Li, Shengxi; (2024) Engineering of Glycol Chitosan Based Amphiphile (qGCP) and Zwitterionic Polymeric Nanoparticles for Drug Delivery to Tumours. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

In this work, we use two glycol chitosan-based micellar systems to specifically explore the role of micelle surface chemistry on intravenous drug delivery in cancer treatment. First, quaternary ammonium palmitoyl glycol chitosan (qGCP) was manufactured. Results obtained show that the critical micelle concentration for these systems is orders of magnitude lower (23.53 ± 2.31 µg/mL) compared with common surfactants like SDS with concentration of 2304 mg/mL (Chapter 2). These qGCP micelle were also efficient at encapsulating paclitaxel (PTX), drug loading of around 15 wt.% (Chapter 3). Furthermore, in Chapter 4, the in vitro and in vivo behaviours of qGCP (PTX) nanoformulation were assessed. The results showed that the cell uptake as well as cytotoxicity increase with the increase in micelle positive surface charge (zeta potential). The pharmacokinetic pilot study illustrated that qGCP was eliminated quickly in the body, possibly due to opsonisation and clearance effects of the positive charge. We therefore designed modifications to the cationic qGCP micelle approach with a view to minimise such interactions and manufactured a zwitterionic micelle (Quaternary Aconitic Acid Glycol Chitosan, dGC-AA-Q) and to prolong circulation time and enhance the likelihood of accumulation in the tumour site through passive targeting (Chapter 5). The drug loading of PTX in this zwitterionic micelle formulation reached up to 44 wt.%, which is significantly higher than that achieved with the cationic qGCP micelle (15 wt.%). Furthermore, the pharmacokinetic evaluation of the dGC-AA-Q (PTX) formulation showed a longer circulation time, with a longer t1/2 (16.94 h), larger AUC0-∞(40.44 µg*h/mL) compared with t1/2 (15.35 h) and AUC0-∞(4.06 µg*h/mL) of qGCP micelle and t1/2 (7.00 h) and AUC0-∞(39.54 µg*h/mL) observed for Taxol. The mechanism for these results potentially could be attributed to dGC-AA-Q's tendency to bind with erythrocytes, prolonging body circulation time and promoting immune evasion.

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