title: In vivo disassembly of IV administered siRNA matrix nanoparticles at the renal filtration barrier.
abstract: Intravenous administration of siRNA nanocarriers may provide unique therapeutic opportunities for tissue-specific gene silencing. Although often engineered to overcome the numerous barriers that exist in the systemic circulation, many nanocarriers fail in extending the circulation time of the siRNA. A more detailed assessment of the different clearance mechanisms that are in play after intravenous injection could therefore be of value to improve siRNA nanocarrier design. In this report, the biodistribution in mice of siRNA loaded dextran nanogels was investigated in detail. Both single photon emission computed tomography (SPECT) imaging and fluorescence single particle tracking (fSPT) indicate that the particles are rapidly cleared from the circulation. PEGylation of the nanogels was not able to increase the half-life in the bloodstream. Carrier disassembly in the systemic circulation and phagocytic clearance are known to facilitate the elimination of siRNA nanoparticles. Additionally, it is demonstrated for dextran nanogels that also the kidneys play an important role in their elimination from the bloodstream. SPECT imaging revealed an accumulation of the siRNA loaded dextran nanogels in the kidneys shortly after intravenous injection and a significantly delayed transition of siRNA from kidney to bladder, as opposed to the injection of free siRNA. These data indicate that components of the glomerular filtration barrier may contribute to the dissociation of siRNA from its carrier, as was recently suggested for cationic cyclodextrin siRNA polyplexes. This clearance mechanism should therefore be taken into account when designing siRNA nanocarriers for intravenous administration.
authors.affiliation: Ghent Research Group on Nanomedicines, Laboratory of General Biochemistry and Physical Pharmacy, Ghent University, Harelbekestraat 72, 9000 Ghent, Belgium.
authors.forename: Broes
authors.initials: B
authors.lastname: Naeye
authors.forename: Hendrik
authors.initials: H
authors.lastname: Deschout
authors.forename: Vicky
authors.initials: V
authors.lastname: Caveliers
authors.forename: Benedicte
authors.initials: B
authors.lastname: Descamps
authors.forename: Kevin
authors.initials: K
authors.lastname: Braeckmans
authors.forename: Christian
authors.initials: C
authors.lastname: Vanhove
authors.forename: Jo
authors.initials: J
authors.lastname: Demeester
authors.forename: Tony
authors.initials: T
authors.lastname: Lahoutte
authors.forename: Stefaan C
authors.initials: SC
authors.lastname: De Smedt
authors.forename: Koen
authors.initials: K
authors.lastname: Raemdonck
mesh_terms: D061605:Administration, Intravenous; D000818:Animals; D055598:Chemical Phenomena; D003911:Dextrans / Q000737:chemistry; D020868:Gene Silencing; D006207:Half-Life; D007668:Kidney / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D000080385:Nanogels; D053758:Nanoparticles / Q000737:chemistry*; D011092:Polyethylene Glycols / Q000737:chemistry; D011094:Polyethyleneimine / Q000737:chemistry; D034741:RNA, Small Interfering / Q000493:pharmacokinetics*; D014018:Tissue Distribution; D015899:Tomography, Emission-Computed, Single-Photon
chemical_list: D003911:Dextrans; D000080385:Nanogels; D034741:RNA, Small Interfering; C413692:polyethylene glycol polyethyleneimine nanogel; D011092:Polyethylene Glycols; D011094:Polyethyleneimine