title: Suppression of inflammation in a mouse model of rheumatoid arthritis using targeted lipase-labile fumagillin prodrug nanoparticles.
abstract: Nanoparticle-based therapeutics are emerging technologies that have the potential to greatly impact the treatment of many human diseases. However, drug instability and premature release from the nanoparticles during circulation currently preclude clinical translation. Herein, we use a lipase-labile (Sn 2) fumagillin prodrug platform coupled with a unique lipid surface-to-surface targeted delivery mechanism, termed contact-facilitated drug delivery, to counter the premature drug release and overcome the inherent photo-instability of fumagillin, an established anti-angiogenic agent. We show that α(v)β(3)-integrin targeted fumagillin prodrug nanoparticles, administered at 0.3 mg of fumagillin prodrug/kg of body weight suppress the clinical disease indices of KRN serum-mediated arthritis in a dose-dependent manner when compared to treatment with the control nanoparticles with no drug. This study demonstrates the effectiveness of this lipase-labile prodrug nanocarrier in a relevant preclinical model that approximates human rheumatoid arthritis. The lipase-labile prodrug paradigm offers a translatable approach that is broadly applicable to many targeted nanosystems and increases the translational potential of this platform for many diseases.
authors.affiliation: Division of Rheumatology, Department of Medicine, Washington University School of Medicine, 660 S. Euclid Avenue, Box 8045, St. Louis, MO 63110, USA.
authors.forename: Hui-Fang
authors.initials: HF
authors.lastname: Zhou
authors.forename: Huimin
authors.initials: H
authors.lastname: Yan
authors.forename: Angana
authors.initials: A
authors.lastname: Senpan
authors.forename: Samuel A
authors.initials: SA
authors.lastname: Wickline
authors.forename: Dipanjan
authors.initials: D
authors.lastname: Pan
authors.forename: Gregory M
authors.initials: GM
authors.lastname: Lanza
authors.forename: Christine T N
authors.initials: CT
authors.lastname: Pham
mesh_terms: D000818:Animals; D001172:Arthritis, Rheumatoid / Q000188:drug therapy*; D003510:Cyclohexanes / Q000737:chemistry / Q000378:metabolism* / Q000627:therapeutic use*; D004586:Electrophoresis; D004797:Enzyme-Linked Immunosorbent Assay; D005231:Fatty Acids, Unsaturated / Q000737:chemistry / Q000378:metabolism* / Q000627:therapeutic use*; D005455:Fluorescent Antibody Technique; D008049:Lipase / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D053758:Nanoparticles / Q000737:chemistry*; D012717:Sesquiterpenes / Q000737:chemistry / Q000378:metabolism / Q000627:therapeutic use
chemical_list: D003510:Cyclohexanes; D005231:Fatty Acids, Unsaturated; D012717:Sesquiterpenes; C026211:fumagillin; D008049:Lipase