Chitosan-based nanogels for selective delivery of photosensitizers to macrophages and improved retention in and therapy of articular joints.
Macrophages play key roles in inflammatory disorders. Therefore, they are targets of treatments aiming at their local destruction in inflammation sites. However, injection of low molecular mass therapeutics, including photosensitizers, in inflamed joints results in their rapid efflux out of the joints, and poor therapeutic index. To improve selective uptake and increase retention of therapeutics in inflamed tissues, hydrophilic nanogels based on chitosan, of which surface was decorated with hyaluronate and which were loaded with one of three different anionic photosensitizers were developed. Optimal uptake of these functionalized nanogels by murine RAW 264.7 or human THP-1 macrophages as models was achieved after <4h incubation, whereas only negligible uptake by murine fibroblasts used as control cells was observed. The uptake by cells and the intracellular localization of the photosensitizers, of the fluorescein-tagged chitosan and of the rhodamine-tagged hyaluronate were confirmed by fluorescence microscopy. Photodynamic experiments revealed good cell photocytotoxicity of the photosensitizers entrapped in the nanogels. In a mouse model of rheumatoid arthritis, injection of free photosensitizers resulted in their rapid clearance from the joints, while nanogel-encapsulated photosensitizers were retained in the inflamed joints over a longer period of time. The photodynamic treatment of the inflamed joints resulted in a reduction of inflammation comparable to a standard corticoid treatment. Thus, hyaluronate-chitosan nanogels encapsulating therapeutic agents are promising materials for the targeted delivery to macrophages and long-term retention of therapeutics in leaky inflamed articular joints.
University Institute of Pathology, University of Lausanne (UNIL) and University Hospital (CHUV), Lausanne, Switzerland.
Frédéric
F
Schmitt
Lucienne
L
Lagopoulos
Peter
P
Käuper
Nathanaël
N
Rossi
Nathalie
N
Busso
Jérôme
J
Barge
Georges
G
Wagnières
Carsten
C
Laue
Christine
C
Wandrey
Lucienne
L
Juillerat-Jeanneret
D000818:Animals; D001172:Arthritis, Rheumatoid / Q000628:therapy; D002460:Cell Line; D048271:Chitosan / Q000627:therapeutic use*; D006801:Humans; D007596:Joints / Q000378:metabolism / Q000473:pathology; D008264:Macrophages / Q000276:immunology / Q000473:pathology; D051379:Mice; D041681:NIH 3T3 Cells; D000080385:Nanogels; D017319:Photosensitizing Agents / Q000008:administration & dosage / Q000627:therapeutic use*; D011092:Polyethylene Glycols; D011094:Polyethyleneimine
D000080385:Nanogels; D017319:Photosensitizing Agents; C413692:polyethylene glycol polyethyleneimine nanogel; D011092:Polyethylene Glycols; D011094:Polyethyleneimine; D048271:Chitosan