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Title: Enzyme responsive nanomaterials for cancer applications
Author: Kalafatovic, Daniela
ISNI:       0000 0004 5347 404X
Awarding Body: University of Strathclyde
Current Institution: University of Strathclyde
Date of Award: 2014
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Expression levels of enzymes dictate the difference between health and disease in many cases, including cancer. This leads scientists to explore strategies to incorporate enzyme sensitivity in materials where the goal is to achieve dynamic and targeted changes in material properties to influence cancer cells. Peptide amphiphiles were designed (PhAc-FFAGLDD (1a) and GFFLGLDD (2a) and their expected products of enzyme cleavage PhAc-FFAG (1b) and GFFLG (2b)) such that, upon cleavage by a disease-associated enzyme, reconfigure from micellar aggregates to fibres. After the designed peptides (1a, 1b, 2a, 2b) were shown to be suitable for controlling the morphology of the supramolecular aggregates based on peptide length, hydrophobicity and charge, the enzyme triggered micelle to fibre transition was explored. Following this it was investigated whether the micelles were capable to perform as mobile vehicles for encapsulation and release of hydrophobic drugs. It was observed that the assembled fibres provide a scaffold for prolonged drug delivery due to the partial entrapment (localised depots) of the drug and the intrinsic biodegradable nature of peptide carriers themselves. The capacity of retention of doxorubicin in the hydrophobic core of the micelles followed by its entrapment in the fibres was exploited in the development of a method for visualisation of fibre formation around cancer cells. In vitro studies were performed on human cancer cell lines using different types of microscopy. MMP-9 activity was quantified in the mentioned cancer cell lines. In addition, preliminary toxicity studies of the designed peptides to cancer cells were performed. Being purely peptidic (compared to conventional aromatic or aliphatic peptide amphiphiles), these systems have the advantage of being non toxic to cells and can be used as carriers for doxorubicin in vivo. They are currently tested on animal models where the cancer growth is slowed down by administration of doxorubicin loaded peptides compared to doxorubicin only. Another, complementary system was investigated based on crosslinked polymer particles- microgels as a possible way to obtain enzyme responsive materials. Amine rich microgels, poly(VAM-co-BEVAME) were synthesised and functionalised post-polymerisation with peptides. Due to aggregation issues these systems were not further explored for biomedical applications.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available