title: Application of Coiled Coil Peptides in Liposomal Anticancer Drug Delivery Using a Zebrafish Xenograft Model.
abstract: The complementary coiled coil forming peptides E4 [(EIAALEK)4] and K4 [(KIAALKE)4] are known to trigger liposomal membrane fusion when tethered to lipid vesicles in the form of lipopeptides. In this study, we examined whether these coiled coil forming peptides can be used for drug delivery applications. First, we prepared E4 peptide modified liposomes containing the far-red fluorescent dye TO-PRO-3 iodide (E4-Lipo-TP3) and confirmed that E4-liposomes could deliver TP3 into HeLa cells expressing K4 peptide on the membrane (HeLa-K) under cell culture conditions in a selective manner. Next, we prepared doxorubicin-containing E4-liposomes (E4-Lipo-DOX) and confirmed that E4-liposomes could also deliver DOX into HeLa-K cells. Moreover, E4-Lipo-DOX showed enhanced cytotoxicity toward HeLa-K cells compared to free doxorubicin. To prove the suitability of E4/K4 coiled coil formation for in vivo drug delivery, we injected E4-Lipo-TP3 or E4-Lipo-DOX into zebrafish xenografts of HeLa-K. As a result, E4-liposomes delivered TP3 to the implanted HeLa-K cells, and E4-Lipo-DOX could suppress cancer proliferation in the xenograft when compared to nontargeted conditions (i.e., zebrafish xenograft with free DOX injection). These data demonstrate that coiled coil formation enables drug selectivity and efficacy in vivo. It is envisaged that these findings are a step forward toward biorthogonal targeting systems as a tool for clinical drug delivery.
authors: Leiden Institute of Chemistry-Supramolecular and Biomaterial Chemistry, Leiden University , Einsteinweg 55, 2333CC Leiden, The Netherlands.
authors: Jian
authors: J
authors: Yang
authors: Institute of Biology, Leiden University , Leiden 2311 EZ, The Netherlands.|Department of Molecular and Cellular Pharmacology, Pharmacogenomics and Pharmacoinformatics, Mie University Graduate School of Medicine , Mie 514-8507, Japan.
authors: Yasuhito
authors: Y
authors: Shimada
authors: Leiden Institute of Chemistry-Supramolecular and Biomaterial Chemistry, Leiden University , Einsteinweg 55, 2333CC Leiden, The Netherlands.
authors: René C L
authors: RC
authors: Olsthoorn
authors: Institute of Biology, Leiden University , Leiden 2311 EZ, The Netherlands.
authors: B Ewa
authors: BE
authors: Snaar-Jagalska
authors: Institute of Biology, Leiden University , Leiden 2311 EZ, The Netherlands.
authors: Herman P
authors: HP
authors: Spaink
authors: Leiden Institute of Chemistry-Supramolecular and Biomaterial Chemistry, Leiden University , Einsteinweg 55, 2333CC Leiden, The Netherlands.
authors: Alexander
authors: A
authors: Kros
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D004317:Doxorubicin / Q000008:administration & dosage*; D016503:Drug Delivery Systems; D006367:HeLa Cells; D064593:Heterografts; D006801:Humans; D008081:Liposomes; D010455:Peptides; D015027:Zebrafish
chemical_list: D008081:Liposomes; D010455:Peptides; D004317:Doxorubicin
keywords: DDS; animal testing; chemotherapeutic agent; lipopeptides; xenotransplantation; α-helices