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Hagan, Susan Anne (1998) Poly(lactic acid)-poly(ethylene glycol) copolymers for use as drug delivery systems. PhD thesis, University of Nottingham.

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Abstract

Block copolymers of polylactide and poly( ethylene glycol) (PLA-PEG) were investigated as biodegradable drug delivery systems. They are defined by the differing molecular weight ratios of polylactide to poly( ethylene glycol). Copolymers containing more hydrophilic PEG than hydrophobic PLA per molecule self-dispersed in water giving spherical nonionic micelles. Purification by gel permeation chromatography gave two peaks. The first peak only formed micelles (the second was PLA-depleted). Analysis by dynamic light scattering (DLS) and transmission electron microscopy (TEM) gave diameters of IS.6nm and 18.9nm for 1.5:2 and 2:5 PLA-PEG micelles respectively.

PLA-PEG copolymers with more PLA than PEG per molecule (4:2 and 6:2 PLA-PEG) formed "solid particles" by the solvent-precipitation method. GPC purification again gave two peaks, but smaller second peaks. DLS analysis gave diameters of 15.1 nm and 20.8nm for 4:2 and 6:2 PLA-PEG particles respectively (confirmed by TEM and atomic force microscopy (AFM)).

Static secondary ion mass spectrometry and X-ray photoelectron spectroscopy showed PEG at the surface of 4:2 and 6:2 PLA-PEG in water and acetone. Stability testing to salt suggested sterically stability. Rheological measurements determined PEG chain layer thicknesses, with the thickest chain for 2:5 PLA-PEG (where PEG chain length is 5000gmol-1 compared with 2000gmol-1).

Testosterone and sudan black B (SBB), were used as "model" drugs with different hydrophobicities. Ultracentrifugation sedimentation velocity studies confirmed drug incorporation. Aromatic SBB loaded readily (≥59.0%w/w) compared with steroidal testosterone <2%w/w). Loading of testosterone esters of varying hydrophobicity into PLA-PEG particles showed little difference compared to between testosterone and SBB, suggesting that aromaticity is more significant. In vitro release studies (4:2 PLA-PEG particles/SBB) showed a small burst release, then linear release to twenty eight days.

In vivo studies in the rat, using a radioactive marker, demonstrated extended blood circulation times for PLA-PEG micelles during the three-hour study, with increased blood levels and lower liver uptake for 1.5:2 over 2:5 PLA-PEG micelles. PLA-PEG particles were directed to the liver.

Item Type:	Thesis (University of Nottingham only) (PhD)
Supervisors:	Illum, Lisbeth Garnett, M.C. Davies, M.C. Davies, S.S.
Keywords:	block copolymers, drug delivery systems
Subjects:	Q Science > QD Chemistry > QD241 Organic chemistry R Medicine > RS Pharmacy and materia medica
Faculties/Schools:	UK Campuses > Faculty of Science > School of Pharmacy
Item ID:	30646
Depositing User:	Hatton, Mrs Kirsty
Date Deposited:	04 Nov 2015 15:27
Last Modified:	15 Dec 2017 05:53
URI:	https://eprints.nottingham.ac.uk/id/eprint/30646

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