Nanomedicine technology for drug delivery in Rheumatoid Arthritis using a synovium-specific targeting peptide

Lead Research Organisation: Queen Mary, University of London
Department Name: William Harvey Research Institute

Abstract

Despite the availability of numerous effective therapeutic agents for the treatment of rheumatoid arthritis (RA), a sizable group of patients (approximately 30-40%) do not respond to current medication. In addition, the risk/benefit ratio profile of current therapies, requires improvement due to systemic exposure leading to potential immune suppression and issues related to off-target adverse effects. One way to combat this is to exploit tissue specific addressin molecules, known to be present in both normal and disease tissues, as targets to deliver/concentrate drugs at the disease tissue site (Ferrari et al., 2016). This has been shown in other conditions such as cancer, to be a powerful tool for drug delivery systems allowing more specific disease tissue targeting, a reduced drug dosage requirement and improved safety profile.

In the case of RA, the Pitzalis' group, using in vivo phage display selection in severe combined immunodeficient (SCID) mice transplanted with human synovium, has identified a distinct target for such disease tissue recognised by a cyclic epta-peptide KSTHDRL, known as peptide 3.1 (Lee et al., 2002) constrained by two terminal cysteines that form a disulphide bond. Previous published work from the same group, has also demonstrated the capability of peptide 3.1 to effectively fuse to and deliver the anti-inflammatory cytokine IL-4, directly to RA synovium transplanted into SCID mice and functionally inhibit inflammation in the grafted tissue (Wythe et al., 2013).

The distinct synovial targeting potential of this peptide was also tested by Professor Macor's group (University of Trieste) who conjugated it to a neutralising antibody for C5 or TNF, and tested it in vivo using the antigen-induced arthritis rat model (AIA), further supporting the notion that peptide 3.1 can be feasibly used for drug delivery specifically to the diseased joints (Macor et al., 2012; Colombo et al., 2016)

The same group also developed a nanomedicine approach arming biodegradable nanoparticles with peptide 3.1 in order to deliver drugs such as Methotrexate (MTX) to diseased joints. Nanoparticle-3.1 was shown to specifically bind its target both in vitro and in vivo and increase MTX efficacy by requiring a lower therapeutic drug dose in order to achieve a similar effect to free-MTX. In addition, they demonstrated by following the distribution of Nanoparticle-3.1 in vivo by immunofluorescence, that it is possible to use this approach for chronic long-term drug delivery and as a diagnostic tool for early detection of inflammation in the joints of potential patients (Colombo et al., 2016). However, these armed nanoparticles have only been tested in animal models such as the AIA rat model. Therefore, in order to translate the development of novel specific therapeutic agents for the treatment of human RA, we propose to use the human-RA/SCID mouse model that has been routinely run in our laboratory for over 17 years (Wahid et al., 2000) to test the capacity of Nanoparticle-3.1 to deliver cargo (e.g. MTX) preferentially to human synovial tissue over skin tissue (control). In order to achieve this, we have established a collaboration with the Macor group (University of Trieste) and the Cruz group (Leiden University Medical Centre) who have produced Nanoparticle-3.1 and successfully used it in conventional animal models e.g AIA.

This project's main objectives are to optimise the pharmokinectics of this nanoparticle armed with peptide 3.1 while loaded with an RA drug (e.g. MTX) and establish its in vivo biodistribution in the human-RA/SCID transplantation model and its efficiency delivering and releasing the therapeutic drug to its specific target in inflamed tissue in order to identify its potential for clinical use.

Skills Priority Alignment: Advanced Therapeutics, Quantitative Biology, Whole Organism

Publications

10 25 50
 
Description Leiden Medical University Centre 
Organisation Leiden University Medical Center
Country Netherlands 
Sector Academic/University 
PI Contribution In vitro experimentation of reagents produced and sent over from Leiden with batch quality control assessment.
Collaborator Contribution Production of nanoparticles armed with targeting antibodies for arthritis as discussed with a control version of the nanoparticles needed.
Impact N/A
Start Year 2017
 
Description University of Trieste 
Organisation University of Trieste
Country Italy 
Sector Academic/University 
PI Contribution Experimenting and testing of antibody and nanotechnology product sent over from collaborators in vitro thus far
Collaborator Contribution Production of the antibody and nanotechnology being used for the project so far
Impact Protocols being established for testing of the antibody and nanotechnology in vitro.
Start Year 2018
 
Description Integrated Away Day at the University of Southampton 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Postgraduate students
Results and Impact PhD students attended an away day at the University of Southampton to present their PhD project backgrounds, aims and hypothesis to mixed groups of faculty and postgraduate students and staffs with a Q&A afterwards. The second year was a 3 minute thesis presentation competition between PhD students in their second year of their PhD. Both days were spent meeting and learning about other students and their research in similar and different research areas.
Year(s) Of Engagement Activity 2018,2019,2020
 
Description Pint of Science 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Public/other audiences
Results and Impact 6 speakers were chosen amongst queen mary university staff to give a 30 minute talk about their area of interest and expertise with questions and discussion afterwards from the audience. Feedback received from the general public and audience were exceedingly positive stating the talks were understandable and activities on the night were enjoyable and left feeling they had learnt something new.
Year(s) Of Engagement Activity 2018,2019