title: Aurora kinase inhibitor nanoparticles target tumors with favorable therapeutic index in vivo.
abstract: 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.
authors: Oncology iMED, AstraZeneca, Macclesfield, Cheshire SK10 4TG, UK.
authors: Susan
authors: S
authors: Ashton
authors: BIND Therapeutics, 325 Vassar Street, Cambridge, MA 02139, USA.
authors: Young Ho
authors: YH
authors: Song
authors: BIND Therapeutics, 325 Vassar Street, Cambridge, MA 02139, USA.
authors: Jim
authors: J
authors: Nolan
authors: Oncology iMED, AstraZeneca, Macclesfield, Cheshire SK10 4TG, UK.
authors: Elaine
authors: E
authors: Cadogan
authors: Pharmaceutical Development, AstraZeneca, Macclesfield, Cheshire SK10 2NX, UK.
authors: Jim
authors: J
authors: Murray
authors: Oncology iMED, AstraZeneca, Macclesfield, Cheshire SK10 4TG, UK.
authors: Rajesh
authors: R
authors: Odedra
authors: Drug Safety and Metabolism, Innovative Medicines, AstraZeneca R&D, Alderley Park, Macclesfield, Cheshire SK10 4TG, UK.
authors: John
authors: J
authors: Foster
authors: Drug Safety and Metabolism, Innovative Medicines, AstraZeneca R&D, Alderley Park, Macclesfield, Cheshire SK10 4TG, UK.
authors: Peter A
authors: PA
authors: Hall
authors: BIND Therapeutics, 325 Vassar Street, Cambridge, MA 02139, USA.
authors: Susan
authors: S
authors: Low
authors: Oncology iMED, AstraZeneca, Macclesfield, Cheshire SK10 4TG, UK.
authors: Paula
authors: P
authors: Taylor
authors: Oncology iMED, AstraZeneca, Macclesfield, Cheshire SK10 4TG, UK.
authors: Rebecca
authors: R
authors: Ellston
authors: Oncology iMED, AstraZeneca, Macclesfield, Cheshire SK10 4TG, UK.
authors: Urszula M
authors: UM
authors: Polanska
authors: Oncology iMED, AstraZeneca, Macclesfield, Cheshire SK10 4TG, UK.
authors: Joanne
authors: J
authors: Wilson
authors: Oncology iMED, AstraZeneca, Macclesfield, Cheshire SK10 4TG, UK.
authors: Colin
authors: C
authors: Howes
authors: Oncology iMED, AstraZeneca, Macclesfield, Cheshire SK10 4TG, UK.
authors: Aaron
authors: A
authors: Smith
authors: Drug Safety and Metabolism, Innovative Medicines, AstraZeneca R&D, Alderley Park, Macclesfield, Cheshire SK10 4TG, UK.
authors: Richard J A
authors: RJ
authors: Goodwin
authors: Drug Safety and Metabolism, Innovative Medicines, AstraZeneca R&D, Alderley Park, Macclesfield, Cheshire SK10 4TG, UK.
authors: John G
authors: JG
authors: Swales
authors: Department of Surgery and Cancer, Imperial College, London SW7 2AZ, UK.
authors: Nicole
authors: N
authors: Strittmatter
authors: Department of Surgery and Cancer, Imperial College, London SW7 2AZ, UK.
authors: Zoltán
authors: Z
authors: Takáts
authors: Biomolecular Imaging and Proteomics, National Center for Mass Spectrometry Imaging, Uppsala University, Uppsala 751 05, Sweden.
authors: Anna
authors: A
authors: Nilsson
authors: Biomolecular Imaging and Proteomics, National Center for Mass Spectrometry Imaging, Uppsala University, Uppsala 751 05, Sweden.
authors: Per
authors: P
authors: Andren
authors: Oncology iMED, AstraZeneca, Macclesfield, Cheshire SK10 4TG, UK.
authors: Dawn
authors: D
authors: Trueman
authors: Oncology iMED, AstraZeneca, Macclesfield, Cheshire SK10 4TG, UK.
authors: Mike
authors: M
authors: Walker
authors: Oncology iMED, AstraZeneca, Gatehouse Park, Waltham, Boston 02451, USA.
authors: Corinne L
authors: CL
authors: Reimer
authors: BIND Therapeutics, 325 Vassar Street, Cambridge, MA 02139, USA.
authors: Greg
authors: G
authors: Troiano
authors: BIND Therapeutics, 325 Vassar Street, Cambridge, MA 02139, USA.
authors: Donald
authors: D
authors: Parsons
authors: BIND Therapeutics, 325 Vassar Street, Cambridge, MA 02139, USA.
authors: David
authors: D
authors: De Witt
authors: Pharmaceutical Development, AstraZeneca, Macclesfield, Cheshire SK10 2NX, UK.
authors: Marianne
authors: M
authors: Ashford
authors: BIND Therapeutics, 325 Vassar Street, Cambridge, MA 02139, USA.
authors: Jeff
authors: J
authors: Hrkach
authors: BIND Therapeutics, 325 Vassar Street, Cambridge, MA 02139, USA. simon.t.barry@astrazeneca.com philip.jewsbury@astrazeneca.com szale@bindtherapeutics.com.
authors: Stephen
authors: S
authors: Zale
authors: Oncology iMED, AstraZeneca, Macclesfield, Cheshire SK10 4TG, UK. simon.t.barry@astrazeneca.com philip.jewsbury@astrazeneca.com szale@bindtherapeutics.com.
authors: Philip J
authors: PJ
authors: Jewsbury
authors: Oncology iMED, AstraZeneca, Macclesfield, Cheshire SK10 4TG, UK. simon.t.barry@astrazeneca.com philip.jewsbury@astrazeneca.com szale@bindtherapeutics.com.
authors: Simon T
authors: ST
authors: Barry
mesh_terms: D000818:Animals; D064127:Aurora Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D001853:Bone Marrow / Q000187:drug effects / Q000473:pathology; D045744:Cell Line, Tumor; D065546:Drug Liberation; D005260:Female; D006801:Humans; D008297:Male; D013058:Mass Spectrometry; D051379:Mice; D016513:Mice, SCID; D053758:Nanoparticles / Q000737:chemistry*; D010755:Organophosphates / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D047428:Protein Kinase Inhibitors / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use*; D011799:Quinazolines / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D011923:Rats, Nude; D016896:Treatment Outcome; D023041:Xenograft Model Antitumor Assays
chemical_list: C520647:2-((3-((4-((5-(2-((3-fluorophenyl)amino)-2-oxoethyl)-1H-pyrazol-3-yl)amino)quinazolin-7-yl)oxy)propyl)(ethyl)amino)ethyl dihydrogen phosphate; D010755:Organophosphates; D047428:Protein Kinase Inhibitors; D011799:Quinazolines; D064127:Aurora Kinases