Imaging-guided Development of Polysarcosine-based Drug-delivery Systems

Aim of the PhD Project:

Polysarcosine (pSar) is an emerging polypeptoid-stealth polymer emerging as an alternative to polyethyleneglycol (PEG).
We will develop multimodal imaging tools (PET/optical) to:
Understand the properties of pSar as a stealth polymer in nanomedicine
Inform the development and clinical translation of novel nanomedicine-based drug delivery systems based on pSar.

Project Description:

Polymers have been extensively and safely used in nanomedicine-based drug delivery systems (DDSs) for their 'stealth' properties. The main role of these stealth polymers is to allow DDSs to delay recognition by the reticuloendothelial system (RES) and prolong their circulation times. This in turn allows increases preferential accumulation of the DDSs in areas of disease, particularly in solid tumours (via the enhanced permeation and retention phenomenon) and areas of inflammation (e.g. rheumatoid arthritis, infection).

The most widely used stealth coating is based on polyethyleneglycol (PEG) polymers, having been used in several clinically-approved DDSs (e.g. Liposomal doxorubicin: Doxil/Caelyx). However, recent studies have shown that the use of PEG (that is present in many pharmaceutical products) results in anti-PEG immunity in humans (induced or pre-existing), resulting in faster RES recognition and hence accelerated blood clearance of PEG-containing pharmaceuticals. As a consequence, since the effectiveness of PEG-DDS rely on long circulation times, anti-PEG immunity has been suggested as one of the main reasons for the decreased therapeutic efficacy of DDSs in humans.

In the search of alternative stealth polymers with improved properties, the polypeptoid polysarcosine (pSar) has emerged as one of the most promising alternatives. pSar has shown stealth and safety properties in the preclinical setting, and benefits from potential advantages compared to PEG such as improved synthetic control leading to highly monodisperse polymers, and low immunogenicity. In addition, since it is not present in other pharmaceutic/cosmetic/household products, it is less likely to suffer by the presence pre-existing antibodies. Despite these advantages, there is a lack of detailed knowledge of the effect of pSar coatings in the short/long-term whole-body biodistribution (bioD) and pharmacokinetics (PK), and safety of DDSs.

In this project we will develop imaging tools to study the effects of pSar-coated DDSs systems based on star polymers [1]. We will modify pSar-DDSs to allow in vivo and ex vivo multiscale and multimodal imaging using positron emission tomography (PET) and fluorescence imaging. This will allow us to investigate the effect of pSar coatings in several important aspects such as:

What is the fate of DDS in vivo? What is the clearance route?
What are the most relevant critical quality attributes (pSar length, DDS size, surface properties) for effective DDS tumour accumulation?
What immune cells and molecules are implicated in the tumour uptake/clearance of DDSs? Do they induce an immune response?
Are there gender-differences in the bioD/PK of pSar-DDSs?
Do pSar DDS distribute in the bone marrow in a sufficient proportion to explore this carrier for therapeutic purposes?
We hope that by developing and integrating these imaging tools into the development of pSar-DDSs from the early stages, we will be able to efficiently inform their clinical translation and ultimately result in improved therapeutic options for patients. In addition, imaging pSar-DDSs may be used in a theranostic approach, by allowing indetification of patients that will truly benefit from pSar-DDSs treatment.

Strains on the healthcare system in the UK create an acute need for finding more effective, efficient, safe, and accurate non-invasive imaging solutions for clinical decision-making, both in terms of diagnosis and prognosis, and to reduce unnecessary treatment procedures and associated costs. Medical imaging is currently undergoing a step-change facilitated through the advent of artificial intelligence (AI) techniques, in particular deep learning and statistical machine learning, the development of targeted molecular imaging probes and novel "push-button" imaging techniques. There is also the availability of low-cost imaging solutions, creating unique opportunities to improve sensitivity and specificity of treatment options leading to better patient outcome, improved clinical workflow and healthcare economics. However, a skills gap exists between these disciplines which this CDT is aiming to fill.

Consistent with our vision for the CDT in Smart Medical Imaging to train the next generation of medical imaging scientists, we will engage with the key beneficiaries of the CDT: (1) PhD students & their supervisors; (2) patient groups & their carers; (3) clinicians & healthcare providers; (4) healthcare industries; and (5) the general public. We have identified the following areas of impact resulting from the operation of the CDT.

- Academic Impact: The proposed multidisciplinary training and skills development are designed to lead to an appreciation of clinical translation of technology and generating pathways to impact in the healthcare system. Impact will be measured in terms of our students' generation of knowledge, such as their research outputs, conference presentations, awards, software, patents, as well as successful career destinations to a wide range of sectors; as well as newly stimulated academic collaborations, and the positive effect these will have on their supervisors, their career progression and added value to their research group, and the universities as a whole in attracting new academic talent at all career levels.

- Economic Impact: Our students will have high employability in a wide range of sectors thanks to their broad interdisciplinary training, transferable skills sets and exposure to industry, international labs, and the hospital environment. Healthcare providers (e.g. the NHS) will gain access to new technologies that are more precise and cost-efficient, reducing patient treatment and monitoring costs. Relevant healthcare industries (from major companies to SMEs) will benefit and ultimately profit from collaborative research with high emphasis on clinical translation and validation, and from a unique cohort of newly skilled and multidisciplinary researchers who value and understand the role of industry in developing and applying novel imaging technologies to the entire patient pathway.

- Societal Impact: Patients and their professional carers will be the ultimate beneficiaries of the new imaging technologies created by our students, and by the emerging cohort of graduated medical imaging scientists and engineers who will have a strong emphasis on patient healthcare. This will have significant societal impact in terms of health and quality of life. Clinicians will benefit from new technologies aimed at enabling more robust, accurate, and precise diagnoses, treatment and follow-up monitoring. The general public will benefit from learning about new, cutting-edge medical imaging technology, and new talent will be drawn into STEM(M) professions as a consequence, further filling the current skills gap between healthcare provision and engineering.

We have developed detailed pathways to impact activities, coordinated by a dedicated Impact & Engagement Manager, that include impact training provision, translational activities with clinicians and patient groups, industry cooperation and entrepreneurship training, international collaboration and networks, and engagement with the General Public.