Use this URL to cite or link to this record in EThOS: https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.733634
Title: The synthesis and application of dendritic polymer for photodynamic therapy
Author: Aboshnaf, Fatema
ISNI:       0000 0004 6494 1600
Awarding Body: University of Sheffield
Current Institution: University of Sheffield
Date of Award: 2018
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Abstract:
Dendrimers and dendrons are highly branched polymers with a three-dimensional structure and diameters around 1-10 nm. Their properties, include, easy modification of the core, surfaces and interior, the ability to control polymer size and high water solubility. Because of these characteristics, these macromolecules have been used for several applications. This research has studied these materials as drug delivery systems for photodynamic therapy (PDT) in cancer dieses. In oncology, photosensitizers (PS) are specific drugs used in PDT. The problems with drugs are poor solubility and they are taken up by healthy as well as cancerous tissues therefore, the success of PDT is limited with these issues. To overcome this problem, dendrimers were synthesised and used to improve the drug solubility and carry drugs to the specific targeted cell. Accordingly, the essential goal of PDT is to induce efficient damage to tumour tissue without any negative effect on healthy cells. Initially, the first part includes the synthesis of water-soluble PAMAM dendrimers from G0.5 to G4.5 via the divergent approach, which involves two steps; a 1,4-Michael addition to yield half-generation dendrimers (ester terminated dendrimers) and an amidation step to synthesise whole generation dendrimers (amine terminated dendrimers). Ethylenediamine (EDA) was chosen as a core for the dendrimers to generate primary and secondary amines within the dendrimer structure. The half-generation dendrimers from G0.5 to G4.5 were successfully converted to OH terminated dendrimers using hydroxymethyl amino methane (TRIS). To investigate our dendrimer as the solubility enhancer, ibuprofen was studied. The study exploits water-soluble PAMAM dendrimers ranging from G 0.5 to G 3.5 for encapsulation of ibuprofen. The G3.5 (96OH) PAMAM dendrimer systems recorded the highest encapsulation when compared to the smaller G1.5 (24OH) and G2.5 (48OH). Encapsulation studies using excess ibuprofen and a dendrimer concentrations ranging from 1x10-4 - 6x10-4 M. These experiments showed that ibuprofen loading was not linear, with a maximum loading of 1.00x10-4 M observed, at all dendrimer concentrations above 2x10-4 M. The reason for this was aggregation of the dendrimers at the higher concentrations. This was confirmed by DLS, which showed 200 nm-sized aggregates, at 1x10-4 M and above. The second part of the work utilises the OH-terminated PAMAM dendrimer from G1.5 to G3.5 for encapsulation of two hydrophobic molecules namely; tetra-phenyl porphyrin (TPP) and zinc Tetraphenylporphyrin (ZnTPP). Both molecules are used as drugs in photodynamic therapy, but have zero solubility in water. The dendrimers were able to solubilize and encapsulate TPP and ZnTPP, but the dendrimers were able to solubilize ten times more of the metalated ZnTPP. The increased solubility came from a secondary interaction generated via coordination between the dendrimer's internal nitrogen(s) and the zinc metal within ZnTPP. As with the ibuprofen, the level of ZnTPP encapsulation increased with the size of the dendrimers, with G3.5 OH being the best host ZnTPP. Despite these results, the solubility of the drug remains below the desired limit for therapeutic applications, with dendrimer to ZnTPP ratios being very low (around 10 dendrimers to 1 ZnTPP). Thus, to increase drug loading, coordination bonding was further exploited and used as an integral part of the dendrimer synthesis. The third part describes the synthesis of PAMAM dendrons, ranging from G 0.5 to G 3.5, and their use as ligands that could assemble around a porphyrin or a phthlocyanine photosensitizer. Tin cored porphyrin SnTPP(OH)2 and tin cored phthlocyanine SnPC(Cl)2 were synthesized as the photosensitiser (PS). When the dendrons were added they could replace the OH or Cl ligands and assemble on either face of the PS. The aqueous solubility of the dendronized photosensetizers was higher than either SnTPP(OH)2 or SnPC(Cl)2, and experiments showed that they could be taken up and internalised by cancer cells. However, they were not soluble at the level required to perform PDT experiments. In addition, the phthalocyanin-dendron systems showed aggregation characteristics in aqueous solution, which may have been good for PDT. However, although soluble, ?max had shifted from 750 nm to 350 nm. At the shorter wavelength they are no longer useful for PDT and were not tested.
Supervisor: Twyman, Lance Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID: uk.bl.ethos.733634  DOI: Not available
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