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Design and Evaluation of a PEGylated Lipopeptide Equipped with Drug-Interactive Motifs as an Improved Drug Carrier

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Abstract

Micelles are attractive delivery systems for hydrophobic drugs due to their small size and the ease of application. However, the limited drug loading capacity and the intrinsic poor stability of drug-loaded formulations represent two major issues for some micellar systems. In this study, we designed and synthesized a micelle-forming PEG-lipopeptide conjugate with two Fmoc groups located at the interfacial region, and two oleoyl chains as the hydrophobic core. The significance of Fmoc groups as a broadly applicable drug-interactive motif that enhances the carrier–drug interaction was examined using eight model drugs of diverse structures. Compared with an analogue without carrying a Fmoc motif, PEG5000-(Fmoc-OA)2 demonstrated a lower value of critical micelle concentration and three-fold increases of loading capacity for paclitaxel (PTX). These micelles showed tubular structures and small particle sizes (∼70 nm), which can be lyophilized and readily reconstituted with water without significant changes in particle sizes. Fluorescence quenching study illustrated the Fmoc/PTX π–π stacking contributes to the carrier/PTX interaction, and drug-release study demonstrated a much slower kinetics than Taxol, a clinically used PTX formulation. PTX/PEG5000-(Fmoc-OA)2 mixed micelles exhibited higher levels of cytotoxicity than Taxol in several cancer cell lines and more potent inhibitory effects on tumor growth than Taxol in a syngeneic murine breast cancer model (4T1.2). We have further shown that seven other drugs can be effectively formulated in PEG5000-(Fmoc-OA)2 micelles. Our study suggests that micelle-forming PEG-lipopeptide surfactants with interfacial Fmoc motifs may represent a promising formulation platform for a broad range of drugs with diverse structures.

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ACKNOWLEDGMENTS

This work was supported in part by NIH grants (R01GM102989, R21CA173887, and R21CA155983) and a DOD grant (BC09603).

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Authors and Affiliations

  1. Center for Pharmacogenetics, School of Pharmacy, University of Pittsburgh, Pittsburgh, Pennsylvania, 15261, USA

    Peng Zhang, Jianqin Lu, Yixian Huang, Yifei Zhang, Xiaolan Zhang, Jiang Li, Xiang Gao & Song Li

  2. Department of Pharmaceutical Sciences, School of Pharmacy, University of Pittsburgh, Pittsburgh, Pennsylvania, 15261, USA

    Peng Zhang, Jianqin Lu, Yixian Huang, Wenchen Zhao, Yifei Zhang, Xiaolan Zhang, Jiang Li, Raman Venkataramanan, Xiang Gao & Song Li

  3. University of Pittsburgh Cancer Institute, University of Pittsburgh, Pittsburgh, Pennsylvania, 15261, USA

    Peng Zhang, Jianqin Lu, Yixian Huang, Yifei Zhang, Xiaolan Zhang, Jiang Li, Xiang Gao & Song Li

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  1. Peng Zhang
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Correspondence to Xiang Gao or Song Li.

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Zhang, P., Lu, J., Huang, Y. et al. Design and Evaluation of a PEGylated Lipopeptide Equipped with Drug-Interactive Motifs as an Improved Drug Carrier. AAPS J 16, 114–124 (2014). https://doi.org/10.1208/s12248-013-9536-9

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  • DOI: https://doi.org/10.1208/s12248-013-9536-9

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