DiamESTar

The main objective of DIAMESTAR project is to evaluate the efficacy of a new small interfering RNA(siRNA)/nanocarrier complex to treat Ewing sarcoma (ES) metastatic tumor xenografted on mice, when this nanomedicine is directed by a fragment of antigen-binding (Fab) against a membrane protein overexpressed in ES cells. Ewing sarcoma is a rare, mostly pediatric bone cancer, with a bad prognosis when metastatic. It is an orphan disease with very few therapeutic options. The oncogene we shall target is a fusion oncogene EWS-FLI1 considered as the main cause of Ewing sarcoma. EWS-FLI1 is a paradigm of fusion oncogenes over the 300 discovered in human up to now. siRNA inhibit with a high specificity the expression of any human gene, and can play a key role in treating many diseases (cancers, cardiovascular and neurological diseases). However they are quickly degraded in organism and penetrate poorly in cells. One solution is to use nanocarriers to deliver active siRNA in the cytoplasm where their antisense effect takes place. Various polymeric nanocarriers have been used, but very few have reached clinical trials. We propose an alternative carrier made of a diamond nanocrystal core with a surface chemically modified to bind siRNA electrostatically and bear the Fab intended for targeting. Nanodiamonds present several interests: (i) they are chemically inert and non toxic on cell cultures; (ii) they can be made intrinsically fluorescent or radioactive, hence traceable on long term scale, by embedding color center or tritium, respectively; (iii) their surface can be modified by a variety of methods to provide cationic or anionic charges or to covalently bind biomolecules. The first task will be to synthesize ND/siRNA/Fab complexes of different types (size, traceable properties, surface functions). Then, the toxicity, pharmacokinetics, and biodistribution will be determined in ES tumor xenografted in mice (including a metastatic model) taking advantage of the intrinsic traceability. The localization of the complex within metastases responsible for the low survival rate will be examined carefully. Finally, the therapeutic efficacy will include in vitro and in vivo measurement of EWS-FLI1 inhibition and of the regression of primary and metastatic tumors. The project should give rise to therapeutic solutions ready to enter regulatory preclinical developments.