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.

Nanoparticle-Based Medicines: A Review of FDA-Approved Materials and Clinical Trials to Date

“…Recently, there has been a move away from cytotoxic cancer drugs towards molecularly targeted agents (MTAs) that have had little attention in the nanomedicine field. While highly efficacious, these drugs are associated with serious toxicity profiles on their own, and therefore the combination with nanoparticles may help to reduce toxicity and allow higher dosing (43). Next generation BIND micelles that incorporate kinase inhibitors as future drug therapeutics have been used to investigate efficacy against metastatic colon cancers, showing promising results in pre-clinical trials.…”

Delayed Sequential Co-Delivery of Gefitinib and Doxorubicin for Targeted Combination Chemotherapy

“…49 The release kinetics of encapsulated drug has significant impacts on the efficacies of drug delivery systems. 49, 50 Burst release would result in similar pharmacokinetics between encapsulated drug and a free form of drug, diminishing advantages of using NP as a drug carrier. Hence, the sustained release of Gi would benefit in vivo application.…”

Standing on the shoulders of giants: a retrospective analysis of kinase drug discovery at AstraZeneca

“…Barasertib has entered clinical trials in elderly patients with acute myeloid leukaemia (AML) and has demonstrated clinically meaningful responses, including complete remission in some patients [36,37]. In 2013, an agreement was signed with BIND Therapeutics to further develop the active ingredient of AZD1152 (AZD1152-hQPA, recently designated AZD2811 (compound 18) [38] using Accurin 1 nanoparticle technology and offering the potential to adapt the therapeutic regimen to different tumours while achieving an improved therapeutic index. AZD2811 has recently commenced Phase I clinical testing in patients with advanced solid tumours.…”