uu.seUppsala University Publications
Change search
ReferencesLink to record
Permanent link

Direct link
Aurora kinase inhibitor nanoparticles target tumors with favorable therapeutic index in vivo
AstraZeneca, Oncol iMED, Macclesfield SK10 4TG, Cheshire, England..
BIND Therapeut, 325 Vassar St, Cambridge, MA 02139 USA..
BIND Therapeut, 325 Vassar St, Cambridge, MA 02139 USA..
AstraZeneca, Oncol iMED, Macclesfield SK10 4TG, Cheshire, England..
Show others and affiliations
2016 (English)In: Science Translational Medicine, ISSN 1946-6234, E-ISSN 1946-6242, Vol. 8, no 325, 325ra17Article in journal (Refereed) PublishedText
Abstract [en]

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.

Place, publisher, year, edition, pages
2016. Vol. 8, no 325, 325ra17
National Category
Cell and Molecular Biology
URN: urn:nbn:se:uu:diva-279559DOI: 10.1126/scitranslmed.aad2355ISI: 000369694300003PubMedID: 26865565OAI: oai:DiVA.org:uu-279559DiVA: diva2:908434
Available from: 2016-03-02 Created: 2016-03-02 Last updated: 2016-03-02Bibliographically approved

Open Access in DiVA

No full text

Other links

Publisher's full textPubMed

Search in DiVA

By author/editor
Nilsson, AnnaAndrén, Per
By organisation
Department of Pharmaceutical Biosciences
In the same journal
Science Translational Medicine
Cell and Molecular Biology

Search outside of DiVA

GoogleGoogle Scholar
The number of downloads is the sum of all downloads of full texts. It may include eg previous versions that are now no longer available

Altmetric score

Total: 224 hits
ReferencesLink to record
Permanent link

Direct link