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Abstract
Polymeric micelles have the potential to be the next generation of “smart” delivery vehicles for drug delivery, especially for anti-cancer therapy. Polymeric micelles can be easily modified to contain desired functionalities to provide protection to the loaded cargo as well as targeting abilities for the micelle. Crosslinking for micelle stabilisation as well as altering the nature of the hydrophilic block are all common modifications. However, the effects of such modifications, as modelled by 2D cell culture models, are often highly discrepant when compared to in vivo studies. Thus, 3D models, such as multicellular tumour spheroids (MCTS), can be seen as an intermediate between the two, providing a more accurate representation of solid tumours.
In the first section of this work, the core-crosslinking nature and density within a poly(ethylene glycol methyl ether acrylate)-b-[poly(carboxyethyl acrylate)-g-paclitaxel] micelle was modified and the effect on cytotoxic behaviour was tested on prostate MCTS. When micelles were irreversibly crosslinked with 1,8-diaminooctane, enhanced cytotoxicity was demonstrated by the crosslinked micelles when compared to both uncrosslinked micelles and free paclitaxel after 4d treatment. After 14 d treatment, both micelle variants performed equally to free paclitaxel, demonstrating the success of the micellar protection for paclitaxel without compromising its effect. The micelles were then crosslinked at different densities using cystamine and it was shown that cytotoxicity decreased with increasing crosslinking density. Thus, crosslinking density should be kept to a minimal when cystamine is employed as the crosslinking agent.
In the second section of this work, a glucosamine-based glycopolymer P(GluHEA) with retained amine functionality was prepared as an alternative to poly(ethyl glycol methyl ether acrylate) for potential use of the micelles as an oral drug delivery system. Amine protection on the glucosamine monomer with trifluoroacetamido groups was ultimately successful and resulted in almost complete deprotection after copolymer synthesis. A poly(butyl acrylate)-bpoly(GluHEA) copolymer self-assembled into 60 nm micelles. The micelles and chitosan could be uptaken by a Caco-2 monolayer, albeit to different degrees, demonstrating the mucoadhesive properties present in both samples. Thus, we were successfully prepared a type of “synthetic chitosan” with mucoadhesive properties for potential oral drug delivery.