Development of novel polymeric nanoparticles for pancreatic cancer therapy
type: CreativeWork
description: Pancreatic cancer sufferers are faced with a dire prognosis in part because no curative chemotherapy regimen exists. The first-line pancreatic cancer combination therapy of folinic acid, 5-fluorouracil, irinotecan and oxaliplatin (FOLFIRINOX) comes with significant toxicity and is only tolerable by some patients. Some improvement of the therapeutic index of existing chemotherapies may be achieved by encapsulation of chemotherapies inside nanoparticles (NPs) which have distinct physicochemical characteristics in comparison to free drugs. This enables a host of therapeutically relevant benefits such as avoidance of poorly tolerated solvents (e.g. Cremophor-EL in the case of paclitaxel), overcoming cellular drug efflux, improved pharmacokinetics and exploitation of the enhanced permeability and retention effect. Through these benefits several NPs are approved for use against pancreatic and other cancers. Despite this, there is great scope for improvement of their therapeutic properties in the second generation of nanomedicines. One area of interest is surface modification of the NPs with ligands of specific affinity to improve tumour specific localisation/internalisation and/or produce a therapeutically beneficial effect at the tumour. This concept is explored in the following thesis through conjugation of shark-derived immunoglobulin fragments known as Variable New Antigenic Receptors (VNARs) to the surface of polymeric NPs. This is a novel use of VNARs for which they have many advantageous properties including high physicochemical stability, small size, and low chemical complexity while still maintaining the ability to bind a diverse range of epitopes with high affinity. The possibility of multiple functional groups being available for targeting ligand conjugation is explored in the first chapter of this work. Polymers bearing vinyl sulfone or sulfonyl fluoride groups were obtained or synthesised, respectively. Both functional groups were incorporated within amphiphi…
abstract: Pancreatic cancer sufferers are faced with a dire prognosis in part because no curative chemotherapy regimen exists. The first-line pancreatic cancer combination therapy of folinic acid, 5-fluorouracil, irinotecan and oxaliplatin (FOLFIRINOX) comes with significant toxicity and is only tolerable by some patients. Some improvement of the therapeutic index of existing chemotherapies may be achieved by encapsulation of chemotherapies inside nanoparticles (NPs) which have distinct physicochemical characteristics in comparison to free drugs. This enables a host of therapeutically relevant benefits such as avoidance of poorly tolerated solvents (e.g. Cremophor-EL in the case of paclitaxel), overcoming cellular drug efflux, improved pharmacokinetics and exploitation of the enhanced permeability and retention effect. Through these benefits several NPs are approved for use against pancreatic and other cancers. Despite this, there is great scope for improvement of their therapeutic properties in the second generation of nanomedicines. One area of interest is surface modification of the NPs with ligands of specific affinity to improve tumour specific localisation/internalisation and/or produce a therapeutically beneficial effect at the tumour. This concept is explored in the following thesis through conjugation of shark-derived immunoglobulin fragments known as Variable New Antigenic Receptors (VNARs) to the surface of polymeric NPs. This is a novel use of VNARs for which they have many advantageous properties including high physicochemical stability, small size, and low chemical complexity while still maintaining the ability to bind a diverse range of epitopes with high affinity. The possibility of multiple functional groups being available for targeting ligand conjugation is explored in the first chapter of this work. Polymers bearing vinyl sulfone or sulfonyl fluoride groups were obtained or synthesised, respectively. Both functional groups were incorporated within amphiphi…
author: Leach, Adam
language: eng
keywords: Cancer, Pancreatic cancer, Nanoparticles, Nanomedicine, Bioconjugation, Antibodies, Variable New Antigen Receptors, Poly(lactic-co-glycolic) acid, Camptothecin, Delta-like ligand 4, Angiogenesis, Nanoparticle corona, Albumin, Secreted Protein Acidic and Rich in Cysteine
date published: 2021-7
date modified: 2026-07-24T03:55:25Z
provider: Queen's University Belfast
publisher: Networked Digital Library of Theses and Dissertations
type: WebPage
source organization: Queen's University Belfast