Multiresponsive Nanomaterials for Anti-Inflammatory Therapies

Abstract

ABSTRACT This thesis focuses on polysulfide-based materials as oxidation-responsive systems for biomedical applications. In Tirelli lab, various sulfur-containing materials have been investigated by virtue of their oxidation-responsive behavior which offers a potential use of these materials for the treatment of inflammatory pathologies. Accordingly, in Chapter 1, we provide a review of 6 different types of sulfur-containing polymers as oxidation-responsive materials with an emphasis on their synthesis and biomedical applications. Hydrophobic polysulfides become hydrophilic upon oxidation. In Chapter 2, we used H2O2 to produce a polysulfoxide and investigated it as stealth and anti-inflammatory material to provide an alternative to PEG, which was demonstrated to cause inflammatory responses upon repeated injections. The MTS assay showed low toxicity and the uptake by activated macrophages was reduced when compared to the same size PEG. In addition, the polysulfoxide was observed to reduce the levels of (i) complement proteins, C3a and C5a, (ii) the oxidants, H2O2 and ClO-, and (iii) a pro-inflammatory cytokine, TNF-α, indicating antioxidant and anti-inflammatory behavior. In Chapter 3, we investigated a PPS-containing block copolymer as an alternative to PEGylated polymers. However, in this case, we designed a novel synthetic pathway to form PPS-macroRAFT agents bearing different RAFT-active groups to synthesize block copolymers with varying DMA and DEA content as hydrophilic blocks via RAFT polymerization. We then investigated the oxidation- and temperature-responsive behavior of the self-assembled structures. Only the highest PDEA content showed temperature-responsive behavior and we observed an increased rate of oxidation with decreasing PDEA content. The polymers were tested in fibroblasts, macrophages, microglia, astrocytes, and primary cortical neurons. The viability was observed to differ in cell types, glial cells being more sensitive than the fibroblasts and macrophages. In the case of primary neurons, the polymer which showed temperature-responsive aggregation was the only one that caused a decrease in cell viability. TNF-α levels were reduced in activated microglia, astrocytes, and primary cortical neurons indicating the anti-inflammatory behavior of these materials.

Date of Award	31 Dec 2022
Original language	English
Awarding Institution	The University of Manchester
Supervisor	Nicola Tirelli (Supervisor) & Annalisa Tirella (Supervisor)