Use this URL to cite or link to this record in EThOS: https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.756185
Title: Engineering of polymeric nanoparticles based on structure-activity relationships (SARs) for oral drug delivery
Author: Odunze, Uchechukwu
ISNI:       0000 0004 7429 1381
Awarding Body: UCL (University College London)
Current Institution: University College London (University of London)
Date of Award: 2018
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Abstract:
The self-assembling polymer N-palmitoyl-N-monomethyl-N,N- dimethyl-N,N,N-trimethyl-6-O-glycolchitosan (GCPQ) has been shown to improve the oral and parenteral delivery of various drugs. GCPQ contains a number of chemical ‘building blocks’ that are amenable to independent modification. The ability to finely control the level of modification for those moieties allows systematic modulation of polymer chemistry to become a tool to understanding the role and relative importance of specific modifications for the process of oral drug delivery. GCPQ polymers with varying molar percentages of palmitoyl (DP) and quaternary ammonium (DQ) groups were synthesized and the effects on physicochemical properties, aggregation, stability and therapeutic applications were examined. Results obtained show that the critical micelle concentration is very low (below 10μM) compared to ≈8mM for sodium dodecyl sulphate and ≈80mM for sodium caprate (C10) and that micelle formation is spontaneous at room temperature. Structural modifications also resulted in a switch from an entropy to an enthalpy driven aggregation at room temperature. The colloidal stability of the synthesized polymers was found to increase with increasing ratio of DQ to DP (QPR) and is greater at acidic pH than at neutral pH. The structural modification also resulted in different morphological characteristics of drug loaded nanoparticles, producing nanocrystals and nano-micelles with varying drug loading capacities. Additionally, in vitro transport studies showed that GCPQ enhances paracellular transport in a graded, modification dependent manner. When compared with C10, GCPQ was found to be a much safer permeation enhancer, potentially more efficient for drug delivery and at least as potent as C10. The mechanism of these effects was found to involve temporary, size selective distortions on the tight junctions which limit the passage of molecules larger than 3.2nm in hydrodynamic radius. Furthermore, it was observed that these modifications did not affect the uptake of encapsulated hydrophobic drugs by transcytosis in an in vivo rodent model.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID: uk.bl.ethos.756185  DOI: Not available
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