In depth characterization of physicochemical critical quality attributes of a clinical drug-dendrimer conjugate.

A deep and detailed understanding of drug-dendrimer conjugates key properties is needed to define the critical quality attributes that affect drug product performance. The characterization must be executed both in the formulation media and in biological matrices. This, nevertheless, is challenging on account of a very limited number of suitable, established methods for characterizing the physicochemical properties, stability, and interaction with biological environment of complex drug-dendrimer conjugates. In order to fully characterize AZD0466, a drug-dendrimer conjugate currently under clinical development by AstraZeneca, a collaboration was initiated with the European Nanomedicine Characterisation Laboratory to deploy a state-of-the-art multi-step approach to measure physicochemical properties. An incremental complexity characterization approach was applied to two batches of AZD0466 and the corresponding dendrimer not carrying any drug, SPL-8984. Thus, the aim of this work is to guide in depth characterization efforts in the analysis of drug-dendrimer conjugates. Additionally, it serves to highlight the importance of using the adequate complementary techniques to measure physical and chemical stability in both simple and biological media, to drive a complex drug-dendrimer conjugate product from discovery to clinical development.
Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: SS, KT, MJ, MA and NA own shares of AstraZeneca. Fanny Caputo, Dora Mehn, Luigi Calzolai, Sven Even Borgos, Astrid Hyldbakk reports financial support was provided by H2020 project (Grant no. 654190). Silvia sonzini, Kevin Treacher, Mark Jackman, Marianne Ashford, Nadim Akhtar reports a relationship with AstraZeneca PLC that includes: employment and equity or stocks. Experiments at the ISIS Neutron and Muon Source were supported by beamtime allocation from STFC, and the SANS data are available at DOI 10.5286/ISIS.E.RB1820524. This work benefited from the use of the SasView application, originally developed under National Science Foundation Award DMR-0520547. SasView also contains a code developed with funding from the European Union’s Horizon 2020 research and innovation program under the SINE2020 project, Grant No. 654000.
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