Doxorubicin-Loaded Polymeric Micelle Overcomes Multidrug Resistance of Cancer by Double-Targeting Folate Receptor and Early Endosomal pH

Authors

  • Dongin Kim,

    1. Department of Pharmaceutics and Pharmaceutical Chemistry University of Utah 421 Wakara Way, Suite 315 Salt Lake City, UT 84108 (USA)
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  • Eun Seong Lee,

    1. Department of Pharmaceutics and Pharmaceutical Chemistry University of Utah 421 Wakara Way, Suite 315 Salt Lake City, UT 84108 (USA)
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  • Kyung Taek Oh,

    1. Department of Pharmaceutics and Pharmaceutical Chemistry University of Utah 421 Wakara Way, Suite 315 Salt Lake City, UT 84108 (USA)
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  • Zhong Gao Gao,

    1. Department of Pharmaceutics and Pharmaceutical Chemistry University of Utah 421 Wakara Way, Suite 315 Salt Lake City, UT 84108 (USA)
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  • You Han Bae

    Corresponding author
    1. Department of Pharmaceutics and Pharmaceutical Chemistry University of Utah 421 Wakara Way, Suite 315 Salt Lake City, UT 84108 (USA)
    • Department of Pharmaceutics and Pharmaceutical Chemistry University of Utah 421 Wakara Way, Suite 315 Salt Lake City, UT 84108 (USA). Fax: (+1) 801-585-3614
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Abstract

An optimized, pH-sensitive mixed-micelle system conjugated with folic acid is prepared in order to challenge multidrug resistance (MDR) in cancers. The micelles are composed of poly(histidine (His)-co-phenylalanine (Phe))-b-poly(ethylene glycol) (PEG) and poly(L-lactic acid) (PLLA)-b-PEG-folate. Core-forming, pH-sensitive hydrophobic blocks of poly(His-co-Phe) of varying composition are synthesized. The pH sensitivity of the micelles is controlled by the copolymer composition and is fine tuned to early endosomal pH by blending PLLA(3K)-b-PEG(2K)-folate in the presence of a basic anticancer drug, doxorubicin (DOX). In vitro tests are conducted against both wild-type (A2780) and DOX-resistant ovarian carcinoma cell lines. A mixed-micelle system composed of poly(His-co-Phe (16 mole%))-b-PEG (80 wt%) and PLLA-b-PEG-folate (20 wt%) is selected to target early endosomal pH. DOX-loaded micelles effectively kill both wild-type sensitive (A2780) and DOX-resistant ovarian MDR cancer-cell lines (A2780/DOXR) through an instantaneous high dose of DOX in the cytosol, which results from active internalization, accelerated DOX release triggered by endosomal pH, and an endosomal membrance disruption.

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