Oil-Filled Lipid Nanoparticles Containing 2′-(2-Bromohexadecanoyl)-Docetaxel for the Treatment of Breast Cancer

Authors

  • Lan Feng,

    1. Center for Nanotechnology in Drug Delivery, Division of Molecular Pharmaceutics, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
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  • Soumya R. Benhabbour,

    1. Center for Nanotechnology in Drug Delivery, Division of Molecular Pharmaceutics, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
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  • Russell J. Mumper

    Corresponding author
    1. Center for Nanotechnology in Drug Delivery, Division of Molecular Pharmaceutics, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA, UNC Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, NC, USA, CB# 7355, 100G Beard Hall, University of North Carolina at Chapel Hill
    • Center for Nanotechnology in Drug Delivery, Division of Molecular Pharmaceutics, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA, UNC Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, NC, USA, CB# 7355, 100G Beard Hall, University of North Carolina at Chapel Hill.

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Abstract

A docetaxel (DX) lipid conjugate 2′-(2-bromohexadecanoyl)-docetaxel (2-Br-C16-DX) is synthesized to enhance the drug loading, entrapment, and retention in liquid oil-filled lipid nanoparticles (NPs). The conjugate is successfully entrapped in the previously optimized NPs with an entrapment efficiency of 56.8%. In-vitro release studies in 100% mouse plasma show an initial 45% burst release with no additional release within 8 h. The conjugate is able to be hydrolyzed to release DX by esterases in-vitro. The conjugate is less potent than unmodified DX in DU-145 and 4T1 cells. However, NPs containing the conjugate show significantly higher cytotoxicity compared to its free form especially in 4T1 cells. In-vivo, the AUC0-∞ value of NP-formulated 2-Br-C16-DX is about 100-fold higher than DX formulated in Taxotere. Furthermore, 2-Br-C16-DX NPs improve DX AUC 4.3-fold compared to Taxotere. The high concentration and prolonged exposure of both 2-Br-C16-DX and DX from 2-Br-C16-DX NPs in circulation result in a 10-fold and 1.5-fold higher accumulation of 2-Br-C16-DX and DX, respectively, in tumors compared to Taxotere. In mice bearing syngeneic 4T1 tumors, 2-Br-C16-DX NPs show markedly greater anticancer efficacy, as well as survival benefit over all controls. The results of these studies support that the oil-filled NPs containing hydrolyzable lipophilic DX prodrug 2-Br-C16-DX improve the therapeutic index of DX and are more efficacious in the treatment of breast cancer.

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