Intraperitoneal administration of chitosan/DsiRNA nanoparticles targeting TNFα prevents radiation-induced fibrosis.
OBJECTIVE
One of the most common and dose-limiting long-term adverse effects of radiation therapy is radiation-induced fibrosis (RIF), which is characterized by restricted tissue flexibility, reduced compliance or strictures, pain and in severe cases, ulceration and necrosis. Several strategies have been proposed to ameliorate RIF but presently no effective one is available. Recent studies have reported that tumor necrosis factor-α (TNFα) plays a role in fibrogenesis.


METHODS
Male CDF1 mice were radiated with a single dose of 45 Gy. Chitosan/DsiRNA nanoparticles targeting TNFα were intraperitoneal injected and late radiation-induced fibrosis (RIF) was assessed using a modification of the leg contracture model. Additionally, the effect of these nanoparticles on tumor growth and tumor control probability in the absence of radiation was examined in a C3H mammary carcinoma model.


RESULTS
We show in this work, that targeting TNFα in macrophages by intraperitoneal administration of chitosan/DsiRNA nanoparticles completely prevented radiation-induced fibrosis in CDF1 mice without revealing any cytotoxic side-effects after a long-term administration. Furthermore, such TNFα targeting was selective without any significant influence on tumor growth or irradiation-related tumor control probability.


CONCLUSIONS
This nanoparticle-based RNAi approach represents a novel approach to prevent RIF with potential application to improve clinical radiation therapeutic strategies.
Nawroth
Isabel
I
Department of Experimental Clinical Oncology, Aarhus University Hospital, Aarhus C, Denmark.
Alsner
Jan
J
Behlke
Mark A
MA
Besenbacher
Flemming
F
Overgaard
Jens
J
Howard
Kenneth A
KA
Kjems
Jørgen
J
D000818:Animals; D048271:Chitosan / Q000008:administration & dosage / Q000494:pharmacology*; D005355:Fibrosis; D007274:Injections, Intraperitoneal; D008297:Male; D008325:Mammary Neoplasms, Experimental / Q000235:genetics / Q000532:radiotherapy*; D053758:Nanoparticles; D034741:RNA, Small Interfering / Q000008:administration & dosage / Q000235:genetics / Q000494:pharmacology*; D011832:Radiation Injuries / Q000235:genetics / Q000517:prevention & control*; D051381:Rats; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism*
D034741:RNA, Small Interfering; D014409:Tumor Necrosis Factor-alpha; D048271:Chitosan