RESUMO
Alveolar rhabdomyosarcoma (ARMS) are aggressive soft tissue tumors harboring specific fusion transcripts, notably PAX3-FOXO1 (P3F). Current therapy concepts result in unsatisfactory survival rates making the search for innovative approaches necessary: targeting PAX3-FOXO1 could be a promising strategy. In this study, we developed integrin receptor-targeted Lipid-Protamine-siRNA (LPR) nanoparticles using the RGD peptide and validated target specificity as well as their post-silencing effects. We demonstrate that RGD-LPRs are specific to ARMS in vitro and in vivo. Loaded with siRNA directed against the breakpoint of P3F, these particles efficiently down regulated the fusion transcript and inhibited cell proliferation, but did not induce substantial apoptosis. In a xenograft ARMS model, LPR nanoparticles targeting P3F showed statistically significant tumor growth delay as well as inhibition of tumor initiation when injected in parallel with the tumor cells. These findings suggest that RGD-LPR targeting P3F are promising to be highly effective in the setting of minimal residual disease for ARMS.
Assuntos
Proteína Forkhead Box O1/genética , Nanopartículas/administração & dosagem , Oligopeptídeos/administração & dosagem , Fator de Transcrição PAX3/genética , Protaminas/administração & dosagem , RNA Interferente Pequeno/administração & dosagem , Rabdomiossarcoma Alveolar/tratamento farmacológico , Animais , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Feminino , Proteína Forkhead Box O1/metabolismo , Proteínas de Fluorescência Verde/genética , Humanos , Lipossomos , Camundongos SCID , Nanopartículas/uso terapêutico , Oligopeptídeos/uso terapêutico , Fator de Transcrição PAX3/metabolismo , Protaminas/uso terapêutico , RNA Mensageiro/metabolismo , RNA Interferente Pequeno/uso terapêutico , Rabdomiossarcoma Alveolar/patologia , Carga Tumoral/efeitos dos fármacosRESUMO
The objective of this prospective clinical study was to calculate the survival rate of IPS-Empress2 crowns and fixed partial dentures (FPD) over a three-year period. In 43 patients 27 IPS-Empress2 crowns and 31 fixed partial dentures were adhesively luted. Crowns were placed on premolars and molars and FPDs were inserted in the anterior and premolar area. Abutments were prepared with a circular 1.2 mm wide shoulder. The clinical follow-up examination took place after 6, 12, 24, 36 and 48 months. After a mean of 38 months, the survival rate (Kaplan-Meier) of all-ceramic crowns was 100% and of the three unit FDP 72.4%. There were a total of six complete failures which occurred only with the three-unit IPS-Empress2 FPDs. Three FPDs exhibited fractures of the framework for which the manufacturer's instructions of connector-dimension was not satisfied, and one FPD exhibited an irreparable incomplete veneer fracture. Further two FPDs showed biological failures. The accuracy of fit and esthetics were clinically satisfactory. The three-year results showed the IPS-Empress2-ceramic as an adequate all-ceramic material for single crowns. The use for FPD needs further critical consideration.
