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	Vol	Issue	Date	Pages	Journal Short Title
Science translational medicine	8	325	2016 Feb 10	325ra17	Sci Transl Med

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	Drugs	Efficacy Evidence	Clinical Trials
AZD2811	AZD2811	0	2

Drug Name	Trade Name	Synonyms	Drug Classes	Drug Description
AZD2811		AZD-2811\|Barasertib-HQPA\|Defosbarasertib	Aurkb Inhibitors 21	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).

Gene	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