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

Publisher： John Wiley & Sons Inc

E-ISSN： 1097-0215|126|8|1966-1981

ISSN： 0020-7136

Source： INTERNATIONAL JOURNAL OF CANCER, Vol.126, Iss.8, 2010-04, pp. : 1966-1981

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Abstract

AbstractTumor‐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/insulin‐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.