Smola, Clemens-Michael; (2020) A novel approach of targeting quaternary ammonium palmitoyl glycol chitosan nanoparticles to organs and solid tumours. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

Nanoparticles offer a potential strategy to create multi-functional delivery platforms that combine a high drug loading capacity with the ability to actively target tumours using specific ligand – receptor interactions. In this work we specifically aim to explore the possibility of creating targeted nanoparticles based on the amphiphilic polymer N-palmitoyl-N-monomethyl-N,N-dimethyl-N,N,N-trimethyl-6-O-glycochitosan (GCPQ). As proof of principle we exploit the receptor for folic acid, a cysteine rich cell surface receptor, as it constitutes a useful target for tumour-specific drug delivery as well as to create a platform for targeted drug delivery with versatile applications. GCPQ was synthesized and subsequently modified for attachment to a polyethylene glycol spacer arm bearing the targeting ligand folic acid. A fluorescent dye (Texas Red -X) was linked to the GCPQ-FA Bioconjugate for movement monitoring within the tumour’s microenvironment when using confocal microscopy and to quantify uptake capacity by flow cytometry. In vitro results clearly indicate the uptake advantages of GCPQ-FA over GCPQ by as much as 7-fold higher, when tested on receptor positive and negative cell lines and further receptor inhibition suggests that receptor-mediated endocytosis being the driving force for uptake of GCPQ-FA. Furthermore, a kinetic study gives rise to the assumption that receptor activation and internalization of the particles may take up to 4 hours for GCPQ-FA, whereas GCPQ uptake happens steadily over time. In addition, in vivo experiments undertaken with a receptor positive breast cancer comparing GCPQ and the new drug delivery platform, underline the assumptions taken from in vitro experiments and further suggest the hypothesis of successful active targeting to the surface cell receptor by showing that GCPQ-FA consistently achieves up to 25-fold higher in vivo uptake into the tumour when compared to GCPQ after 6 hours incubation, while also reducing uptake into the liver. Particle transport into the spleen was neglectable for both polymers.

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