Neurotensin: a candidate for peptide-guided drug delivery

Bird, Joanna (2015) Neurotensin: a candidate for peptide-guided drug delivery. MRes thesis, University of Lincoln.

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Abstract

Modern pharmacotherapy, especially with regards to the treatment of cancer, has been faced
with one major obstacle for many years: poor drug specificity. The use of many biotherapeutic/chemotherapeutic
drugs for the treatment of cancer is largely dose-limited due to
their highly toxic nature and largely unspecific mode of action, causing 'off target' drug
interactions, inadequate drug concentrations at 'on target' areas and poor patient compliance
due to the necessity to receive large amounts of a drug that hinder quality of life. Currently
available research into the development of recombinant biotherapeutic drugs, targeted to specific
ligand receptors, has presented a new mode of drug delivery, which could potentially avoid these
problems – drug delivery selective to the tissue of choice with minimal damage to physiologically
normal cells. Neurotensin (NT) is a tridecapeptide known to exert a variety of effects on the
human body; it has a dual role as both a neuromodulator in the central nervous system and as a
local hormone in the periphery. The actions of neurotensin are mediated by specific interactions
with one of three neurotensin receptors: NTS1, NTS2 and NTS3, all of which are known to
internalise upon interaction with neurotensin. NTS1 in particular is thought to play the biggest
role in eliciting the actions of neurotensin and is the main focus of this study; as NTS1 is known to
be up regulated in a variety of different cancer types, including pancreatic and breast tumours, it
could potentially serve as a target for neurotensin-mediated drug-delivery.
The data presented in this study characterises the extent of expression of NTS1 in both polarised
and non-polarised Caco-2, and HEK293 cell lines. The uptake and transport of two NT-conjugated
fluorophores (GFP and fluorescein) were compared to evaluate the affect of cargo size on cellular
uptake. Investigation into uptake and transport of the two fluorophores, elicited by neurotensin,
showed both to be internalised in a receptor mediated fashion with the smaller of the two
(fluorescein) exhibiting internalisation and transport to a greater extent than the larger (GFP).
Visualisation by confocal microscopy showed fluorophore localisation close to the nucleus of the
cell.
From a more general perspective, this work aims to elucidate the potential for neurotensin to
be employed to enhance the delivery of bio-therapeutics to treat 'difficult' cancers, such as
pancreatic cancer, which is notorious for poor survival rates and is known to overexpress
receptors for neurotensin. If successful, neurotensin-conjugation of bio-therapeutics could
improve survival rates by lowering necessary dosages and increasing cancer cell specificity.

Keywords:Drug delivery
Subjects:B Subjects allied to Medicine > B200 Pharmacology, Toxicology and Pharmacy
Divisions:College of Science > School of Life Sciences
ID Code:23700
Deposited On:24 Aug 2016 11:44

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