title: Folate-functionalized dendrimers for targeting Chlamydia-infected tissues in a mouse model of reactive arthritis.
abstract: Chlamydia trachomatis is an intracellular human pathogen that causes a sexually transmitted disease which may result in an inflammatory arthritis designated Chlamydia-induced reactive arthritis (ReA). The arthritis develops after dissemination of infected cells from the initial site of chlamydial infection. During Chlamydia-associated ReA, the organism may enter into a persistent infection state making treatment with antibiotics a challenge. We hypothesize that folate receptors (FR), which are overexpressed in Chlamydia-infected cells, and the associated inflammation would allow folate-targeted nanodevices to better treat infections. To investigate this, we developed a folate-PAMAM dendrimer-Cy5.5 conjugate (D-FA-Cy5.5), where Cy5.5 is used as the near-IR imaging agent. Uptake of D-FA-Cy5.5 upon systemic administration was assessed and compared to non-folate conjugated controls (D-Cy5.5), using a mouse model of Chlamydia-induced ReA, and near-IR imaging. Our results suggested that there was a higher concentration of folate-based nanodevice in sites of infection and inflammation compared to that of the control nanodevice. The folate-conjugated nanodevices localized to infected paws and genital tracts (major sites of inflammation and infection) at 3-4 fold higher concentrations than were dendrimer alone, suggesting that the overexpression of folate receptors in infected and inflamed tissues enables higher dendrimer uptake. There was an increase in uptake into thymus, spleen, and lung, but no significant differences in the uptake of the folate nanodevices in other organs including kidney and heart, indicating the 'relative specificity' of the D-FA-Cy5.5 conjugate nanodevices. These results suggest that folate targeting dendrimers are able to deliver drugs to attenuate infection and associated inflammation in Chlamydia-induced ReA.
authors.affiliation: Department of Immunology & Microbiology, School of Medicine, Wayne State University, 540 East Canfield Avenue, Detroit, MI 48201, United States.
authors.forename: Ilyes
authors.initials: I
authors.lastname: Benchaala
authors.affiliation: Department of Chemical Engineering and Materials Science, College of Engineering, Wayne State University, Detroit, MI 48202, United States.
authors.forename: Manoj K
authors.initials: MK
authors.lastname: Mishra
authors.affiliation: Department of Immunology & Microbiology, School of Medicine, Wayne State University, 540 East Canfield Avenue, Detroit, MI 48201, United States.
authors.forename: Susan M
authors.initials: SM
authors.lastname: Wykes
authors.affiliation: Department of Immunology & Microbiology, School of Medicine, Wayne State University, 540 East Canfield Avenue, Detroit, MI 48201, United States.
authors.forename: Mirabela
authors.initials: M
authors.lastname: Hali
authors.affiliation: Department of Chemical Engineering and Materials Science, College of Engineering, Wayne State University, Detroit, MI 48202, United States. Electronic address: krangar1@jhmi.edu.
authors.forename: Rangaramanujam M
authors.initials: RM
authors.lastname: Kannan
authors.affiliation: Department of Immunology & Microbiology, School of Medicine, Wayne State University, 540 East Canfield Avenue, Detroit, MI 48201, United States. Electronic address: jhudson@med.wayne.edu.
authors.forename: Judith A
authors.initials: JA
authors.lastname: Whittum-Hudson
mesh_terms: D000818:Animals; D016918:Arthritis, Reactive / Q000378:metabolism*; D002232:Carbocyanines / Q000008:administration & dosage* / Q000737:chemistry; D002690:Chlamydia Infections / Q000378:metabolism*; D002692:Chlamydia trachomatis; D050091:Dendrimers / Q000008:administration & dosage* / Q000737:chemistry; D005260:Female; D005456:Fluorescent Dyes / Q000008:administration & dosage* / Q000737:chemistry; D005492:Folic Acid / Q000008:administration & dosage* / Q000737:chemistry; D051379:Mice; D008807:Mice, Inbred BALB C; D000091402:Prohibitins
chemical_list: C098793:CY5.5 cyanine dye; D002232:Carbocyanines; D050091:Dendrimers; D005456:Fluorescent Dyes; C104700:PAMAM Starburst; C000717331:PHB2 protein, human; D000091402:Prohibitins; D005492:Folic Acid
keywords: Folate targeting; Inflammation; Near-IR in vivo imaging; PAMAM dendrimer; Reactive arthritis