Intervention of radiation‐induced skin fibrosis by RNA interference

Publikation: Bog/antologi/afhandling/rapportPh.d.-afhandling


  • Isabel Nawroth, Danmark
Radiation therapy is a cornerstone of cancer treatment for many types of cancer, but is often
limited by normal tissue toxicity. One of the most common and dose‐limiting long‐term adverse
effects is radiation‐induced fibrosis (RIF), which is characterized by restricted tissue flexibility,
reduced compliance or strictures, pain and in severe cases, ulceration and necrosis. A limited
number of treatments to prevent or ameliorate established RIF have shown promising results in
clinical trials; however, presently no effective therapy for RIF is available. Recent studies
suggest tumor necrosis factor‐α (TNFα) production by macrophages might promote RIF.
RNA interference (RNAi) is an evolutionary conserved gene‐silencing mechanism capable of
degrading mRNA containing a homologous sequence to an exogenously introduced double
stranded small interfering RNA (siRNA). These siRNAs can induce RNAi and inhibit the
expression of target proteins. Therefore, siRNAs are considered as promising therapeutics for
treatment of various diseases including genetic and viral diseases, and cancer.
In this study, the therapeutic potential of RNA interference was investigated as an intervention
strategy for radiation‐induced skin fibrosis. Chitosan‐based nanoparticles (or polyplexes)
formed by self‐assembly with siRNA were applied to overcome extracellular and intracellular
barriers and deliver siRNA site‐specific.
In this work we show that intraperitoneal administration of chitosan/DsiRNA nanoparticles
targeting TNFα knockdown in macrophages prevents RIF in irradiated hind legs of mice.
Furthermore, such TNFα targeting was selective without any significant influence on tumor
growth or irradiation related tumor control probability, promoting its use in cancer treatment.
In addition, histopathological analysis of liver, lung, spleen and kidney did not reveal cytotoxic
side effects after long‐term administration of the nanoparticle formulations. This nanoparticlebased
RNAi approach represents a novel approach to prevent RIF in mice with potential
application to improve clinical radiation therapeutic strategies.
ForlagAarhus Universitet
Antal sider124
StatusUdgivet - 1 feb. 2011

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