Polymer nanoparticles for biomedical applications

Free drugs often suffer from low bioavailability, poor cellular uptake, and side effects from off-target interactions. Polymer nanoparticles (NPs) can improve bioavailability and reduce off-target accumulation via various targeting methods, meaning dosages can be improved to reduce the risk of side effects. Uptake of polymer NPs into cells is well established, and can be accomplished with high selectivity to target cells by using specific modifications. Boron neutron capture therapy (BNCT) and treatment for inflammatory diseases, specifically multiple sclerosis and rheumatoid arthritis, suffer heavily from the above issues, meaning polymer NP systems could provide useful improvements.
In chapter 2, a boron containing methacrylate monomer, 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl methacrylate (OxM2), was used alongside 2-(dimethylamino)ethyl methacrylate, poly(ethylene glycol) methyl ether methacrylate (PEGMA), and methacrylic acid (MAA) to synthesise a library of statistical copolymers via reversible addition-fragmentation chain-transfer (RAFT) solution polymerisation. The statistical copolymers formed NPs by solvent switching, and were then characterised by DLS and TEM. NP size was assessed over three repeats showing the replicability of the solvent switching method. Finally, the statistical copolymer NPs were assessed for cytotoxicity using MTT assays, and cellular uptake studies were attempted to determine the system’s applicability for use in BNCT. Cellular survival of two of the PEGMA/OxM2 statistical copolymers was >80%, indicating low cytotoxicity, but cellular uptake could not be confirmed.
In chapter 3, poly[(glycerol monomethacrylate)51-block-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl methacrylate)x] (p(G51-b-Oxx)) diblock copolymer NPs were synthesised by aqueous emulsion RAFT-mediated polymerisation-induced self-assembly (PISA). After analysis of the diblock copolymers by 1H NMR spectroscopy, DLS, SEC, and TEM a small amount of methanol was added as a cosolvent to improve the polymerisation, Đ values, and the stability of the NPs formed. Despite altering the w/w % and chain length of the OxM2 block, the system remained kinetically trapped to spherical NPs. The p(G51-b-Oxx) diblock copolymer NPs were assessed for oxidation response with hydrogen peroxide at 37 °C. 1H NMR spectroscopy confirmed OxM2 breakdown, but DLS and TEM showed no change in size or morphology of the NPs, limiting the system’s usage as an oxidation responsive drug delivery system (DDS) for inflammatory diseases.
In chapter 4, poly[(glycerol monomethacrylate)51-block-((hydroxypropyl methacrylate)x-stat-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl methacrylate)y)] (p(G51-b-(Hx-s-Oxy))) statistical diblock copolymer NPs were synthesised via an aqueous dispersion RAFT-mediated PISA system. A feed of OxM2 was used with variable chain lengths of (2-hydroxypropyl methacrylate) HPMA to alter the statistical ratio. The polymerisation was optimised to include a small amount of methanol after the statistical diblock copolymers were found to have high Đ values. Pure sphere, worm, and vesicle phases were found for the p(G51-b-(Hx-s-Oxy)) system. Oxidation response testing revealed that OxM2 was broken down by hydrogen peroxide to MAA, but no size or morphological change was observed. Upon the addition of a base the vesicle and worm samples transitioned into spheres. The dual response of the polymer system is classified as an “AND gate”, which could prove to be highly useful for targeting specific inflammatory diseases as a DDS.