caa a22 4500 44531253X CHVBK 20180317142635.0 cr unu---uuuuu 170323e20111201xx s 000 0 eng 10.1007/s11095-011-0495-5 doi (NATIONALLICENCE)springer-10.1007/s11095-011-0495-5 Novel Integrin-Targeted Binding-Triggered Drug Delivery System for Methotrexate [Elektronische Daten] [Phanidhara Kotamraj, Wade Russu, Bhaskara Jasti, Jay Wu, Xiaoling Li] ABSTRACT: Purpose: To design a binding-induced conformation change drug delivery system for integrin-targeted delivery of methotrexate and prove the feasibility of using hairpin peptide structure for binding triggered drug delivery. Methods: Methotrexate prodrugs were synthesized using solid phase peptide synthesis techniques by conjugating methotrexate to Arg-Gly-Asp (RGD) or a hairpin peptide, RWQYVDPGKFTVQRGD (hairpin-RGD). Levels of integrin αVβ3 in HUVEC were up-regulated using adenoviral system and knocked down using siRNA. Stability of prodrugs and methotrexate release from prodrugs were evaluated in plasma, in presence or absence of integrin αVβ3-expressing cells. Molecular modeling was performed to support experimental results using MOE. Results: Prodrugs recognized and bound to integrin αVβ3-expressing cells in integrin αVβ3 expression level-dependent manner. Prodrug with hairpin peptide could resist Streptomyces griseus-derived glutamic acid-specific endopeptidase (SGPE) and plasma enzyme hydrolysis. Drug release was triggered in presence of HUVEC cells and SGPE. Analysis of conformation energy supported that conformational change in MTX-hairpin-RGD led to exposure of labile link upon binding to integrin αVβ3-expressing cells. Conclusions: Binding-induced conformation change of hairpin peptide can be used to design integrin-targeted drug delivery system. Springer Science+Business Media, LLC, 2011 hairpin peptide nationallicence integrin αVβ3 nationallicence methotrexate nationallicence targeted delivery nationallicence triggered release nationallicence Kotamraj Phanidhara Department of Pharmaceutics & Medicinal Chemistry, T. J. Long School of Pharmacy & Health Sciences, University of the Pacific, 95211, Stockton, California, USA aut Russu Wade Department of Pharmaceutics & Medicinal Chemistry, T. J. Long School of Pharmacy & Health Sciences, University of the Pacific, 95211, Stockton, California, USA aut Jasti Bhaskara Department of Pharmaceutics & Medicinal Chemistry, T. J. Long School of Pharmacy & Health Sciences, University of the Pacific, 95211, Stockton, California, USA aut Wu Jay VM Discovery, Fremont, California, USA aut Li Xiaoling Department of Pharmaceutics & Medicinal Chemistry, T. J. Long School of Pharmacy & Health Sciences, University of the Pacific, 95211, Stockton, California, USA aut Pharmaceutical Research Springer US; http://www.springer-ny.com 28/12(2011-12-01), 3208-3219 0724-8741 28:12<3208 2011 28 11095 https://doi.org/10.1007/s11095-011-0495-5 text/html Onlinezugriff via DOI 1 research-article jats NATIONALLICENCE 856 40 https://doi.org/10.1007/s11095-011-0495-5 text/html Onlinezugriff via DOI NATIONALLICENCE 700 1- Kotamraj Phanidhara Department of Pharmaceutics & Medicinal Chemistry, T. J. Long School of Pharmacy & Health Sciences, University of the Pacific, 95211, Stockton, California, USA aut NATIONALLICENCE 700 1- Russu Wade Department of Pharmaceutics & Medicinal Chemistry, T. J. Long School of Pharmacy & Health Sciences, University of the Pacific, 95211, Stockton, California, USA aut NATIONALLICENCE 700 1- Jasti Bhaskara Department of Pharmaceutics & Medicinal Chemistry, T. J. Long School of Pharmacy & Health Sciences, University of the Pacific, 95211, Stockton, California, USA aut NATIONALLICENCE 700 1- Wu Jay VM Discovery, Fremont, California, USA aut NATIONALLICENCE 700 1- Li Xiaoling Department of Pharmaceutics & Medicinal Chemistry, T. J. Long School of Pharmacy & Health Sciences, University of the Pacific, 95211, Stockton, California, USA aut NATIONALLICENCE 773 0- Pharmaceutical Research Springer US; http://www.springer-ny.com 28/12(2011-12-01), 3208-3219 0724-8741 28:12<3208 2011 28 11095 Metadata rights reserved Springer special CC-BY-NC licence nationallicence BK010053 XK010053 XK010000 NATIONALLICENCE NATIONALLICENCE NL-springer