Abstract
YM155 (Sepantronium Bromide) is a potent survivin inhibitor that is the subject of clinical trials for multiple types of cancer including melanoma, lypmphoma, lung cancer, prostate and breast cancer. YM155 is a therapeutic candidate for the treatment of glioblastoma (GBM), however, its rapid plasma clearance and minimal blood-brain barrier penetration are obstacles to clinical translation (1). The encapsulation of drugs in nanoparticles can help increase drug circulation time by reducing clearance, and nanoparticles have the ability to increase drug concentration in the tumor through the enhanced permeability and retention effect (2). Here, we encapsulated YM155 in poly(lactic acid)-b-poly(ethylene glycol) nanoparticles (NPs) and evaluated the potency of YM155 in 4 glioma cell lines in vitro. Additionally, we investigated the ability of systemically administered NPs to inhibit tumor growth in vivo in mice bearing orthotopic gliomas. In vitro potency of YM155 was measured by CellTiter Glo in 3 immortalized GBM lines (GL261, U118, U87), as well as in patient derived tumor cells (GB7). Tumor growth inhibition was evaluated in C57 albino mice bearing orthotopic GL261-luc2 tumors. Mice were treated for 3 consecutive days with saline, free YM155 or NPs by tail vein injection, and tumor growth was measured by bioluminescence using an IVIS imaging system. All cells tested were sensitive to both free and encapsulated YM155. GL261 was the least sensitive of the cells tested, with an IC50 of 196 nM, while U118 and U87 had IC50s of 61 and 32 nM, respectively. The patient derived GB7 cells were the most sensitive to YM155, with an IC50 of 22 nM. Tumors grew exponentially for mice treated with free YM155 or saline, whereas tumor growth was halted in 2/5 subjects after one cycle of treatment with NPs. This work shows the potency of YM155 against multiple glioma cell lines in vitro. In vivo, free YM155 does not affect the growth of an orthotopic glioma; however, our initial treatment study provides evidence systemically administered YM155-loaded NPs allow for the delivery of a therapeutically relevant dose to orthotopic GBM. Success of this work shows the ability to encapsulate a water soluble drug in polymeric nanoparticles, which can be used to generate new options in the treatment of GBM. Further work will evaluate drug efficacy in additional patient derived cells and investigate the ability of NP encapsulated YM155 alone or in conjunction with radiation to treat mice bearing patient derived xenograft tumors.
References:
1. Minematsu T, Sonoda T, Hashimoto T, Iwai M, Oppeneer T, Felder L, et al. Pharmacokinetics, distribution and excretion of YM155 monobromide, a novel small-molecule survivin suppressant, in male and pregnant or lactating female rats. Biopharm Drug Dispos. 2012;33:160–9.
2. Householder KT, DiPerna DM, Chung EP, Wohlleb GM, Dhruv HD, Berens ME, et al. Intravenous delivery of camptothecin-loaded PLGA nanoparticles for the treatment of intracranial glioma. Int J Pharm. 2015;479:374–80.
Citation Format: Kyle T. Householder, Danielle M. DiPerna, Jonathan T. Yamaguchi, Nader Sanai, Shwetal Mehta, Rachael W. Sirianni. Use of polymeric nanoparticles for the delivery of YM155 to glioma cells in vitro and in vivo. [abstract]. In: Proceedings of the AACR Special Conference: Advances in Brain Cancer Research; May 27-30, 2015; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2015;75(23 Suppl):Abstract nr B21.
