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.
Prakash
Jai
J
Department of Pharmacokinetics, Toxicology and Targeting, Groningen Research Institute for Pharmacy, University of Groningen, The Netherlands.|BiOrion Technologies BV, Groningen, The Netherlands.
Beljaars
Leonie
L
Department of Pharmacokinetics, Toxicology and Targeting, Groningen Research Institute for Pharmacy, University of Groningen, The Netherlands.
Harapanahalli
Akshay K
AK
Department of Pharmacokinetics, Toxicology and Targeting, Groningen Research Institute for Pharmacy, University of Groningen, The Netherlands.
Zeinstra-Smith
Mieke
M
Department of Pharmacokinetics, Toxicology and Targeting, Groningen Research Institute for Pharmacy, University of Groningen, The Netherlands.|BiOrion Technologies BV, Groningen, The Netherlands.
de Jager-Krikken
Alie
A
Department of Pharmacokinetics, Toxicology and Targeting, Groningen Research Institute for Pharmacy, University of Groningen, The Netherlands.
Hessing
Martin
M
BiOrion Technologies BV, Groningen, The Netherlands.
Steen
Herman
H
BiOrion Technologies BV, Groningen, The Netherlands.
Poelstra
Klaas
K
Department of Pharmacokinetics, Toxicology and Targeting, Groningen Research Institute for Pharmacy, University of Groningen, The Netherlands.|BiOrion Technologies BV, Groningen, The Netherlands.
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