title: Improvement of pharmacokinetic and antitumor activity of PEGylated liposomal doxorubicin by targeting with N-methylated cyclic RGD peptide in mice bearing C-26 colon carcinomas.
abstract: Cyclic Arg-Gly-Asp (cRGD) pentapeptides engrafted liposomes have attracted considerable attention for targeting integrin receptors on tumor vasculature. In this study PEGylated liposomal doxorubicin (PLD) was decorated with three cRGD peptides including Arg-Gly-Asp-D-Tyr-Cys (RGDyC), Arg-Gly-Asp-D-Phe-Lys (RGDfK) and Arg-Gly-Asp-D-Phe-[N-Methyl]Lys (RGDf[N-Met]K). The in vitro liposome-cell-association and cytotoxicity experiments demonstrated the RGD-PLDs capability of internalization into integrin expressing HUVEC cells via receptor mediated endocytosis. The biodistribution studies revealed that decreasing the hydrophilicity of the peptide greatly reduces the RGD-PLDs blood clearance rate and increases their localization in C-26 colon carcinoma tumor model. Meanwhile, the most selective version, RGDf[N-Met]K, which has intermediate hydrophilicity revealed the lowest unwanted interactions with other integrin presenting sites, further localization in tumor, and lower doxorubicin (Dox) side effects. RGDf[N-Met]K-PLD demonstrated a superior control of tumor growth and increased the survival of mice. In this study, we introduced RGDf[N-Met]K for the first time, as a promising ligand for active targeting of liposomes to solid tumor which merits further investigations.
authors.affiliation: Biotechnology Research Center, Nanotechnology Research Center, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad 91775-1365, Iran.
authors.forename: Mohamadreza
authors.initials: M
authors.lastname: Amin
authors.forename: Ali
authors.initials: A
authors.lastname: Badiee
authors.forename: Mahmoud Reza
authors.initials: MR
authors.lastname: Jaafari
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000493:pharmacokinetics* / Q000494:pharmacology; D002277:Carcinoma / Q000188:drug therapy / Q000378:metabolism*; D002478:Cells, Cultured; D003110:Colonic Neoplasms / Q000188:drug therapy / Q000378:metabolism*; D004317:Doxorubicin / Q000031:analogs & derivatives* / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D004705:Endocytosis; D005260:Female; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D008024:Ligands; D008657:Metabolic Clearance Rate; D051379:Mice; D008807:Mice, Inbred BALB C; D010456:Peptides, Cyclic / Q000378:metabolism*; D011092:Polyethylene Glycols / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology; D014018:Tissue Distribution
chemical_list: D000970:Antineoplastic Agents; D008024:Ligands; D010456:Peptides, Cyclic; C507169:cyclic arginine-glycine-aspartic acid peptide; C506643:liposomal doxorubicin; D011092:Polyethylene Glycols; D004317:Doxorubicin
keywords: Ammonium sulfate (PubChem CID: 6097028); C-26 colon carcinoma; Cholesterol (PubChem CID: 5997); Doxorubicin; Doxorubicin HCl (PubChem CID: 443939); Ethylenediaminetetraacetic acid (PubChem CID: 6049); HEPES (PubChem CID: 23831); Hydroxylamine hydrochloride (PubChem CID: 443297); Isopropanol (PubChem CID: 3776); Liposomes; Methylphenazonium methosulfate (PubChem CID: 9285); RGD peptides; Sodium azide (PubChem CID: 33557); Vascular targeting; α-Tocopherol (PubChem CID: 2116)