Journal
MOLECULAR CANCER THERAPEUTICS
Volume 16, Issue 6, Pages 1114-1123Publisher
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/1535-7163.MCT-16-0541
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Funding
- NCI-DHHS-NIH T32 Training Grant [T32CA009666]
- NCI [P50 CA083639, P50 CA098258, U54 CA151668, UH3 TR000943]
- CPRIT [RP110595, RP120214]
- Ovarian Cancer Research Fund Program Project Development Grant
- Frank McGraw Memorial Chair in Cancer Research
- RGK Foundation
- Judi A. Rees Ovarian Cancer Research Fund
- Meyer and Ida Gordon Foundation
- American Cancer Society Research Professor Award
- Ann Rife Cox Chair in Gynecology
- Blanton-Davis Ovarian Cancer Research Program
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To address the need for efficient and biocompatible delivery systems for systemic siRNA delivery, we developed 1,2-Dioleoylsn-Glycero-3-Phosphatidylcholine (DOPC) nanoliposomal EphA2-targeted therapeutic (EPHARNA). Here, we performed safety studies of EPHARNA in murine and primate models. Single dosing of EPHARNA was tested at 5 concentrations in mice (N - 15 per group) and groups were sacrificed on days 1, 14, and 28 for evaluation of clinical pathology and organ toxicity. Multiple dosing of EPHARNA was tested in mice and Rhesus macaques twice weekly at two dose levels in each model. Possible effects on hematologic parameters, serum chemistry, coagulation, and organ toxicity were assessed. Following single-dose EPHARNA administration to mice, no gross pathologic or dose-related microscopic findings were observed in either the acute (24 hours) or recovery (14 and 28 days) phases. The no-observed-adverseeffect level (NOAEL) for EPHARNA is considered >225 mu g/kg when administered as a single injection intravenously in CD-1 mice. With twice weekly injection, EPHARNA appeared to stimulate a mild to moderate inflammatory response in a dose-related fashion. There appeared to be a mild hemolytic reaction in the female mice. In Rhesus macaques, minimal to moderate infiltration of mononuclear cells was found in some organs including the gastrointestinal tract, heart, and kidney. No differences attributed to EPHARNA were observed. These results demonstrate that EPHARNA is well tolerated at all doses tested. (C)2017 AACR.
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