title: Anticancer and antiangiogenic activity of HPMA copolymer-aminohexylgeldanamycin-RGDfK conjugates for prostate cancer therapy.
abstract: Tumor progression is dependent on neoangiogenesis for blood supply. Neovasculature over-express α(v)β(3) integrins which recognize the Arg-Gly-Asp (RGD) sequence in the extracellular matrix. N-(2-hydroxypropyl)methacrylamide (HPMA) copolymers containing side chains terminated in cyclic RGD analogs such as RGDfK show increased accumulation in prostate tumors. Geldanamycin and their derivatives (e.g., aminohexylgeldanamycin (AH-GDM)) are benzoquinone ansamycins that have both antiangiogenic and antitumor activity. In this work the antiangiogenic and antitumor activities of targetable HPMA copolymer-RGDfK-AH-GDM conjugates were compared with non-targetable systems in vitro and in vivo. Copolymer-drug conjugates containing RGDfK in the side chains showed superior activity against endothelial and prostate cancer cell lines in vitro, as well as higher inhibition of angiogenesis in vivo. At equimolar doses of the drug, the RGDfK containing conjugates showed significantly higher antitumor activity in nude mice bearing DU-145 human prostate cancer xenografts. These findings suggest the utility of HPMA copolymer-RGDfK conjugates for targeted delivery of geldanamycin analogs with a dual mode of action.
authors.affiliation: Department of Pharmaceutics and Pharmaceutical Chemistry, University of Utah, Salt Lake City, UT 84108, USA.
authors.forename: Khaled
authors.initials: K
authors.lastname: Greish
authors.forename: Abhijit
authors.initials: A
authors.lastname: Ray
authors.forename: Hillevi
authors.initials: H
authors.lastname: Bauer
authors.forename: Nate
authors.initials: N
authors.lastname: Larson
authors.forename: Alexander
authors.initials: A
authors.lastname: Malugin
authors.forename: Daniel
authors.initials: D
authors.lastname: Pike
authors.forename: Mohamed
authors.initials: M
authors.lastname: Haider
authors.forename: Hamidreza
authors.initials: H
authors.lastname: Ghandehari
mesh_terms: D020533:Angiogenesis Inhibitors / Q000008:administration & dosage / Q000138:chemical synthesis / Q000737:chemistry / Q000627:therapeutic use*; D000818:Animals; D016227:Benzoquinones / Q000008:administration & dosage / Q000138:chemical synthesis / Q000737:chemistry / Q000627:therapeutic use*; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D042783:Endothelial Cells / Q000187:drug effects; D006801:Humans; D047029:Lactams, Macrocyclic / Q000008:administration & dosage / Q000138:chemical synthesis / Q000737:chemistry / Q000627:therapeutic use*; D008297:Male; D051379:Mice; D008819:Mice, Nude; D015394:Molecular Structure; D008970:Molecular Weight; D009389:Neovascularization, Pathologic / Q000473:pathology / Q000517:prevention & control*; D010456:Peptides, Cyclic / Q000008:administration & dosage / Q000138:chemical synthesis / Q000737:chemistry / Q000627:therapeutic use*; D011109:Polymethacrylic Acids / Q000008:administration & dosage / Q000138:chemical synthesis / Q000737:chemistry / Q000627:therapeutic use*; D011471:Prostatic Neoplasms / Q000098:blood supply* / Q000188:drug therapy* / Q000473:pathology; D023041:Xenograft Model Antitumor Assays
chemical_list: D020533:Angiogenesis Inhibitors; D016227:Benzoquinones; D047029:Lactams, Macrocyclic; D010456:Peptides, Cyclic; D011109:Polymethacrylic Acids