Niitsoo, Liisa; (2022) Novel insights into the formation of folate conjugated glycol chitosan nanoparticles for active tumour targeting and as a potential platform for ligand multiplexing. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

This thesis provides novel insights into strategies for the formation of ligand conjugated glycol chitosan nanoparticles for active tumour targeting. The low molecular weight folic acid is chosen as initial model ligand. First, the synthesis of quaternary ammonium palmitoyl glycol chitosan (GCPQ), an amphiphilic derivative of chitosan with drug carrier potential, is explored. Then, the modification of GCPQ with thiol groups is outlined in detail, including optimisation of the feed of Traut’s reagent. Active targeting is generally achieved by conjugation of specific ligands to NP surface that specifically bind to overexpressed receptors at the tumour site with high affinity and avidity to improve the delivery of chemotherapeutics. In this work, the functionalisation of GCPQ with PEG-folic acid is systematically investigated, via thiol maleimide coupling or NHS chemistry, highlighting the potential of GCPQ to act as a platform for ligand multiplexing through these different chemistries. In-depth chemical characterisation of the conjugates is discussed, as well as physicochemical characterisation of the formed nanoparticles. In particular, the thesis explores the self-assembly of mono-functional polymers to provide multi-functional nanoparticles with targeting as well as fluorescent groups. In vitro uptake studies show preferential uptake in folate receptor positive cells compared to cells that do not overexpress folate receptors. In vivo biodistribution pilot study was carried out in six female Balb/c mice after inoculation with 4T1 mouse xenograft tumours, followed by dissociation of the tumours, livers, and spleens. Flow cytometric analysis was used to quantify the nanoparticle distribution. The results of this study show promise towards developing a synthetic strategy for the modification of GCPQ with multiple ligands, to allow it to perform as a multiplex nano-platform for the active targeting of chemotherapeutics.

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