Effect of Hydrophilic Brush Length and Hydrophobic Chain on Biodistribution of Polymethacrylate-Based Statistical Copolymers

We systematically explored PEG alternatives by synthesizing a combinatorial library of nine copolymers composed of three hydrophilic monomers including oligo(ethylene glycol) methyl ether methacrylate and 2-(methylsulfinyl)ethyl methacrylate and three hydrophobic monomers. These copolymers were evaluated for their hydrophobicity by reversed-phase chromatography and LCST behavior, and for their biodistribution. Extended hydrophilic brushes enhanced blood retention and tumor accumulation. For copolymers with the longest brushes, hydrophobic side chains minimally influenced kidney accumulation, whereas kidney accumulation of copolymers with medium-length brushes was strongly influenced. Liver accumulation of the copolymers was hardly affected by the hydrophobic side chain, except for the copolymer with the longest brushes and the most hydrophobic side chains, which showed increased liver accumulation. This study highlights the critical role of hydrophilic brushes and hydrophobic side chains in modulating biodistribution of polymeric carriers and provides a foundation for rational design of drug delivery systems.