'Hide-and-Seek'- targeted drug delivery to intracellular pathogens
Lead Research Organisation:
University of Nottingham
Department Name: Sch of Pharmacy
Abstract
Infectious diseases caused by pathogens such as bacteria, viruses and fungi are the second leading cause of death worldwide. Many pathogenic bacteria are capable of evading host defence mechanisms by hiding and replicating host immune cells, such as macrophages. From a therapeutic viewpoint, treatment of such infections can be very challenging, as many of current antimicrobial drug molecules do not efficiently cross plasma membrane of infected host cells, and thus cannot reach intracellular organelles where these pathogens are located. Thus, more effective strategies to address this clinical issue are urgently needed.
This project will address this therapeutic problem by engineering drug delivery nanovectors able to target specific endocytic receptors in infected host cells and deliver antimicrobial agents to intracellular pathogens. One of the significant advantages of this approach is that it allows for the use of antimicrobial agents which would not normally cross the cell membrane of infected host cells, thus potentially expanding the range of available drugs to treat these infections, which can be key when therapeutic options are restricted due to antimicrobial resistance.
Initially, this project will engineer targeted nanovectors by decorating liposomes with a range of ligands based on carbohydrates and/or short peptides - commercially available, and/or synthesised as part of this study. These nanovectors will incorporate fluorescent probes to facilitate their tracking in subsequent biomedical assays, and selected antimicrobial agents which will be tested on existing intracellular infection in vitro models.
In this project the lipid composition of these nanovectors, the chemical nature, size and topology of ligands, and type of antimicrobial drug will be systematically varied to gain a first structure-activity relationship for these novel targeted nanomedicines.
Project aligned to Advanced Product Design
This project will address this therapeutic problem by engineering drug delivery nanovectors able to target specific endocytic receptors in infected host cells and deliver antimicrobial agents to intracellular pathogens. One of the significant advantages of this approach is that it allows for the use of antimicrobial agents which would not normally cross the cell membrane of infected host cells, thus potentially expanding the range of available drugs to treat these infections, which can be key when therapeutic options are restricted due to antimicrobial resistance.
Initially, this project will engineer targeted nanovectors by decorating liposomes with a range of ligands based on carbohydrates and/or short peptides - commercially available, and/or synthesised as part of this study. These nanovectors will incorporate fluorescent probes to facilitate their tracking in subsequent biomedical assays, and selected antimicrobial agents which will be tested on existing intracellular infection in vitro models.
In this project the lipid composition of these nanovectors, the chemical nature, size and topology of ligands, and type of antimicrobial drug will be systematically varied to gain a first structure-activity relationship for these novel targeted nanomedicines.
Project aligned to Advanced Product Design
Planned Impact
Pharmaceutical technologies underpin healthcare product development. Medicinal products are becoming increasingly complex, and while the next generation of research scientists in the life- and pharmaceutical sciences will require high competency in at least one scientific discipline, they will also need to be trained differently than the current generation. Future research leaders need to be equipped with the skills required to lead innovation and change, and to work in, and connect concepts across diverse scientific disciplines and environments. This CDT will train PhD scientists in cross-disciplinary areas central to the pharmaceutical, healthcare and life sciences sectors, whilst generating impactful research in these fields. The CDT outputs will benefit the pharmaceutical and healthcare sectors and will underpin EPSRC call priorities in the development of low molecular weight molecules and biologics into high value products.
Benefits of cohort research training: The CDT's most direct beneficiaries will be the graduates themselves. They will develop cross-disciplinary scientific knowledge and expertise, and receive comprehensive soft skills training. This will render them highly employable in R&D in the pharmaceutical, healthcare and wider life-sciences sectors, as is evidenced by the employment record in R&D intensive jobs of graduates from our predecessor CDTs. Our students will graduate into a supportive network of alumni, academic, and industrial scientists, aiding them to advance their professional careers.
Benefits to industry: The pharmaceutical sector is a key part of the UK economy, and for its future success and international competitiveness a skilled workforce is needed. In particular, it urgently needs scientists trained to develop medicines from emerging classes of advanced active molecules, which have formulation requirements that are very different from current drugs. The CDT will make a considerable impact by delivering a highly educated and skilled cohort of PhD graduates. Our industrial partners include big pharma, SMEs, CROs, CMOs, CMDOs and start-up incubators, ensuring that CDT training is informed by, and our students exposed to research drivers in, a wide cross-section of industry. Research projects in the CDT will be designed through a collaborative industry-academia innovation process, bringing direct benefits to the companies involved, and will help to accelerate adoption of new science and approaches in the medicines development. Benefit to industry will also be though potential generation of IP-protected inventions in e.g. formulation materials and/or excipients with specific functionalities, new classes of drug carriers/formulations or new in vitro disease models. Both universities have proven track records in IP generation and exploitation. Given the value added by the pharma industry to the UK economy ('development and manufacture of pharmaceuticals', contributes £15.7bn in GVA to the UK economy, and supports ~312,000 jobs), the economic impacts of high-level PhD training in this area are manifest.
Benefits to society: The CDT's research into the development of new medical products will, in the longer term, deliver potent new therapies for patients globally. In particular, the ability to translate new active molecules into medicines will realise their potential to transform patient treatments for a wide spectrum of diseases including those that are increasing in prevalence in our ageing population, such as cardiovascular (e.g. hypertension), oncology (e.g. blood cancers), and central nervous system (e.g. Alzheimer's) disorders. These new medicines will also have major economic benefits to the UK. The CDT will furthermore proactively undertake public engagement activities, and will also work with patient groups both to expose the public to our work and to foster excitement in those studying science at school and inspire the next generation of research scientists.
Benefits of cohort research training: The CDT's most direct beneficiaries will be the graduates themselves. They will develop cross-disciplinary scientific knowledge and expertise, and receive comprehensive soft skills training. This will render them highly employable in R&D in the pharmaceutical, healthcare and wider life-sciences sectors, as is evidenced by the employment record in R&D intensive jobs of graduates from our predecessor CDTs. Our students will graduate into a supportive network of alumni, academic, and industrial scientists, aiding them to advance their professional careers.
Benefits to industry: The pharmaceutical sector is a key part of the UK economy, and for its future success and international competitiveness a skilled workforce is needed. In particular, it urgently needs scientists trained to develop medicines from emerging classes of advanced active molecules, which have formulation requirements that are very different from current drugs. The CDT will make a considerable impact by delivering a highly educated and skilled cohort of PhD graduates. Our industrial partners include big pharma, SMEs, CROs, CMOs, CMDOs and start-up incubators, ensuring that CDT training is informed by, and our students exposed to research drivers in, a wide cross-section of industry. Research projects in the CDT will be designed through a collaborative industry-academia innovation process, bringing direct benefits to the companies involved, and will help to accelerate adoption of new science and approaches in the medicines development. Benefit to industry will also be though potential generation of IP-protected inventions in e.g. formulation materials and/or excipients with specific functionalities, new classes of drug carriers/formulations or new in vitro disease models. Both universities have proven track records in IP generation and exploitation. Given the value added by the pharma industry to the UK economy ('development and manufacture of pharmaceuticals', contributes £15.7bn in GVA to the UK economy, and supports ~312,000 jobs), the economic impacts of high-level PhD training in this area are manifest.
Benefits to society: The CDT's research into the development of new medical products will, in the longer term, deliver potent new therapies for patients globally. In particular, the ability to translate new active molecules into medicines will realise their potential to transform patient treatments for a wide spectrum of diseases including those that are increasing in prevalence in our ageing population, such as cardiovascular (e.g. hypertension), oncology (e.g. blood cancers), and central nervous system (e.g. Alzheimer's) disorders. These new medicines will also have major economic benefits to the UK. The CDT will furthermore proactively undertake public engagement activities, and will also work with patient groups both to expose the public to our work and to foster excitement in those studying science at school and inspire the next generation of research scientists.
