Bioresponsive polymer-protection conjugates as a unimolecular drug delivery system

Gilbert, Helena Rosalind Petra 2007. Bioresponsive polymer-protection conjugates as a unimolecular drug delivery system. PhD Thesis, Cardiff University.

Preview

PDF - Accepted Post-Print Version Download (35MB) | Preview

Abstract

PEGylation has become very popular for the generation of nanomedicines with improved protein delivery properties, despite its lack of biodegradability. Researchers usually try to maximise retained protein activity during PEGylation. However, this proof of principle study aimed to create an inactive peptide or enzyme product, using a biodegradable polymer, that would elicit minimal activity/non-specific toxicity on administration. Following triggered site-specific degradation of the polymer, the hypothesis was that protein activity could be slowly regenerated in the general circulation or localised to a specific target site. Model conjugates were synthesised by coupling dextrin degraded by amylase to trypsin and melanocyte stimulating hormone MSH, to test this concept and targeted delivery for both an enzyme and a receptor-binding ligand. Hyaluronic acid HA degraded by hyaluronidase conjugates of trypsin and ribonuclease A were also synthesised. The latter was intended to develop the possibility of designing novel anti cancer conjugates. A higher molecular weight dextrin 47,200 g/mol, 26 mol succinoylation was shown to best mask 34 trypsin activity and reinstate 58 of the activity by addition of amylase. When a HA fraction molecular weight 130,000 g/mol was prepared by acid hydrolysis and conjugated to trypsin 4 w/w, trypsin activity was masked to 6 and immediately re-instated to 24 on addition of hyaluronidase. Similarly, the dextrin-MSH conjugate reduced melanin production to 11 of the control and only restored to 33 on addition of amylase. RNase A alone was not cytotoxic up to 1 mg/mL, whereas, the HA-RNase A conjugate 0.1 mg/mL RNase A equivalent was cytotoxic in B16F10 and CV-1 cells 72 h. This work provides proof of principle for the concept of using biodegradable polymers to mask and reinstate conjugated protein activity in the presence of the appropriate enzyme 'unmasking' trigger.

Item Type:	Thesis (PhD)
Status:	Unpublished
Schools:	Pharmacy
Subjects:	R Medicine > RM Therapeutics. Pharmacology
ISBN:	9781303182129
Funders:	BBRSC
Date of First Compliant Deposit:	30 March 2016
Last Modified:	20 Sep 2024 14:59
URI:	https://orca.cardiff.ac.uk/id/eprint/55685

Citation Data

Actions (repository staff only)

Edit Item