- Title
- Multifunctional nanomedicines based on albumin for targeted breast cancer therapy
- Creator
- Heravi Shargh, Vahid
- Relation
- University of Newcastle Research Higher Degree Thesis
- Resource Type
- thesis
- Date
- 2017
- Description
- Research Doctorate - Doctor of Philosophy (PhD)
- Description
- Albumin can promote intratumoural drug accumulation and uptake due to its interaction with albumin-binding proteins in tumour microenvironment, therefore albumin has emerged as an attractive drug carrier for cancer diagnosis and treatment. Tropomyosin receptor kinase A (TrkA) is regarded as one of the potential therapeutic targets in oncology and, in breast cancer, is associated with the stimulation of tumour growth and metastasis. By taking advantage of these two perspectives, in this project, we have developed novel albumin-based nanoparticles (NPs) to enable targeted delivery of TrkA inhibitors for breast cancer therapy. In the first part of this project, novel albumin hybrid NPs (Alb-HNPs) loaded with a selective TrkA inhibitor GNF-5837 were prepared and evaluated for antineoplastic efficacy in a panel of breast cancer cell lines. The nanomedicines (GNF-Alb-HNPs) were formed through a unique polyelectrolyte complexation process where albumin and GNF-5837 were encapsulated by a stabilising layer of oppositely charged chitosan and dextran sulphate polysaccharides. GNF-Alb-HNPs showed a particle size of ∼150 nm and excellent colloidal stability, which makes them ideal for passive targeting to tumours through the enhanced permeability and retention (EPR) effect. GNF-Alb-HNPs were shown to specifically inhibit TrkA phosphorylation and downstream mitogen-activated protein kinase (MAPK) signalling in MDA-MB-231 breast cancer cells, resulting in anti-proliferative and pro-apoptotic effects. Compared with the free GNF-5837, the GNF-Alb-HNPs not only exhibited an enhanced anti-proliferative and anti-invasive effects but also significantly increased the apoptosis of cancer cells. In the second part of this project, we aimed to develop on-demand Alb-HNPs that can respond to the tumour microenvironment and facilitate deep tumour penetration. Gelatine-albumin hybrid NPs (Gel-Alb HNPs) were developed for the delivery of the TrkA inhibitor GNF-5837, where the overexpression of matrix metalloproteinase (MMP) enzymes in the tumour can trigger site-specific release of the small drug-bound albumins for efficient uptake by cancer cells. The nanomedicines (Gel-Alb-GNF HNPs) were prepared using a pH-controlled complexation process from the pre-synthesised cationic gelatine, dextran sulphate and albumin-bound GNF-5837. Gel-Alb-GNF HNPs had a particle size of ~130 nm with narrow size distribution (polydispersity index: 0.15). They displayed excellent colloidal stability but disassembled in the presence of MMP-2 which is elevated in the extracellular matrix of tumours and can degrade cationic gelatine. Gel-Alb-GNF HNPs were shown to significantly inhibit malignant TrkA phosphorylation and downstream MAPK or Akt signalling in breast cancer cells but markedly increased their caspase-dependant apoptosis. Moreover, the migration and invasion activities of cancer cells were dramatically suppressed and the inhibitory effects were more prominent with Gel-Alb-GNF HNPS than the GNF-Alb-HNPs. Overall, results suggest that both Alb-HNPs and Gel-Alb HNPs are able to markedly improve the efficacy and specificity of encapsulated TrkA inhibitor GNF-5837 for breast cancer therapy. As TrkA receptor has been implicated in chemosensitisation as well as neuropathic pain, it is anticipated that these novel therapeutic approaches will be adaptable for the treatment of chemotherapy resistance and cancer associated pain.
- Subject
- TrkA inhibitor; breast cancer; targeted delivery; thesis by publication; hybrid nanoparticles; matrix metalloproteinase; albumin hybrid nanoparticles; targeted therapy; antibody conjugation; cancer therapy; multifunctional nanoparticles; nanomedicines
- Identifier
- http://hdl.handle.net/1959.13/1337710
- Identifier
- uon:27891
- Rights
- Copyright 2017 Vahid Heravi Shargh
- Language
- eng
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| Thumbnail | File | Description | Size | Format | |||
|---|---|---|---|---|---|---|---|
| View Details Download | ATTACHMENT01 | Thesis | 5 MB | Adobe Acrobat PDF | View Details Download | ||
| View Details Download | ATTACHMENT02 | Abstract | 558 KB | Adobe Acrobat PDF | View Details Download |