Cartlidge, Susan A (1985) Evaluation of crosslinked soluble N-(2-Hydroxypropyl) Methacrylamide copolymers as a potential drug carrier. Doctoral thesis, Keele University.

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Abstract

Soluble crosslinked hydroxypropyl(methacrylamide) copolymers
have been studied in the rat, both in vitro and in vivo, in order to assess their suitability as drug carriers in a targetable drug delivery system.
The lO radiolabelled copolymers used were of Mw 31,000 ->400,000, and their crosslinks contained oligopeptides potentially degradable by lysosomal enzymes.
In vitro studies included the uptake and intracellular degradation of copolymers of different molecular sizes by the rat visceral yolk sac and the everted rat jejunal sac. The rate of uptake of copolymer by the yolk sac decreased with increasing molecular size, but molecular size had no effect on the extent of intracellular degradation of the copolymer. The use of metabolic and lysosomal enzyme inhibitors demonstrated that uptake of copolymers was by pinocytosis and that lysosomal thiol-proteinases were at least partially responsible for the degradation observed.
Copolymers were pinocytosed and partially degraded by the rat intestine cultured in vitro and were also translocated to a small extent across the tissue. Uptake and translocation were both inhibited at 15°C. Accumulation of copolymer by intestinal tissue increased with increasing copolymer size.
Following intravenous administration to rats, larger copolymer fractions were retained in the circulation and did not readily accumulate in any tissue. Copolymer crosslinks were stable in plasma.
The incorporation of a galactosamine side-chain into the copolymer resulted in rapid clearance of copolymer from the bloodstream and accumulation by the liver. Targeting of this copolymer to the liver was also achieved, at lower rates, following intraperitoneal and subcutaneous, but not following oral administration.
Both unmodified copolymer and copolymer containing galactosamine were virtually cleared from the body within 32 days.
Rat liver lysosomal enzymes were isolated and incubated with the different copolymers. The rate of crosslink cleavage was dependent on the length and/or structure of the oligopeptide
sequence.

Item Type: Thesis (Doctoral)
Subjects: Q Science > QH Natural history > QH301 Biology
Divisions: Faculty of Natural Sciences > School of Life Sciences
Depositing User: Lisa Bailey
Date Deposited: 06 Dec 2019 09:32
Last Modified: 06 Dec 2019 09:32
URI: https://eprints.keele.ac.uk/id/eprint/7339

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