Tumor-targeted intracellular delivery of anticancer drugs through the mannose-6-phosphate/insulin-like growth factor II receptor

Jai Prakash*, Leonie Beljaars, Akshay K. Harapanahalli, Mieke Zeinstra-Smith, Alie De Jager-Krikken, Martin Hessing, Herman Steen, Klaas Poelstra

*Corresponding author for this work

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    Abstract

    Tumor-targeting of anticancer drugs is an interesting approach for the treatment of cancer since chemotherapies possess several adverse effects. In the present study, we propose a novel strategy to deliver anticancer drugs to the tumor cells through the mannose-6-phosphate/insutin-like growth factor receptor (M6P/IGF-IIR) which are abundantly expressed in several human tumors. We developed a drug carrier against M6P/IGF-II receptor by modifying human serum albumin (HSA) with M6P moieties. M6P-HSA specifically bound and Internalized into M6P/IGF-IIR-expressing B16 melanoma cells as demonstrated with radioactive studies and anti-HSA immunostaining. In vivo, M6P-HSA rapidly accumulated in subcutaneous tumors in tumor and stromal components after an intravenous injection. To demonstrate the application of M6P-HSA as a drug carrier, we coupled doxorubicin to it. Dox-HSA-M6P conjugate could release doxorubicin at lysosomal pH and showed M6P-specific binding and uptake in tumor cells. In vitro, a short exposure with Dox-HSA-M6P induced killing of tumor cells, which could be blocked by excess M6P-HSA. In vivo, Dox-HSA-M6P distributed to tumors and some other organs while free doxorubicin distributed to all organs but slightly to tumors. In B16 tumor-bearing mice, Dox-HSA-M6P significantly inhibited the tumor growth whereas an equimolar dose of free doxorubicin did not show any anti-tumor effect. In addition, targeted doxorubicin did not show any side-effects on liver and kidney function tests, body weight and blood cell counts. In conclusion, M6P-HSA is a suitable carrier for delivery of anticancer drugs to tumors through M6P/IGF-IIR. Improved antitumor effects of the targeted doxorubicin by M6P-HSA suggest that this novel approach may be applied to improve the therapeutic efficacy of anticancer drugs.

    Original languageEnglish
    Pages (from-to)1966-1981
    Number of pages16
    JournalInternational journal of cancer
    Volume126
    Issue number8
    DOIs
    Publication statusPublished - 15 Apr 2010

    Keywords

    • Insulin-like growth factor receptor
    • Intracellular delivery
    • Mannose-6-phosphate
    • Stromal targeting

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  • Cite this

    Prakash, J., Beljaars, L., Harapanahalli, A. K., Zeinstra-Smith, M., De Jager-Krikken, A., Hessing, M., ... Poelstra, K. (2010). Tumor-targeted intracellular delivery of anticancer drugs through the mannose-6-phosphate/insulin-like growth factor II receptor. International journal of cancer, 126(8), 1966-1981. https://doi.org/10.1002/ijc.24914