title: Development of a novel cyclic RGD peptide for multiple targeting approaches of liposomes to tumor region.
abstract: Liposomes containing cytotoxic agents and targeted with Arg-Gly-Asp based peptides have frequently been used against αvβ3 integrin on tumor neovasculature. However, like many other ligand modified liposomes these preparations suffered from enhanced uptake by the reticulo endothelial system (RES) and off-targeted interaction with integrin receptors vastly expressed in normal organs causing poor biodistribution and toxic effects. Here we mainly focus on development of a RGD-modified liposomal delivery system to enhance both targeting selectivity and tumor uptake. First, sterically stabilized liposomal doxorubicin (SSLD) prepared and decorated with cRGDfK and RGDyC peptides differ in their physical properties. Stability assessments as well as in vitro and in vivo studies revealed that increasing the peptide hydrophobicity promotes the therapeutic efficacy of RGD-SSLD in a C-26 tumor model due to decreased recognition by RES and opsonization and limited off-targeted interactions. Then a novel N-methylated RGD peptide was designed and its capability in targeting integrin presenting cells was comprehensively assessed both in vitro and in vivo. RGDf[N-methyl]C promotes the liposome internalization by HUVEC via integrin mediated endocytosis. Intravital microscopy in window chamber bearing mice illustrated the capability of RGDf[N-methyl]C-liposomes in targeting both tumor vasculature and tumor cells in murine B16F0 and human BLM tumor models. Quantitative biodistribution in mice bearing B16F0 tumor revealed its high affinity to tumor with no considerable affinity to normal organs. Treatment by high dose of RGDf[N-methyl]C-SSLD was found more effective than non-targeted SSLD and no toxic side effect was observed. In conclusion, the RGDf[N-methyl]C-liposome was found promising in targeting tumor vasculature as well as other cells inside the tumor.
authors.affiliation: Biotechnology Research Center, Nanotechnology Research Center, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad 91775-1365, Iran; Laboratory Experimental Surgical Oncology, Section Surgical Oncology, Department of Surgery, Erasmus Medical Center, 3000CA Rotterdam, The Netherlands.
authors.forename: Mohamadreza
authors.initials: M
authors.lastname: Amin
authors.affiliation: Biotechnology Research Center, Nanotechnology Research Center, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad 91775-1365, Iran.
authors.forename: Mercedeh
authors.initials: M
authors.lastname: Mansourian
authors.affiliation: Laboratory Experimental Surgical Oncology, Section Surgical Oncology, Department of Surgery, Erasmus Medical Center, 3000CA Rotterdam, The Netherlands.
authors.forename: Gerben A
authors.initials: GA
authors.lastname: Koning
authors.affiliation: Nanotechnology Research Center, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad 91775-1365, Iran.
authors.forename: Ali
authors.initials: A
authors.lastname: Badiee
authors.affiliation: Biotechnology Research Center, Nanotechnology Research Center, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad 91775-1365, Iran. Electronic address: Jafarimr@mums.ac.ir.
authors.forename: Mahmoud Reza
authors.initials: MR
authors.lastname: Jaafari
authors.affiliation: Laboratory Experimental Surgical Oncology, Section Surgical Oncology, Department of Surgery, Erasmus Medical Center, 3000CA Rotterdam, The Netherlands. Electronic address: t.l.m.tenhagen@erasmusmc.nl.
authors.forename: Timo L M
authors.initials: TLM
authors.lastname: Ten Hagen
mesh_terms: D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000008:administration & dosage* / Q000737:chemistry / Q000493:pharmacokinetics; D045744:Cell Line, Tumor; D015179:Colorectal Neoplasms / Q000098:blood supply / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D004317:Doxorubicin / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000737:chemistry / Q000493:pharmacokinetics; D004337:Drug Carriers; D004339:Drug Compounding; D004355:Drug Stability; D061307:Human Umbilical Vein Endothelial Cells / Q000378:metabolism; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D007275:Injections, Intravenous; D000069416:Intravital Microscopy; D008546:Melanoma, Experimental / Q000098:blood supply / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018613:Microscopy, Confocal; D010456:Peptides, Cyclic / Q000008:administration & dosage / Q000737:chemistry / Q000378:metabolism*; D011092:Polyethylene Glycols / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics; D012878:Skin Neoplasms / Q000098:blood supply / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D014018:Tissue Distribution; D023041:Xenograft Model Antitumor Assays
chemical_list: D000903:Antibiotics, Antineoplastic; D004337:Drug Carriers; D010456:Peptides, Cyclic; C099250:cyclic (arginyl-glycyl-aspartyl-phenylalanyl-lysyl); C000611301:cyclo(arginyl-glycyl-aspartyl-phenylalanyl-(N-methyl)cysteinyl); C000611300:cyclo(arginyl-glycyl-aspartyl-tyrosyl-cysteinyl); C506643:liposomal doxorubicin; D011092:Polyethylene Glycols; D004317:Doxorubicin
keywords: Cyclic RGD peptides; Liposomes; Multiple targeting; Tumor