Development of multifunctional polymeric drug delivery systems for penetrating the blood-brain barrier
Lead Research Organisation:
University of Warwick
Department Name: Warwick Medical School
Abstract
This MRC-funded doctoral training partnership (DTP) brings together cutting-edge molecular and analytical sciences with innovative computational approaches in data analysis to enable students to address hypothesis-led biomedical research questions. This is a 4-year programme whose first year involves a series of taught modules and two laboratory-based research projects that lead to an MSc in Interdisciplinary Biomedical Research. The first two terms consist of a selection of taught modules that allow students to gain a solid grounding in multidisciplinary science. Students also attend a series of masterclasses led by academic and industry experts in areas of molecular, cellular and tissue dynamics, microbiology and infection, applied biomedical technologies and artificial intelligence and data science. During the third and summer terms students conduct two eleven-week research projects in labs of their choice.
Project:
Improvements in life expectancy at an older age are continuously rising. However, the ageing population poses new challenges, such as neurodegenerative diseases (ND). For example, incidences of dementia increased more than two-fold from 1990. Delivery of medicines to the brain is challenging, primarily due to the blood-brain barrier (BBB) - a highly selective barrier which limits transportation of drugs to the brain. The latter is a major obstacle in treating diseases of the CNS, especially ND. Notably, there is evidence that the circadian clock modulates BBB permeability. The latter is important because NDs such as Alzheimer's can disrupt circadian rhythms and BBB integrity. In fact, BBB "leakiness" is associated with cognitive dysfunction. It is well known that small, lipophilic molecules can cross the BBB, whereas larger molecules or peptides cannot. To circumvent this, polymers can be chemically functionalised to facilitate and monitor BBB penetration but the general mechanics of how polymers penetrate the BBB is still unclear. This project aims to employ novel polymerisation techniques that enable the synthesis of precisely functionalised polymers, to characterise their physicochemical and biophysical properties and relate these to their ability to cross the BBB. The student will achieve this by synthesising a library of polymers with variable surface charges, shape and surface modifications based on chemical moieties present on cell-penetrating peptides, such as viral peptide Tat, and then test BBB penetration and circadian rhythm of polymer uptake in both advanced in vitro microfluidic and in vivo model systems. This will provide interdisciplinary training in polymer chemistry, cell culture, microfluidics and animal husbandry.
Project:
Improvements in life expectancy at an older age are continuously rising. However, the ageing population poses new challenges, such as neurodegenerative diseases (ND). For example, incidences of dementia increased more than two-fold from 1990. Delivery of medicines to the brain is challenging, primarily due to the blood-brain barrier (BBB) - a highly selective barrier which limits transportation of drugs to the brain. The latter is a major obstacle in treating diseases of the CNS, especially ND. Notably, there is evidence that the circadian clock modulates BBB permeability. The latter is important because NDs such as Alzheimer's can disrupt circadian rhythms and BBB integrity. In fact, BBB "leakiness" is associated with cognitive dysfunction. It is well known that small, lipophilic molecules can cross the BBB, whereas larger molecules or peptides cannot. To circumvent this, polymers can be chemically functionalised to facilitate and monitor BBB penetration but the general mechanics of how polymers penetrate the BBB is still unclear. This project aims to employ novel polymerisation techniques that enable the synthesis of precisely functionalised polymers, to characterise their physicochemical and biophysical properties and relate these to their ability to cross the BBB. The student will achieve this by synthesising a library of polymers with variable surface charges, shape and surface modifications based on chemical moieties present on cell-penetrating peptides, such as viral peptide Tat, and then test BBB penetration and circadian rhythm of polymer uptake in both advanced in vitro microfluidic and in vivo model systems. This will provide interdisciplinary training in polymer chemistry, cell culture, microfluidics and animal husbandry.
