Strategies to Improve the Lipophilicity of Hydrophilic Macromolecular Drugs

Macromolecular drugs, including peptides, proteins, oligonucleotides, and polysaccharides, have shown remarkable therapeutic potential due to their high specificity, potency, and low toxicity profiles. However, their clinical translation, particularly for oral administration, remains limited by poor bioavailability arising from poor membrane permeability and enzymatic instability. Enhancing the lipophilicity of these molecules is a critical strategy to overcome these challenges, improving their membrane permeability, stability, and pharmacokinetic properties. This review discusses current strategies to improve the lipophilicity of macromolecular drugs, focusing on covalent and non-covalent lipidation. Covalent lipidation, which involves the conjugation of lipids such as fatty acids or steroids, provides stable chemical modifications that have led to several commercially successful products. However, it also presents regulatory complexities due to the formation of new active pharmaceutical ingredients. In contrast, non-covalent lipidation methods, such as hydrophobic ion pairing and reverse micelle formation, offer reversible alternatives that preserve the native structure of the drug, simplify regulatory procedures, and allow flexible tuning of delivery properties. Notably, reverse micelle systems demonstrate superior performance compared to hydrophobic ion pairs, particularly in enhancing the lipophilicity of larger, more complex macromolecules. While lipidation strategies have significantly advanced the field, substantial challenges remain, especially in achieving consistent bioavailability and translating preclinical success into clinical efficacy. Future progress will require innovative ideas and the integration of emerging technologies to fully unlock the potential of lipidated macromolecular therapeutics.