Chitosan-based nanogels for selective delivery of photosensitizers to macrophages and improved retention in and therapy of articular joints

Abstract

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 b 4 h 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.

Multifunctional Chitosan Nanoparticles for Tumor Imaging and Therapy

“…In vivo PDT with chitosan was performed by Schmitt et al [77]. They used chitosan nanogel prepared by crosslinking with tripolyphosphonate and Ce6, as photosensitizer.…”

Designing micro- and nano-particles for treating rheumatoid arthritis

“…Key design parameters of micro-and nano-particles and considerations for treating RA of nanoparticles. Chitosan-based nanogels containing anionic photosensitizers that induce cell death were fabricated for selective targeting to synovial macrophages (Schmitt et al, 2010). Anionic PS was attached to cationic chitosan, resulting in neutralization of the positive charge of chitosan and reducing nonspecific cellular toxicity.…”

“…Recently, photosensitizer-loaded chitosan nanogel decorated with hyaluronate was selectively delivered to macrophages and exhibited extended retention time in the inflamed joint of a murine model compared to free photosensitizer (Schmitt et al, 2010).…”

Bacterial Cellulose Membranes as a Potential Drug Delivery System for Photodynamic Therapy of Skin Cancer

“…28 Recently, our group has reported a system based on BC membranes incorporated with the photosensitizer chloroaluminum phthalocyanine (ClAlPc) and luminescent upconversion nanoparticles, which emits light at the wavelength range of ClAlPc absorption under infrared irradiation, within the biological transparency window. 29 Chitosan, which is chemically related to cellulose and plant cellulose nanocrystals, has been studied by Schmitt et al 30 and Drogat et al 31 in photodynamic therapy. In view of these facts, the development of new delivery systems that can efficiently deliver ClAlPc could enable its clinical use for topical PDT.…”