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dc.contributor.advisorGamble, Allan
dc.contributor.advisorHook, Sarah
dc.contributor.authorDadhwal, Sumit
dc.date.available2018-10-10T03:47:11Z
dc.date.copyright2018
dc.identifier.citationDadhwal, S. (2018). Development and Applications of Stimuli-Responsive Drug Delivery Strategies (Thesis, Doctor of Philosophy). University of Otago. Retrieved from http://hdl.handle.net/10523/8425en
dc.identifier.urihttp://hdl.handle.net/10523/8425
dc.description.abstractIn this thesis, bioorthogonal chemistry was explored as a means of developing stimuli-responsive nanoparticles and hydrogels. It has been hypothesised that the use of stimuli-responsive drug delivery systems will improve the efficacy of treatments and/or reduce off-target toxicities. A strain promoted 1,3-dipolar cycloaddition reaction between a trans-cyclooctenol (TCO) and an azide was used for the drug delivery applications. As the reduction of an azide by hydrogen sulfide (H2S, a potential endogenous stimulus in cancer cells) has also been reported, the implications of this for cancer drug delivery was investigated. Synthesis of a block copolymer containing the TCO and H2S-responsive aryl azide group was attempted with various polymerization techniques, and successfully isolated following ATRP polymerization (Chapter 2). The block copolymer was used to make polymersomes (Chapter 3) and different methods were explored to optimise the size (to around 200 nm) and homogeneity (PDI <0.3) of the polymersomes. The diffusion of the stimulus (TCO and H2S) into the bilayer of polymersomes was confirmed by FTIR, which showed no azide peak after reaction of the azide-polymersomes with the stimulus. An anticancer drug doxorubicin (DOX) was encapsulated into the polymersomes and stimuli-responsiveness to TCO and H2S was explored using in vitro cell-free and cell-based assays. TCO-triggered azide-polymersomes were shown to form stable cycloaddition conjugates (triazolines) at neutral pH (7.4) in the hydrophobic bilayer of the polymersomes (triazoline-polymersomes). The triazoline-polymersomes, which were relatively stable at pH 7.4, showed a pH-sensitivity with higher drug release and faster release observed as the solution was made more acidic (pH 4.5, 6.0, 6.5). Under more acidic conditions, it is hypothesised that proton diffusion into the hydrophobic bilayer is increased and this leads to more efficient hydrolysis of the triazoline (and subsequent imine) to generate the aniline which undergoes a 1,6-self-immolation to result in cross-linking of the polymer chains and leaky polymersomes. The in vitro cell-free release of the drug from the azide-polymersomes was also tested with H2S, which showed a faster release (96% after 24 h) of the drug compared to triazoline-polymersomes (12% after 24 h) at pH 7.4 and azide-polymersomes with H2S (10% after 24 h). The functional impact of stimuli-responsiveness was determined by incubating DOX-loaded formations with murine melanoma (B16.F10) cells in vitro. Stimuli-responsive polymersomes showed lower IC50 values (triazoline-polymersomes 3.2 µM, azide-polymersomes 8.0 µM) compared to stimuli-insensitive control-polymersomes (46.8 µM). The in vivo efficacy of polymersomes was explored in a therapeutic B16.F10 murine melanoma model. Treatment of mice with a single dose of triazoline-polymersomes did not improve the median survival of the mice and we hypothesize the slow release of DOX from the triazoline-polymersomes could not maintain a therapeutic concentration of DOX. However, mice treated with H2S-triggerable azide-polymersomes showed improved survival and delayed tumour growth compared to mice treated with non-responsive DOX-loaded polymersomes or unformulated DOX The bioorthogonal TCO-azide strategy was also used to develop stimuli-responsive dipeptide hydrogels. An azide-containing capping moiety was attached at the N-terminus of dipeptide (PhePhe) via an azido-PABC linker to give hydrogelator-1 (Chapter 4), which formed a fibrous network in a buffer to make a hydrogel. The hydrogel showed a gel-sol transition in the presence of 5 mM and 10 mM TCO, whereas control experiments where no TCO was added or cis-cyclooctenol (CCO) was added to the hydrogel showed no sign of degradation over 24 h. In vitro cell-free studies using DOX as the model entrapped cargo in the hydrogel, demonstrated that controlled release of the cargo could be obtained with TCO (5 mM). Further, a new hydrogelator-2 was designed with an azido-tetrafluorophenyl moiety as the capping group for the dipeptide (Chapter 5). The tetrafluoro-substitution improved the mechanical properties as well as the sensitivity of the hydrogel compared with non-fluorinated hydrogel. The fluorinated hydrogel also demonstrated controlled release of the model drug cargo (DOX) when triggered by TCO (1 mM). Overall, the results suggest that TCO and H2S stimuli-responsive azide-polymersomes and hydrogels could have future potential as drug delivery or immunotherapy delivery platforms that can overcome some of the current challenges in chemotherapy.
dc.language.isoen
dc.publisherUniversity of Otago
dc.rightsAll items in OUR Archive are provided for private study and research purposes and are protected by copyright with all rights reserved unless otherwise indicated.
dc.subjectBioorthogonal
dc.subjectStimuli-responsive
dc.subjectDrug-delivery
dc.titleDevelopment and Applications of Stimuli-Responsive Drug Delivery Strategies
dc.typeThesis
dc.date.updated2018-10-10T01:21:10Z
dc.language.rfc3066en
thesis.degree.disciplinePharmacy
thesis.degree.nameDoctor of Philosophy
thesis.degree.grantorUniversity of Otago
thesis.degree.levelDoctoral
otago.interloanno
otago.openaccessAbstract Only
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