ArticleInternational journal of pharmaceutics: X2026
A DoE-Dual centrifugation-driven screening platform for liposomal incorporation of poorly soluble APIs: Application to the PROTAC ACBI2.
Article in International journal of pharmaceutics: X, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.
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Abstract
A fast and efficient screening platform is presented for formulating poorly soluble drugs, such as proteolysis-targeting chimeras (PROTACs), into liposomes. Driven by Design of Experiments (DoE) and powered by dual centrifugation, this platform enables high-throughput parallel preparation alongside a newly validated, single-run HPLC method for the simultaneous quantification of all lipid components and hydrophobic payloads. Extended applicability of this HPLC method is demonstrated across three distinct PROTACs and diverse lipid matrices. Mechanistic protocol implementation using the SMARCA2-degrader ACBI2 reveals that the anionic phospholipid DOPG drastically enhances incorporation, whereas cholesterol hinders it due to electrostatic forces and bilayer flexibility demands. Notably, biophysical analysis shows that ACBI2 modulates bilayers in a cholesterol-like manner, increasing lipid packing order in the liquid-crystalline phase while reducing it in the gel phase. Thus, cholesterol-induced packing density directly impairs drug loading. Guided by the DoE model, four uniform lead ACBI2 formulations were identified, achieving robust drug concentrations of up to 2.3 mM, which corresponds to a drug-to-lipid ratio of 5.5-6.0% (
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