Novel Survivin-Targeted Small Interfering RNA Delivered by Nanoparticles.

BACKGROUND: The aim of the present study was to investigate the antitumor effect of our novel survivin-targeted small interfering RNA (siRNA) nanoliposomes on xenograft mouse models with human cervical carcinoma HeLa cells, and to evaluate pharmacokinetics. MATERIALS AND METHODS: siRNA nanoliposome was prepared and transfected into xenograft mouse models. Tumor growth in mice was determined and survivin expression was analyzed by using histologic and immunohischemical staining. Furthermore, low, moderate and high doses of survivin siRNA nanoliposomes were injected in 3 groups, and plasma concentrations were detected at various time points by reverse transcription quantitative polymerase chain reaction. Biodistribution of siRNA in tumor and other important organs were also determined. RESULTS: Survivin expression was significantly downregulated by survivin siRNA delivery mediated by nanoliposome, along with significant suppression of cell growth. Peak concentrations were obtained at 15 minutes after injection in each group, with 1,042,538.00, 6,837,099.54 and 14,631,333.15pg/mL, respectively, and the plasma concentration decreased significantly after 24 hours. The half-time life of survivin siRNA nanoliposomes in each group was 3.60, 2.64 and 2.80 hours, respectively. The area under curve values were 952,190.88, 6,800,687.79 and 13,803,680.96h/pg/mL, and the total drug clearance were 1,050.12, 441.13 and 434.67mL/h/kg. A significant accumulation of Cy5-labeled siRNA was found in the tumor, and a nonspecific accumulation was reduced significantly in lung. CONCLUSIONS: Our findings revealed that survivin suppression by siRNA may contribute to tumor inhibition through both proliferation inhibition and apoptosis promotion effect, and the pharmacokinetic characteristics serve as a fundamental role for further studies on its applicability for cancer therapy.

[Clinical efficacy of CCG7942/POG9354 protocol in treatment of peripheral primitive neuroectodermal tumor in children].

OBJECTIVE: To investigate the clinical manifestations, diagnosis, and treatment of peripheral primitive neuroectodermal tumor (pPNET) in children and the survival of patients treated with the CCG7942/POG9354 protocol. METHODS: A retrospective analysis was performed on the clinical data of 10 patients with pPNET admitted from October 2008 to October 2013. Of the 10 patients, 3 had metastasis, while others had no metastasis. The 7 patients without metastasis were treated with the Children's Cancer Study Group 7942 (CCG7942) protocol, and the other 3 patients with metastasis with the Pediatric Oncology Group 9354 (POG9354) protocol. The therapeutic response and chemotherapy-related toxicities were evaluated by WHO criteria and Common Terminology Criteria for Adverse Events (version 4.0). RESULTS: In the 7 patients treated with the CCG7942 protocol, 4 achieved a complete remission (CR), 1 had stable disease, 2 developed progressive disease (PD), and 2 had recurrence. In the 3 patients treated with the POG9354 protocol, 1 achieved a CR, 2 developed PD, 2 had recurrence, and 2 died. For the 7 patients without metastasis, the survival time was 5-60 months, and the event-free survival rate was 71%. For the 3 patients with metastasis, the survival time was 13-25 months, and the event-free survival rate was 33%. All patients developed grade 4 bone marrow suppression, and other grade 1-2 toxicities, including gastrointestinal reactions, liver function impairment, and renal function impairment, were also seen. CONCLUSIONS: CCG7942 protocol is effective and safe for children with non-metastatic pPNET. However, POG9354 protocol has unsatisfactory efficacy in children with metastatic pPNET, so further studies are needed to improve the therapy for this disease.