title: Increasing the antitumor efficacy of doxorubicin-loaded liposomes with peptides anchored via a chelator lipid.
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 (NTA(3)-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), NTA(3)-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 NTA(3)-DTDA into liposomal drugs could represent a simple modification to the drug to allow engraftment of targeting molecules and to increase its efficacy.
authors.affiliation: Division of Biomedical Science and Biochemistry, Research School of Biology, ANU College of Medicine, Biology and Environment, The Australian National University, Canberra, ACT, Australia.
authors.forename: Thomas P
authors.initials: TP
authors.lastname: Herringson
authors.forename: Joseph G
authors.initials: JG
authors.lastname: Altin
mesh_terms: D000588:Amines / Q000737:chemistry*; D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000627:therapeutic use*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D002614:Chelating Agents / Q000737:chemistry*; D004305:Dose-Response Relationship, Drug; D004317:Doxorubicin / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000627:therapeutic use*; D004337:Drug Carriers / Q000737:chemistry*; D004339:Drug Compounding; D005260:Female; D005434:Flow Cytometry; D008546:Melanoma, Experimental / Q000188:drug therapy; D051379:Mice; D008810:Mice, Inbred C57BL; D041681:NIH 3T3 Cells; D009571:Nitrilotriacetic Acid / Q000031:analogs & derivatives* / Q000737:chemistry; D010316:Particle Size; D010446:Peptide Fragments / Q000737:chemistry*; D014018:Tissue Distribution; D023041:Xenograft Model Antitumor Assays
chemical_list: D000588:Amines; D000903:Antibiotics, Antineoplastic; D002614:Chelating Agents; D004337:Drug Carriers; D010446:Peptide Fragments; C405382:nitrilotriacetic acid ditetradecylamine; D004317:Doxorubicin; D009571:Nitrilotriacetic Acid