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: Mohamadreza Amin, Mercedeh Mansourian, Gerben A Koning, Ali Badiee, Mahmoud Reza Jaafari, Timo L M Ten Hagen
• Journal: Journal of controlled release : official journal of the Controlled Release Society (J Control Release) Vol. 220 Issue Pt A Pg. 308-315 (Dec 28 2015) ISSN: 1873-4995 [Electronic] Netherlands
• PMID: 26526970 (Publication Type: Journal Article)
• Copyright: Copyright © 2015 Elsevier B.V. All rights reserved.

Chemical References

• Antibiotics, Antineoplastic
• Drug Carriers
• Peptides, Cyclic
• cyclic (arginyl-glycyl-aspartyl-phenylalanyl-lysyl)
• cyclo(arginyl-glycyl-aspartyl-phenylalanyl-(N-methyl)cysteinyl)
• cyclo(arginyl-glycyl-aspartyl-tyrosyl-cysteinyl)
• liposomal doxorubicin
• Polyethylene Glycols
• Doxorubicin

Topics

• Animals
• Antibiotics, Antineoplastic (administration & dosage, chemistry, pharmacokinetics)
• Cell Line, Tumor
• Colorectal Neoplasms (blood supply, drug therapy, metabolism, pathology)
• Doxorubicin (administration & dosage, analogs & derivatives, chemistry, pharmacokinetics)
• Drug Carriers
• Drug Compounding
• Drug Stability
• Human Umbilical Vein Endothelial Cells (metabolism)
• Humans
• Hydrophobic and Hydrophilic Interactions
• Injections, Intravenous
• Intravital Microscopy
• Melanoma, Experimental (blood supply, drug therapy, metabolism, pathology)
• Mice
• Mice, Inbred BALB C
• Mice, Inbred C57BL
• Microscopy, Confocal
• Peptides, Cyclic (administration & dosage, chemistry, metabolism)
• Polyethylene Glycols (administration & dosage, chemistry, pharmacokinetics)
• Skin Neoplasms (blood supply, drug therapy, metabolism, pathology)
• Tissue Distribution
• Xenograft Model Antitumor Assays