Principal Supervisor: Dr. Lissette Sanchez-ArangurenLink opens in a new window

Co-supervisor: Dr. Raj Badhan, Dr. Mandeep Marwah

PhD project title: Novel controlled-released nanoparticle formulations for healthy vascular ageing

University of Registration: University of Aston

Project outline:

Ageing of the vasculature is implicated in cardio-cerebro-vascular diseases thus plays a central role in the morbidity and mortality of the elderly population. In the UK, these conditions are the most common cause of death among people aged >65. With this population increasing from 12% to 22% over the coming decades, healthy vascular ageing is of increasing concern. Current therapeutic approaches for vascular ageing aim to target atherosclerosis and endothelial dysfunction. However, due to the complex pathophysiology of these conditions, there is a need for better therapeutic options. Hydrogen sulphide (H₂S) has been observed to have a critical role in the vascular system involved in the regulation of energy production, anti-oxidant and -inflammatory processes. Evidence has shown H₂S donors have potential in the treatment of cardio- and cerebro-vascular conditions associated with ageing by reducing cholesterol levels and decreasing inflammatory response, thus reversing damage to the vasculature.

Efficient drug delivery plays a crucial role in molecules reaching the clinic for disease treatment and this remains an important medical challenge. Many delivery challenges are associated with H₂S donors, including their rapid H₂S release rates, the gaseous nature of H₂S, poor aqueous stability and potential toxicity when present in excess. Therefore, to translate the potential therapeutic applications of H₂S donors to the clinical setting, an efficient method for delivery at a controlled rate, enough to maintain a sustained level of H₂S is required. Such ‘next-generation’ approaches to treatment depend on formulations delivering precise and controlled drug delivery. To this end, drug delivery systems provide many advantages, including a wide range of administration techniques, increased efficacy and longer circulation times. These delivery systems include tablets, capsules, suspension or solutions with an increasing emphasis on nanoparticles.

Addressing age-related vascular diseases is of critical importance to provide better quality care for older adults and reduce the burden costs for the health system. There is vast expertise in the Translational Medicine Research Group demonstrating potential therapeutic applications for H₂S donors. This study aims to further explore and develop formulation approaches for H₂S donors that may overcome current challenges and offer patient friendly options in the treatment of conditions associated with ageing vasculature. This exciting project will combine multidisciplinary aspects from biochemistry to polymer science, with potential for real impact using cellular models. We have initiated the design, characterisation and detection of nanoparticle systems loaded with H₂S donors and established such systems are able to ameliorate the release of H₂S. Further, we have established protocols and techniques for 2D and 3D cellular exploration of molecular mechanism of ageing. This project aims to design and develop novel biodegradable/biocompatible polymer/lipid-based nanoparticles for the controlled release of H₂S donors whilst screening and validating their potential for promoting blood vessel generation and repair, reduction of oxidative stress, inflammation and cellular senescence associated with ageing. To achieve this goal, a set of formulation and cell culture methods will be employed. This exciting project will benefit from collaboration with Dr Raj Badhan, expert in in-vitro targeting and biodisposition and Dr Mandeep Marwah, with vast experience in drug delivery systems.

Key objectives are:

• Design, characterisation and detection of polymer/lipid-based H₂S donor loaded micro/nanoparticles.
• Determination of uptake/kinetics in vitro of both the H₂S donor and H₂S itself.
• Demonstrate functions and mechanisms of these H₂S donor loaded nanoparticles using 2D and 3D spheroid cell culture models.

 

BBSRC Strategic Research Priority: Understanding the rules of life - Immunology and Integrated Understanding of Health - Ageing

Techniques that will be undertaken during the project:

This studentship aims to train the student in different areas of biomedical research including pharmaceutical approaches for drug delivery and cellular and molecular research to explore molecular mechanisms of vascular ageing. The student will learn/apply multidisciplinary skills for the design and formulation of novel polymeric nanoparticles for controlled drug delivery, subsequent characterisation techniques including dynamic light scattering, differential scanning calorimetry and HPLC techniques. The student will also develop advanced cellular and molecular biology skills including 2D and 3D cell culture, RNA gene silencing, fluorescence and confocal microscopy, real-time cellular bioenergetics and gene and protein expression.

Contact: Dr. Lissette Sanchez-ArangurenLink opens in a new window