A structure-activity relationship (SAR) study was conducted using a series of PEGylated Fmoc-amino acid conjugates (PFA) as a simple model to gain more insight into carrier-drug interaction. Among the eight PEG2000-Fmoc conjugates with different neighboring structures of Fmoc motif, PEG2000-Fmoc-Lys (Cbz) (PFA2)-based nanomicelles exhibited the smallest particle size distribution, lowest critical micelle concentration (CMC) value, and highest loading capacity with paclitaxel (PTX). These biophysical properties were largely attributed to the strengthened carrier-carrier and carrier-drug interaction, including π-π stacking, hydrophobic, and hydrogen bonding interaction, as confirmed by fluorescence quenching and (13)C NMR study. In vitro and in vivo evaluation further demonstrated the effectiveness of PFA2 as a nanocarrier for efficient delivery of PTX to achieve improved antitumor activity. Importantly, PFA2 was also effective in formulating eight other model drugs of diverse structures, indicating a broad application potential. This work may shed insights into the molecular basis for the structural optimization of nanocarriers for improved delivery efficacy.
Keywords: 9-fluorenylmethoxycarbonyl; carrier−drug interaction; micelle; paclitaxel; structure−activity relationship.