We have synthetized a series of biological relevant O-glycans, known to be key binders to specific bacterial surfaces, as well as their corresponding glycodendrons ready to be conjugated to water soluble fluorescent and multifunctional CDots. The synthetic schemes used to obtain the glycan structures, CDots and glyco-CDots are all novels. New technology has been developed to control density and distribution of surface glycans on CDots as well as multifunctionality (e.g. glycan or glycan combinations as well as glycan/drug conjugates) to enhance particle bioavailability, stability and targeting ability for specific biological studies (e.g. lectin binding as well as bacteria targeting). Studies of cell internalization and localization of the novel glycan-nanoprobes and analysis of their cytotoxicity mechanisms as well as their uptake mechanism has been carried out within the proposed work. After selecting the optimal glycan- or glycan/drug-nanodot combinations, we have validated our glycan-based targeted drug delivery systems (Smart Glyco-CDots) using traditional antibiotics known for their ability to target bacteria, but that have become less effective against resistant strains (e.g. oxazolidinones). The novel glycan/drug-CDots using combinations of specific glycans/antibotics has been evaluated for their ability to selectively deliver the drug to specific bacteria in bacterial binding and killing assays (against a range of clinically relevant bacterial pathogens e.g. E. coli; S. aureus, P. aeruginosa) and screened for selective labelling and drug release. This work has been carried out in collaboration with Dr. J. Spencer (School of Cellullar and Molecular Medicine, Bristol) and FluoretiQ (Quantum enhaced fluoresce sensor specifically for our CDots).
The final results derived from the implementation of this action could be disseminated at two different levels: 1) via publication in international scientific journals: leading scientific multidisciplinary journals such Science, Nature (including its specific Nature sister journals), or chemistry journals such as ACIE, JACS or Chem. Sci., depending on the novelty of the discovery. In accordance with the principles of H2020, results will be published in open access whenever possible; and 2) the results could also be disseminated to industrial partners. In this context, potential intellectual property arising from BioNanoProbes could be evaluated and managed by the Technology Transfer Unit of University of Bristol. The research results could be disclosed to potentially interested industrial contacts in the context of non-disclosure agreements, and the possibilities for collaboration with additional industrial funding, and for licensing could be explored. This project could significantly streamline the synthesis of new bio-inspired glyco-nanoprobes as diagnostic tools and antimicrobial pro-drugs, and thus, it is likely that important industrial applications will result. The data sets collected during this MSCA will inform and enhance dozens of publications in the coming years.
