Gel–Liposome-Mediated Co-Delivery of Anticancer Membrane-Associated Proteins and Small-Molecule Drugs for Enhanced Therapeutic Efficacy

Authors

  • Tianyue Jiang,

    1. Joint Department of Biomedical Engineering, University of North Carolina at Chapel Hill and North Carolina State University, Raleigh, NC, USA
    2. Molecular Pharmaceutics Division, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
    3. State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, China
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  • Ran Mo,

    1. Joint Department of Biomedical Engineering, University of North Carolina at Chapel Hill and North Carolina State University, Raleigh, NC, USA
    2. Molecular Pharmaceutics Division, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
    3. State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, China
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  • Adriano Bellotti,

    1. Joint Department of Biomedical Engineering, University of North Carolina at Chapel Hill and North Carolina State University, Raleigh, NC, USA
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  • Jianping Zhou,

    Corresponding author
    1. State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, China
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  • Zhen Gu

    Corresponding author
    1. Joint Department of Biomedical Engineering, University of North Carolina at Chapel Hill and North Carolina State University, Raleigh, NC, USA
    2. Molecular Pharmaceutics Division, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
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Abstract

A programmed drug-delivery system that can transport different anticancer therapeutics to their distinct targets holds vast promise for cancer treatment. Herein, a core–shell-based “nanodepot” consisting of a liposomal core and a crosslinked-gel shell (designated Gelipo) is developed for the sequential and site-specific delivery (SSSD) of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) and doxorubicin (Dox). As a small-molecule drug intercalating the nuclear DNA, Dox is loaded in the aqueous core of the liposome, while TRAIL, acting on the death receptor (DR) on the plasma membrane, is encapsulated in the outer shell made of crosslinked hyaluronic acid (HA). The degradation of the HA shell by HAase that is concentrated in the tumor environment results in the rapid extracellular release of TRAIL and subsequent internalization of the liposomes. The parallel activity of TRAIL and Dox show synergistic anticancer efficacy. The half-maximal inhibitory concentration (IC50) of TRAIL and Dox co-loaded Gelipo (TRAIL/Dox-Gelipo) toward human breast cancer (MDA-MB-231) cells is 83 ng mL–1 (Dox concentration), which presents a 5.9-fold increase in the cytotoxicity compared to 569 ng mL–1 of Dox-loaded Gelipo (Dox-Gelipo). Moreover, with the programmed choreography, Gelipo significantly improves the inhibition of the tumor growth in the MDA-MB-231 xenograft tumor animal model.

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