A PEG-Fmoc conjugate as a nanocarrier for paclitaxel

We report here that a simple, well-defined, and easy-to-scale up nanocarrier, PEG₅₀₀₀-lysyl-(α-Fmoc-ε-t-Boc-lysine)₂ conjugate (PEG-Fmoc), provides high loading capacity, excellent formulation stability and low systemic toxicity for paclitaxel (PTX), a first-line chemotherapeutic agent for various types of cancers. 9-Fluorenylmethoxycarbonyl (Fmoc) was incorporated into the nanocarrier as a functional building block to interact with drug molecules. PEG-Fmoc was synthesized via a three-step synthetic route, and it readily interacted with PTX to form mixed nanomicelles of small particle size (25-30nm). The PTX loading capacity was about 36%, which stands well among the reported micellar systems. PTX entrapment in this micellar system is achieved largely via an Fmoc/PTX π-π stacking interaction, which was demonstrated by fluorescence quenching studies and ¹³C NMR. PTX formulated in PEG-Fmoc micelles demonstrated sustained release kinetics, and invivo distribution study via near infrared fluorescence imaging demonstrated an effective delivery of Cy5.5-labled PTX to tumor sites. The maximal tolerated dose for PTX/PEG-Fmoc (MTD>120mg PTX/kg) is higher than those for most reported PTX formulations, and invivo therapeutic study exhibited a significantly improved antitumor activity than Taxol, a clinically used formulation of PTX. Our system may hold promise as a simple, safe, and effective delivery system for PTX with a potential for rapid translation into clinical study.