title: Synthesis and biological evaluation of dimeric RGD peptide-paclitaxel conjugate as a model for integrin-targeted drug delivery.
abstract: Targeting drugs to receptors involved in tumor angiogenesis is a novel and promising approach to improve cancer treatment. In this study, we evaluated the antitumor activity of paclitaxel (PTX) conjugated with a bicyclic peptide E[c(RGDyK)](2) (RGD) in a metastatic breast cancer cell line (MDA-MB-435). The cyclic RGD peptide selectively binds to alpha(v) integrin receptors that are highly expressed in metastatic cancer cells. PTX, an antimicrotubule agent, is a potent antitumor agent commonly used in the treatment of advanced metastatic breast cancer. The in vitro results showed that RGD peptide inhibited cell cycle proliferation by arresting cells in G(0)/G(1)-phase. The PTX-RGD conjugate inhibited cell proliferation with activity comparable to that observed for paclitaxel, both of which were mediated by an arrest of G(2)/M-phase of the cell cycle followed by apoptosis. Although the PTX-RGD conjugate showed slightly decreased integrin binding affinity than the unconjugated peptide, it indicated integrin specific accumulation in vivo. (125)I-Labeled PTX-RGD showed highest tumor uptake at 2 h postinjection (2.72 +/-0.16%ID/g) and best tumor/background contrast after 4 h postinjection. Our results demonstrate the potential of tumor-targeted delivery of paclitaxel based on the specific recognition of cell adhesion molecule alpha(v)beta(3) integrin to reduce toxicity and enhance selective killing of cancer cells.
authors.affiliation: Department of Radiology, University of Southern California, Los Angeles, California 90033, USA. shawchen@stanford.edu
authors.forename: Xiaoyuan
authors.initials: X
authors.lastname: Chen
authors.forename: Carmen
authors.initials: C
authors.lastname: Plasencia
authors.forename: Yingping
authors.initials: Y
authors.lastname: Hou
authors.forename: Nouri
authors.initials: N
authors.lastname: Neamati
mesh_terms: D020533:Angiogenesis Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D017209:Apoptosis; D001667:Binding, Competitive; D045744:Cell Line, Tumor; D019281:Dimerization; D016503:Drug Delivery Systems; D005260:Female; D039564:Integrin alphaV / Q000378:metabolism*; D008325:Mammary Neoplasms, Experimental / Q000098:blood supply / Q000378:metabolism; D051379:Mice; D008819:Mice, Nude; D009842:Oligopeptides / Q000737:chemistry / Q000494:pharmacology*; D017239:Paclitaxel / Q000737:chemistry / Q000494:pharmacology*; D011869:Radioligand Assay; D014018:Tissue Distribution
chemical_list: D020533:Angiogenesis Inhibitors; D000970:Antineoplastic Agents; D039564:Integrin alphaV; D009842:Oligopeptides; C047981:arginyl-glycyl-aspartic acid; D017239:Paclitaxel