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Title: The synthesis of star copolymers for the delivery of macromolecular guest and photodynamic therapy
Author: Kadhim, Alaa
ISNI:       0000 0004 7428 2565
Awarding Body: University of Sheffield
Current Institution: University of Sheffield
Date of Award: 2018
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Traditional delivery systems use polymeric structures that contain internal voids or specific functionality that can be used to encapsulate smaller molecules, protecting them from external environments and delivering them to specific sites. Although considerable success has been achieved in the delivery of small organic molecules, these systems are not suitable for the delivery of (larger) biomolecular drug moieties. This project has addressed this issue by constructing and studying nano-sized macromolecular carriers with the capacity to form and maintain a large volume of free internal space. A star polymeric core was synthesised to generate a suitable environment that can be used to encapsulate large macromolecular guest. The synthesis of the star copolymers involved a multi-step reaction process using a single pot procedure. Initially, a core functionalized with hydroxyl end groups (trimethylol propane TMP) was used as an initiator to ring open and polymerize caprolactone. The resulting hydrophobic star polymers (star poly(caprolactone) (SPCL)) which possessed a nucleophilic end group, were used to initiate a second ring opening polymerization (ROP) using a branched hydrophilic monomer (glycidol). Three star copolymers (SPCL-HPGs) were prepared with different chain length and similar size of the capping group (SPCL15-HPG90, SPCL35-HPG90 and SPCL60- HPG90) in order to study the effect of the chain length upon encapsulating large molecule. Hydrophilic HPG was synthesised as the only control system of our proposed drug delivery system. The aggregation was then studied using pyrene as probe. The study showed that both the star copolymer (SPCL60-HPG90) and the control (TMP1-HPG90) aggregate and form micelles at 10-20 µg/mL and 150 µg/mL, respectively. Having synthesised successfully the proposed drug delivery system and the control, a model macromolecular guest, a synthetic mimic of hemoglobin, was selected for the encapsulation. It is proposed that encapsulation of the synthetic mimic of hemoglobin (TAPP-HBP 15) within the core of the star copolymers improved its water solubility and making it artificial blood product. The guest was synthesised successfully with an average molecular weight of 18K Da. Upon encapsulation, significant amount of the guest was loaded within the star copolymers than the control system by 10 factors. The encapsulation of the guest is thought to happen with the aggregated structure of the polymer rather than within the structure of the host. This was concluded because although the HPG does not have hydrophobic segment, it has encapsulated the large guest. The second part of the project discussed the synthesis of star copolymers with porphyrin core for photodynamic therapy (PDT). PDT is one of the outstanding protocols for cancer treatment, which involves the combined action of photosensitizer (PS), once accumulated into cancer cells, and irradiation with the light of appropriate wavelength. Porphyrins and their derivatives have been used extensively in PDT. Although PDT is an alternative therapeutic method to traditional cancer treatment, there are still a number of problems, which limit its clinical application. These include selectivity, solubility and therapeutic efficiency. In this study, the solubility of porphyrins in aqueous solution was enhanced significantly via covalent incorporation within aggregated water-soluble polymers (porphyrin cored star copolymers). Two porphyrin molecules with hydroxyl end group were selected as a core for the star copolymer, these are: tetrakis(3,5-dihydroxyphenyl) porphyrin) (TDHPP), and tetrakis(4- (hydroxyphenyl)porphyrin (THPP). However, TDHPP and THPP were very unreactive initiators and did not polymerise with the caprolactone until a spacer was added to the porphyrin so that the lone pair of their terminal hydroxyl group cannot be part of the porphyrin conjugation system. Thus, two star copolymers were synthesised from spacer-porphyrin (STHPP-PCL-HPG) and S-TDHPP-PCL-HBP). The control (porphyrin-HPG) were synthesised from porphyrins with and without spacer units. The particle size of all the aggregated polymers was between 100-200 nm determined by DLS. As such, favourable/selective delivery via the enhanced permittivity and retention effect (the EPR effect) was expected. The polymers were analysed for their PDT behaviour via a simple MTT assay, using EJ bladder carcinoma cell line. The relative viability of the polymers and its controls in the dark were higher than 0.8 at 100 µM except the THPP-HPG polymer which had aviability of 0.2. Under light irradiation (10 mW/cm2 ), significant toxicity was observed at 1 µM for the free THPP and at 10 µM for the free TDHPP porphyrin. While phototoxicity of the polymers, considerable cell death was obvious at polymers concentration of 10 µM for the THPP cored polymers except the star copolymer, which did not show any significant toxicity at this concentration. The phototoxicity of TDHPP cored polymers were significant for TDHPP-HPG and S-TDHPP-HPG at 100 µM for and poor for the star copolymer at the same concentration. The intracellular localisation of the molecules porphyrin cored polymers into the EJ cells was imaged by confocal microscopy. Both of the free porphyrin (THPP and TDHPP) molecules diffused within the cell at 10 µM. Porphyrin cored HPG polymers also diffused within the cells but as the spacer was added the diffused the fluorescence decreased. The porphyrin-PCLHPGs star copolymers showed no diffusion into the cells. Thus, porphyrin-cored HPG polymers was deemed to be promising photosensitizers for photodynamic therapy (PDT) rather than the star copolymers.
Supervisor: Twyman, Lance Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available