Use this URL to cite or link to this record in EThOS: https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.822434
Title: Synthesis of novel polyester-based nanomedicines for colorectal cancer drug encapsulation
Author: Blackmore, Sarah
ISNI:       0000 0005 0287 9837
Awarding Body: University of Liverpool
Current Institution: University of Liverpool
Date of Award: 2020
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Abstract:
Drug encapsulation within nanocarriers provides a solution to the poor bioavailability and offsite toxicities seen for poorly water soluble active agents. Nanocarriers formulated from biodegradable, biocompatible polyesters such as PLA and PCL are capable of being cleared from the body whilst functionalisation of the monomer species offers pathways for the tuning of polymer physicochemical properties to aid drug encapsulation. Here the application of substituted caprolactone monomers in MSA catalysed ROP produced a range of e-CL-based polyesters of varying architecture with the ultimate goal of creating a range polymeric nanoparticles capable of encapsulating active metabolite 7-ethyl-10-hydroxycamptothecin, SN-38. Baeyer Villiger oxidation allowed the synthesis of 4 new e-CL based monomers with increasing alkyl side chain lengths plus the additional bis-lactone monomer, 4,4'-bioxepanyl7,7'-dione, BOD. Henceforth capabilities of MSA-catalysed ROP in the construction of a variety of polymer architectures was explored avoiding traditional SnOct2 and mitigating the risk of residual metal in polymers bound for pharmacological use. PEG2/5K-OH macroinitiators were synthesised to complete the library of polymers taken forward for (co)nanoprecipitation studies. PCL polymers were initially used for more in depth studies producing stable aqueous nanoparticle dispersions with hydrodynamic diameters > 110 nm. Co-nanoprecipitation with amphiphilic PEG-b-PCL40 polymers showed a reduction in zeta potential with increasing PEGb-PCL40 content with both Mn for the hydrophilic PEG blocks. In view of these preliminary results, the full library of polymers were investigated and comparable nanoparticle characteristics such as size, PdI and zeta potential were achieved. Encapsulation ability of these systems was assessed with the introduction of guest molecules, such as oil red, docetaxel and SN-38 pentanoate, successfully producing stable nanoparticle dispersions at 2.43 wt% drug loading. Conversely failure to yield SN-38 encapsulating nanoparticles via co-nanoprecipitation led to the employment of thin film hydration. This allowed drug loadings from 2.43 wt% to 95 wt% to be achieved with increasing particle size of 45 to 240 nm. Supplementary studies allowed the characterisation of both the thin films and resulting dispersions as well as the determination of stability both in dry and hydrated states. Finally, preliminary pharmacological analysis, in vitro gave an important comparison to free SN-38 highlighting retardation of release and reduced macrophage uptake that had been gained by encapsulating the active compound.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID: uk.bl.ethos.822434  DOI:
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