Abstract
Nanodiamonds of detonation origin are promising delivery agents of anti-cancer therapeutic compounds in a whole organism like mouse, owing to their versatile surface chemistry and ultra-small 5 nm average primary size compatible with natural elimination routes. However, to date, little is known about tissue distribution, elimination pathways and efficacy of nanodiamonds-based therapy in mice. In this report, we studied the capacity of cationic hydrogenated detonation nanodiamonds to carry active small interfering RNA (siRNA) in a mice model of Ewing sarcoma, a bone cancer of young adults due in the vast majority to the EWS-FLI1 junction oncogene. Replacing hydrogen gas by its radioactive analog tritium gas led to the formation of labeled nanodiamonds and allowed us to investigate their distribution throughout mouse organs and their excretion in urine and feces. We also demonstrated that siRNA directed against EWS-FLI1 inhibited this oncogene expression in tumor xenografted on mice. This work is a significant step to establish cationic hydrogenated detonation nanodiamond as an effective agent for in vivo delivery of active siRNA.
Highlights
The use of nanoparticles as vectors for drug delivery has been largely described by the scientific community during these past decades, with numerous applications [1,2]
We report on the use of cationic detonation nanodiamonds (DND) for the delivery of small interfering RNA (siRNA) directed against Ewing sarcoma (ES) junction oncogene EWS-FLI1 to ES tumor xenografted on mice
We described that hydrogenated DND (H-DND) can carry efficiently siRNA to ES cultured cells and promote specific targeted EWS-FLI1 oncogene inhibition [16]
Summary
The use of nanoparticles as vectors for drug delivery has been largely described by the scientific community during these past decades, with numerous applications [1,2]. Nanoparticles facilitate intracellular delivery and protection of the cargo against degradation, they present many advantages for the vectorization of small nucleic acids such as small interfering RNA (siRNA) The latter are used to control gene expression by silencing targeted genes. Polymer coating may lead to the formation of large aggregates by crosslinking DND to other DND via polymer chains bridging Another strategy, the one selected for this study, is based on the direct surface modification of DND using hydrogen gas combined with microwave plasma or with annealing method. Considering the very high chemical stability of diamond, these further investigations have to consider the risk of accumulation in the body after inoculation, as already described for larger nanodiamonds (around 50 nm diameter), produced by a different process than detonation [17] Owing to their small unitary size (3–8 nm) DND are good candidates for in vivo applications. We show that siRNA (i) can be loaded onto hydrogenated or tritiated DND (H-DND and T-DND, respectively), (ii) can efficiently inhibit EWS-FLI1 in ES tumor model xenografted on mice and (iii) that the organ distribution and elimination of T-DND can be measured thanks to its radioactivity
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