Final Report Summary - BIONANOMUTT (Multi-compartmental Biomolecular Nanocarriers for Multi-modal Targeted Therapies)
During the BioNanoMuTT project we have been developing multifunctional self-assembled nanoparticle structures for application in biomedical drug delivery applications. We have successfully formulated a range of poorly water soluble drugs into lipid bilayer nanodisc particles without significant perturbation of the nanodisc structure or that of its stabilising protein belt. By investigation of 12 different poorly water soluble drugs, we found a correlation between the ability of drugs to thin and soften the lipid bilayer membrane and their drug loading efficiency in nanodisc systems. Drug release profiles from nanodiscs were tuneable by modulation of their lipid composition. Nanodiscs could be further modulated for traceable delivery by enzymatic labelling of the scaffold protein; these nanodiscs were used to demonstrate uptake into HELA cells. Size-limited nanoscale vesicle clusters have also been developed and characterised by the DNA-mediated adhesion of Janus-textured liposomes composed of CL/DOPC/DPPC/cholesterol mixtures; these structures could be further functionalised with stealth properties by inclusion of DOPE-PEG2000 lipids, which do not inhibit nanocluster formation. pH-responsive i-motif sequences also allow pH-triggered disassembly of DNA-linked vesicles. Towards applications in treatment of superficial bladder cancer we have screened for and characterised novel specific binding reagents with nM binding affinities for known tumour biomarkers, including FGFR1 and FGFR3. These reagents were shown to be able to target vesicle nanoparticles to receptor upregulating cell lines, compared to negligible uptake in control cell lines. Results gained in this project have supported the successful application for further research funding from UK research councils, charities and industry. Dissemination activities have included two public lectures at science cafes in the West Yorkshire region, Art-Science collaborative projects with BioLeeds including a comparative exploration of biological and modern architecture, and coverage in the scientific media of our DNA-linked vesicle work in an article in Lab Times magazine. Knowledge transfer to the host institution was primarily conducted through internal seminars, a workshop on biomembranes and teaching activities from levels one through to five on chemistry and nanotechnology degree programmes. Over the course of this career integration grant project, the Beales group has grown in size to 5 PhD students, 4 PDRAs and 3 project students including the establishment of productive collaborations in Leeds, the UK and internationally which will continue beyond the funding period of this project. Successful EU reintegration is demonstrated by Dr Beales attaining a permanent tenured position as a lecturer with his own laboratory in the School of Chemistry at the University of Leeds.