title: SiRNA-mediated in vivo gene knockdown by acid-degradable cationic nanohydrogel particles.
abstract: Cationic nanohydrogel particles have become an attractive tool for systemic siRNA delivery, but improvement of their in vivo tolerance is desirable, especially to prevent potential long term side effects by tissue and cellular accumulation. Here, we designed novel ketal cross-linked cationic nanohydrogel particles that were assessed for reduced tissue accumulation and robust siRNA delivery in vitro and in vivo. An oligo-amine cross-linker equipped with a ketal moiety in its core was synthesized and applied to nanohydrogel cross-linking of self-assembled reactive ester block copolymers in DMSO. The resulting acid-sensitive cationic nanoparticles spontaneously disassembled over time in acidic milieu, as investigated by dynamic light scattering. Fluorescent correlation spectroscopy showed effective complexation with siRNA as well as its release upon particle degradation at endosomal pH. These properties resulted in an enhanced in vitro gene knockdown for the acid-degradable cationic nanoparticles compared to their non-degradable spermine analogues. In a murine liver fibrosis model enhanced carrier and payload accumulation in the fibrotic tissue facilitated sequence-specific gene knockdown and prevented fibrosis progression. Long-term monitoring of the carrier in the body showed an enhanced clearance for the acid-degradable carrier, even after multiple dosing. Therefore, these acid-degradable cationic nanohydrogel particles can be considered as promising siRNA carriers for in vivo purposes towards therapeutic applications.
authors.affiliation: Institutes of Organic Chemistry, Johannes Gutenberg-University of Mainz, Duesbergweg 10-14, 55128 Mainz, Germany.
authors.forename: Nadine
authors.initials: N
authors.lastname: Leber
authors.affiliation: Institute of Translational Immunology and Research Center for Immunotherapy (FZI), University Medical Center of the Johannes Gutenberg-University Mainz, Obere Zahlbacher Str. 63, 55131 Mainz, Germany.
authors.forename: Leonard
authors.initials: L
authors.lastname: Kaps
authors.affiliation: Institute of Translational Immunology and Research Center for Immunotherapy (FZI), University Medical Center of the Johannes Gutenberg-University Mainz, Obere Zahlbacher Str. 63, 55131 Mainz, Germany; Department of Microbiology, Shaheed Benazir Bhutto Women University, Peshawar, Pakistan.
authors.forename: Misbah
authors.initials: M
authors.lastname: Aslam
authors.affiliation: Department of Dermatology, University Medical Center of the Johannes Gutenberg-University Mainz, Langenbeckstr. 1, 55131 Mainz, Germany.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Schupp
authors.affiliation: Institute of Translational Immunology and Research Center for Immunotherapy (FZI), University Medical Center of the Johannes Gutenberg-University Mainz, Obere Zahlbacher Str. 63, 55131 Mainz, Germany.
authors.forename: Alexander
authors.initials: A
authors.lastname: Brose
authors.affiliation: Max-Planck-Institute for Polymer Research, Ackermannweg 10, 55128 Mainz, Germany.
authors.forename: David
authors.initials: D
authors.lastname: Schäffel
authors.affiliation: Institutes of Physical Chemistry, Johannes Gutenberg-University of Mainz, Duesbergweg 10-14, 55128 Mainz, Germany.
authors.forename: Karl
authors.initials: K
authors.lastname: Fischer
authors.affiliation: TRON - Translational Oncology, University Medical Center of the Johannes Gutenberg-University Mainz, Freiligrathstraße 12, 55131 Mainz, Germany.
authors.forename: Mustafa
authors.initials: M
authors.lastname: Diken
authors.affiliation: First Department of Internal Medicine, University Medical Center of the Johannes Gutenberg University Mainz, Langenbeckstr. 1, 55131 Mainz, Germany.
authors.forename: Dennis
authors.initials: D
authors.lastname: Strand
authors.affiliation: Max-Planck-Institute for Polymer Research, Ackermannweg 10, 55128 Mainz, Germany.
authors.forename: Kaloian
authors.initials: K
authors.lastname: Koynov
authors.affiliation: Department of Dermatology, University Medical Center of the Johannes Gutenberg-University Mainz, Langenbeckstr. 1, 55131 Mainz, Germany.
authors.forename: Andrea
authors.initials: A
authors.lastname: Tuettenberg
authors.affiliation: Institutes of Organic Chemistry, Johannes Gutenberg-University of Mainz, Duesbergweg 10-14, 55128 Mainz, Germany; Department of Pharmaceutics, Ghent University, Ottergemsesteenweg 460, 9000 Ghent, Belgium. Electronic address: lutz.nuhn@ugent.be.
authors.forename: Lutz
authors.initials: L
authors.lastname: Nuhn
authors.affiliation: Institutes of Organic Chemistry, Johannes Gutenberg-University of Mainz, Duesbergweg 10-14, 55128 Mainz, Germany. Electronic address: zentel@uni-mainz.de.
authors.forename: Rudolf
authors.initials: R
authors.lastname: Zentel
authors.affiliation: Institute of Translational Immunology and Research Center for Immunotherapy (FZI), University Medical Center of the Johannes Gutenberg-University Mainz, Obere Zahlbacher Str. 63, 55131 Mainz, Germany; Division of Gastroenterology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, United States. Electronic address: detlef.schuppan@unimedizin-mainz.de.
authors.forename: Detlef
authors.initials: D
authors.lastname: Schuppan
mesh_terms: D016475:3T3 Cells; D000818:Animals; D002412:Cations / Q000737:chemistry; D005260:Female; D005355:Fibrosis; D055785:Gene Knockdown Techniques; D020100:Hydrogels / Q000737:chemistry*; D008099:Liver / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D053758:Nanoparticles / Q000737:chemistry; D011108:Polymers / Q000737:chemistry; D000067996:RAW 264.7 Cells; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000008:administration & dosage* / Q000235:genetics / Q000493:pharmacokinetics
chemical_list: D002412:Cations; D020100:Hydrogels; D011108:Polymers; D034741:RNA, Small Interfering
keywords: Acid degradable; Cationic nanohydrogels; Fibrosis; Ketal cross-linker; siRNA