Characterisation of nanomedicine heterogeneity with potential for impact on product performance

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.

The CDT in Molecules to Product has the potential to make a real impact as a consequence of the transformative nature of the underpinning 'design and supply' paradigm. Through the exploitation of the generated scientific knowledge, a new approach to the product development lifecycle will be developed. This know-how will impact significantly on productivity, consistency and performance within the speciality chemicals, home and personal care (HPC), fast moving consumer goods (FMCG), food and beverage, and pharma/biopharma sectors.
UK manufacturing is facing a major challenge from competitor countries such as China that are not constrained by fixed manufacturing assets, consequently they can make products more efficiently and at significantly lower operational costs. For example, the biggest competition for some well recognised 'high-end' brands is from 'own-brand' products (simple formulations that are significantly cheaper). For UK companies to compete in the global market, there is a real need to differentiate themselves from the low-cost competition, hence the need for uncopiable or IP protected, enhanced product performance, higher productivity and greater consistency. The CDT is well placed to contribute to addressing this shift in focus though its research activities, with the PGR students serving as ambassadors for this change. The CDT will thus contribute to the sustainability of UK manufacturing and economic prosperity.
The route to ensuring industry will benefit from the 'paradigm' is through the PGR students who will be highly employable as a result of their unique skills-set. This is a result of the CDT research and training programme addressing a major gap identified by industry during the co-creation of the CDT. Resulting absorptive capacity is thus significant. In addition to their core skills, the PGR students will learn new ones enabling them to work across disciplinary boundaries with a detailed understanding of the chemicals-continuum. Importantly, they will also be trained in innovation and enterprise enabling them to challenge the current status quo of 'development and manufacture' and become future leaders.
The outputs of the research projects will be collated into a structured database. This will significantly increase the impact and reach of the research, as well as ensuring the CDT outputs have a long-term transformative effect. Through this route, the industrial partners will benefit from the knowledge generated from across the totality of the product development lifecycle. The database will additionally provide the foundations from which 'benchmark processes' are tackled demonstrating the benefits of the new approach to transitioning from molecules to product.
The impact of the CDT training will be significantly wider than the CDT itself. By offering modules as Continuing Professional Development courses to industry, current employees in chemical-related sectors will have the opportunity to up-skill in new and emerging areas. The modules will also be made available to other CDTs, will serve as part of company graduate programmes and contribute to further learning opportunities for those seeking professional accreditation as Chartered Chemical Engineers.
The CDT, through public engagement activities, will serve as a platform to raise awareness of the scientific and technical challenges that underpin many of the items they rely on in daily life. For example, fast moving consumer goods including laundry products, toiletries, greener herbicides, over-the-counter drugs and processed foods. Activities will include public debates and local and national STEM events. All events will have two-way engagement to encourage the general public to think what the research could mean for them. Additionally these activities will provide the opportunity to dispel the myths around STEM in terms of career opportunities and to promote it as an activity to be embraced by all thereby contributing to the ED&I agenda.