Reference Detail

Ref Type Journal Article
PMID (26865565)
Authors Ashton S, Song YH, Nolan J, Cadogan E, Murray J, Odedra R, Foster J, Hall PA, Low S, Taylor P, Ellston R, Polanska UM, Wilson J, Howes C, Smith A, Goodwin RJ, Swales JG, Strittmatter N, Takats Z, Nilsson A, Andren P, Trueman D, Walker M, Reimer CL, Troiano G, Parsons D, De Witt D, Ashford M, Hrkach J, Zale S, Jewsbury PJ, Barry ST
Title Aurora kinase inhibitor nanoparticles target tumors with favorable therapeutic index in vivo.
Journal Science translational medicine
Vol 8
Issue 325
Date 2016 Feb 10
URL
Abstract Text Efforts to apply nanotechnology in cancer have focused almost exclusively on the delivery of cytotoxic drugs to improve therapeutic index. There has been little consideration of molecularly targeted agents, in particular kinase inhibitors, which can also present considerable therapeutic index limitations. We describe the development of Accurin polymeric nanoparticles that encapsulate the clinical candidate AZD2811, an Aurora B kinase inhibitor, using an ion pairing approach. Accurins increase biodistribution to tumor sites and provide extended release of encapsulated drug payloads. AZD2811 nanoparticles containing pharmaceutically acceptable organic acids as ion pairing agents displayed continuous drug release for more than 1 week in vitro and a corresponding extended pharmacodynamic reduction of tumor phosphorylated histone H3 levels in vivo for up to 96 hours after a single administration. A specific AZD2811 nanoparticle formulation profile showed accumulation and retention in tumors with minimal impact on bone marrow pathology, and resulted in lower toxicity and increased efficacy in multiple tumor models at half the dose intensity of AZD1152, a water-soluble prodrug of AZD2811. These studies demonstrate that AZD2811 can be formulated in nanoparticles using ion pairing agents to give improved efficacy and tolerability in preclinical models with less frequent dosing. Accurins specifically, and nanotechnology in general, can increase the therapeutic index of molecularly targeted agents, including kinase inhibitors targeting cell cycle and oncogenic signal transduction pathways, which have to date proved toxic in humans.

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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Therapy Description
AZD2811 AZD2811 is nanoparticle formulation of Barasertib (AZD1152), which inhibits Aurora kinase B to induce cell cycle arrest and results in tumor regression (PMID: 26865565, PMID: 28292940).
Drug Name Trade Name Synonyms Drug Classes Drug Description
AZD2811 Aurkb Inhibitors 17 AZD2811 is nanoparticle formulation of Barasertib (AZD1152), which inhibits Aurora kinase B to induce cell cycle arrest and results in tumor regression (PMID: 26865565, PMID: 28292940).
Variant Impact Protein Effect Variant Description Associated with drug Resistance
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
Unknown unknown colon cancer not applicable AZD2811 Preclinical - Cell line xenograft Actionable In a preclinical study, treatment with AZD2811 nanoparticles resulted in tumor regression in colon cancer xenograft models (PMID: 26865565). 26865565