Increasing the antitumor efficacy of doxorubicin-loaded liposomes with peptides anchored via a chelator lipid
Date
2011
Authors
Herringson, Thomas
Altin, Joseph
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Publisher
Informa Healthcare
Abstract
The therapeutic efficacy of anticancer drugs like doxorubicin can be significantly increased by their incorporation into liposomes, but an ability to actively target the drug-containing liposomes to tumors could well provide an even greater curative effect. In this work, a commercial preparation of doxorubicin-loaded liposomes (Caelyx) was modified by incorporation of the metal chelator lipid 3(nitrilotriacetic acid)-ditetradecylamine (NTA3-DTDA) to enable engraftment of histidine-tagged targeting molecules. Our results show that when engrafted with p15-RGR, a His-tagged peptide containing a sequence purported to bind platelet-derived growth factor receptor β (PDGFRβ), NTA3-DTDA-containing Caelyx (3NTA-Caelyx) can be targeted to NIH-3T3 cells in vitro, leading to increased cytotoxicity compared with non-targeted 3NTA-Caelyx. PDGFRβ is known to be expressed on pericytes in the tumor vasculature; however, when radiolabeled p15-RGR liposomes were administered to mice bearing subcutaneous B16-F1 tumors, minimal accumulation into tumors was observed. In contrast, an alternative targeting peptide, p46-RGD, was found to actively direct liposomes to tumors (4.7 %ID/g). Importantly, when injected into tumor-bearing mice, p46-RGD-engrafted 3NTA-Caelyx significantly decreased the tumor growth rate compared with controls. These results indicate that the incorporation of NTA3-DTDA into liposomal drugs could represent a simple modification to the drug to allow engraftment of targeting molecules and to increase its efficacy.
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Keywords
Keywords: 3 (nitrilotriacetic acid)ditetradecylamine; chelating agent; doxorubicin; liposome; platelet derived growth factor beta receptor; unclassified drug; animal experiment; animal model; antineoplastic activity; article; cell strain 3T3; controlled study; cyto Caelyx; Chelator lipid; Long-circulating liposomes; Nanoparticles; Tumor targeting
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Source
Journal of Drug Targeting
Type
Journal article
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2037-12-31
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