynamic light scattering, zeta potential analysis, HPLC, and encapsulation efficiency measurements. Visual inspection will assess physical stability, with comparative studies across platforms providing insight into the most promising strategies.
Comprehensive Stability and Bioavailability Assessment
To support oral delivery development, the research will include extensive stability studies investigating formulation and active ingredient performance against gastric acid, bile salts and pancreatic lipases in the gastrointestinal tract through in vitro testing. Formulation stability and release mechanisms will be assessed through particle size analysis, HPLC, and sub-visible/visible particle assessment.
Solubility experiments using Sirius T3 or alternative methods will explore how solubility changes across GI tract conditions, including pH variations and media switches between SGF and FeSSIF. In vivo pharmacokinetic studies will determine oral bioavailability of optimized formulations.
Clinical Development Impact
The project's deliverables are designed to provide a practical toolkit for selecting and developing formulations compatible with PROTACs (搜索) and suitable for progression into preclinical development. By screening diverse compounds and formulations, the research will define strategies most likely to enhance solubility without introducing chemical instability across various physicochemical profiles.
The integration of formulation understanding into compound design cycles aims to develop PROTACs (搜索) with improved absorption and oral bioavailability. The comprehensive approach addresses the critical need for oral PROTAC delivery, potentially accelerating the clinical development timeline for this promising therapeutic modality by enabling more reliable preclinical experiments and faster progression to proof-of-concept studies.