An optimized therapeutic nanoparticle delivery platform of miRNA in preclinical murine models of malignancy
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AbstractINTRODUCTION: We have previously shown robust therapeutic efficacy of miRNAs in preclinical murine models of glioblastoma and were one of the first groups to deliver therapeutic miRNAs intravenously. However a major hurdle to clinical translation is a scalable formulation that affords protection against circulatory RNAses. Nanoparticles can encapsulate and protect the miRNA from degradation and enhance delivery into the immune cell compartment facilitating antitumor effects, in part through the reversal of tumor-mediate immune suppression and increased expression of effector cytokines - thus, overcoming the need for direct tumor delivery of the therapeutic agent.METHODS: FDA acceptable lipid nanoparticles were devised to enhance delivery of miRNA into the peripheral blood mononuclear cells (PBMCs) and verified by in vivo compartmental pharmacokinetic analysis and functional immune monitoring. Nanoparticle test articles contain an active immune modulatory agent - miR-124, which inhibits the signal transducer and activator of transcript 3 (STAT3) pathway. The lead candidate was designated LUNAR-301, and further refinements included unlocking the nucleic acids (LUNAR-302) to enhance efficacy. Nanoparticle formulations were tested in multiple murine models of malignancy including established intracerebral gliomas.RESULTS: In non-tumor bearing mice dosed with intravenous LUNAR-301, miR-124 was delivered to the peripheral blood mononuclear cells (PBMCs) with no clinical signs of toxicity or organ damage on histopathologic exam. In an intracerebral GL261 model, lower pSTAT3 expression was observed in mice treated with LUNAR-301 compared to both empty nanoparticle treated mice or untreated mice, p = 0.0081 and p = 0.0001 respectively. Similarly, lower Foxp3 expression was observed in the LUNAR-301 treated mice, p = 0.0057 and p = 0.0223 respectively. Median survival time for mice treated with LUNAR-301 exceeded 70 days, compared to only 32.5 days for mice treated with the previous gold-standard, miR-124 + lipofectamine. The cure rate difference between LUNAR-301 (9 out of 15 mice) and LUNAR-302 (2 out of 10 mice) was 40% (P = 0.0576); the difference in cure rates between LUNAR-301 and miR-124 + lipofectamine (4 out of 16 mice) was 35% (P = 0.0532). In a subcutaneous murine model of melanoma, tumor growth rate per day without treatment was 44% (i.e., tumor volume was expected to increase 44% cumulatively on a daily basis), while it was reduced to 26.1% in the LUNAR-301-treated group (P = 0.007), and to 16.2% in the LUNAR-302-treated group (P>0.001).CONCLUSIONS: Nanoparticle delivery of miR-124 has a favorable safety and efficacy profile to justify implementation in client-owned canines or human clinical trials for the treatment of gliomas.Citation Format: Nasser K. Yaghi, Jun Wei, Ling-Yuan Kong, Yuuri Hashimoto, Edjah K. Nduom, Neal Huang, Xiaoyang Ling, Shouhao Zhou, Jonathan M. Levine, Virginia R. Fajt, Kiyoshi Tachikawa, Padmanabh Chivukula, David C. Webb, Joseph E. Payne, Amy B. Heimberger. An optimized therapeutic nanoparticle delivery platform of miRNA in preclinical murine models of malignancy. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4291. doi:10.1158/1538-7445.AM2015-4291
Yaghi, N. K., Wei, J., Kong, L., Hashimoto, Y., Nduom, E. K., Huang, N., ... Heimberger, A. B.
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Yaghi, Nasser K||Wei, Jun||Kong, Ling-Yuan||Hashimoto, Yuuri||Nduom, Edjah K||Huang, Neal||Ling, Xiaoyang||Zhou, Shouhao||Levine, Jonathan M||Fajt, Virginia R||Tachikawa, Kiyoshi||Chivukula, Padmanabh||Webb, David C||Payne, Joseph E||Heimberger, Amy B
