Characterisation of nanomedicine heterogeneity with potential for impact on product performance

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Aims:Nanomedicine formulations are well known to exhibit significant polydispersity in properties between individual nanoparticles in a formulation. These heterogeneities are not well studied and little is known about the impact of these heterogeneities on product performance. The ensemble average properties of a formulation are characterised, while this may vary significantly within nanoparticle sub-fractions. We aim to get a better understanding of the impact of heterogeneities on nanomedicine properties to guide future optimisation of product design in this field. 1. Characterisation of heterogeneity in vesicle and cubosome nanomedicine formulations using asymmetric flow field flow fractionations (AF4) with potential for negative impact on product performance. 2. Characterisation of superselective targeting of nanomedicines by Quartz Crystal Microbalance with Dissipation (QCM-D) using the CBM40-GM3 interaction, relevant in active drug targeting to some cancers. 3. Determination of the impact of sample heterogeneity on superselective targeting efficacy of a nanomedicine.Methodology:The primary technique used for fractionating polydisperse nanomedicine samples will be AF4, which is a chromatography technique that separates particles by size and shape. Inline characterisation by multi-angle light scattering and dynamic light scattering (as well as UV/vis and RI) will give information on the size and shape of sub-fractions separated from within these formulations. We will develop workflows to investigate how drug encapsulation and drug release profiles vary across these sub-fractions and also conduct further offline characterisation of these fractions, such as by TEM. Superselective targeting will be investigated using low affinity, high selectivity CBM-40/GM3 interactions, which is an established targeting system in the group of Ralf Richter for linear polymers. This project will explore how the properties of superselective targeting may be modulated in spherical self-assembled nanoparticle formulations by QCM-D with CBM-40 functionalised nanomedicines targeting GM3 functionalised membrane surfaces. This will also be complemented by TIRF microscopy. We will characterisation on and off rates as well as Kd and residence times of nanomedicines on the membrane with varying GM3 concentration and varied CBM-40 functionalisation on the particles. Finally these two strands will be brought together to characterise the impact of nanomedicine heterogeneity (fractionation by AF4) on superselective targeting of nanomedicines (QCM-D). Impact:Nanomedicines hold great promise in enhancing the pharmacological properties of drugs through enhancing the spatial and temporal localisation of the therapeutic in the body. Despite their promise, following some early successes, drug nanoformulations have been slow to translate to the clinic. There are also significant regulatory challenges due to all particles not being identical (as is the case for a small molecule drug alone). Heterogeneous properties in nanomedicine formulations are likely to be one significant cause of reduced or unexpected performance of nanomedicines when conducting in vivo studies. A better understanding of these heterogeneities and their impact on relevant properties of these nanoparticles that impact function is required to facilitate improved product design and facilitate the product development pipeline in this field. Expected Deliverables:1. Characterisation of heterogeneities in size, shape, composition, drug loading and release profiles in two model nanomedicine formulations. 2. An understanding of how principles of superselective targeting translate to soft, spherical nanoparticle formulations. 3. An understanding of how product heterogeneity will impact the targeting performance of sub-populations of heterogeneous nanomedicine formulations.