Abstract 3678: Imaging AZD1152HQPA Accurin™ nanoparticle accumulation in preclinical tumors

Abstract

Abstract AZD1152HQPA Accurin is a passively targeted nanoparticle containing the active metabolite of the Aurora B kinase prodrug AZD1152. In preclinical studies, AZD1152HQPA Accurin displays reduced bone marrow toxicity associated with AZD1152 together with increases in anti-tumour activity. Nanoparticles are proposed to enable delivery and retention of drug to the tumour thereby increasing efficacy and modifying therapeutic index. While it is possible to demonstrate increased duration of modulation of pharmacodynamic biomarkers and drug exposure by nanoparticle delivery, directly demonstrating that nanoparticles accumulate in the tumour is challenging. To investigate the intra tumoural distribution of AZD1152HQPA Accurin nanoparticles we have employed mass spectrometry techniques to image samples derived from human colorectal cancer SW620 studies in rats. We have separately identified the nanoparticle itself, drug encapsulated in nanoparticle, and drug released from nanoparticle; the latter by detecting a metabolite that is only generated from released drug. First MALDI (matrix assisted laser desorption ionization) which offers 20 μm spatial resolution, was used to detect AZD1152-hQPA (released and encapsulated). Second LESA (liquid extraction surface analysis), which offers 1000 μm spatial resolution, was used to detect drug and metabolite, enabling co-distribution to be demonstrated. Finally DESI (desorption electrospray ionization) which offers 100 μm spatial resolution was used to detect drug, metabolite and nanoparticle constituent showing the co-distribution in more detail. Using this combination of approaches it is possible to demonstrate the presence of nanoparticle-delivered AZD1152HQPA metabolite in the tumour at extended timepoints; co-located with nanoparticle and unchanged (encapsulated) drug. At these time points no drug remains if delivered as a simple IV infusion. Collectively this imaging mass spectrometry analysis demonstrates AZD1152HQPA Accurin accumulation in pre-clinical tumours and confirms that the Accurin accesses the tumour and achieves sustained drug release within the tumour. Citation Format: Richard Goodwin, John Swales, Anna Nilsson, Per Andren, Nicola Strittmatter, Zoltan Takats, Colin Howes, Paula Taylor, Susan Ashton, Philip Jewsbury, Simon T. Barry. Imaging AZD1152HQPA Accurin™ nanoparticle accumulation in preclinical tumors. [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 3678. doi:10.1158/1538-7445.AM2015-3678