Tumor-targeted intracellular delivery of anticancer drugs through the mannose-6-phosphate/insulin-like growth factor II receptor.
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/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.
Department of Pharmacokinetics, Toxicology and Targeting, Groningen Research Institute for Pharmacy, University of Groningen, The Netherlands.|BiOrion Technologies BV, Groningen, The Netherlands.
Jai
J
Prakash
Department of Pharmacokinetics, Toxicology and Targeting, Groningen Research Institute for Pharmacy, University of Groningen, The Netherlands.
Leonie
L
Beljaars
Department of Pharmacokinetics, Toxicology and Targeting, Groningen Research Institute for Pharmacy, University of Groningen, The Netherlands.
Akshay K
AK
Harapanahalli
Department of Pharmacokinetics, Toxicology and Targeting, Groningen Research Institute for Pharmacy, University of Groningen, The Netherlands.|BiOrion Technologies BV, Groningen, The Netherlands.
Mieke
M
Zeinstra-Smith
Department of Pharmacokinetics, Toxicology and Targeting, Groningen Research Institute for Pharmacy, University of Groningen, The Netherlands.
Alie
A
de Jager-Krikken
BiOrion Technologies BV, Groningen, The Netherlands.
Martin
M
Hessing
BiOrion Technologies BV, Groningen, The Netherlands.
Herman
H
Steen
Department of Pharmacokinetics, Toxicology and Targeting, Groningen Research Institute for Pharmacy, University of Groningen, The Netherlands.|BiOrion Technologies BV, Groningen, The Netherlands.
Klaas
K
Poelstra
D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000493:pharmacokinetics; D015153:Blotting, Western; D045744:Cell Line, Tumor; D004317:Doxorubicin / Q000008:administration & dosage* / Q000493:pharmacokinetics; D004337:Drug Carriers / Q000494:pharmacology; D016503:Drug Delivery Systems; D005455:Fluorescent Antibody Technique; D006801:Humans; D007150:Immunohistochemistry; D008360:Mannosephosphates / Q000008:administration & dosage* / Q000493:pharmacokinetics; D051379:Mice; D009374:Neoplasms, Experimental / Q000188:drug therapy*; D017527:Receptor, IGF Type 2 / Q000378:metabolism*; D012709:Serum Albumin / Q000008:administration & dosage* / Q000493:pharmacokinetics
D000970:Antineoplastic Agents; D004337:Drug Carriers; D008360:Mannosephosphates; D017527:Receptor, IGF Type 2; D012709:Serum Albumin; C027693:mannose-6-phosphate; D004317:Doxorubicin