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

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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