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Title: Developing a theranostic silica nanoparticle for fluorescent imaging and therapy of colorectal cancer
Author: Sulaiman Khaled, Yazan
ISNI:       0000 0004 9357 933X
Awarding Body: University of Leeds
Current Institution: University of Leeds
Date of Award: 2020
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Background: Treatment of colorectal cancer (CRC) fails in 50% of cases, as evidenced by cancer deaths, and treatment itself can be associated with substantial morbidity and mortality. Residual micro-metastases are associated with increased risk of relapse while developing targeted strategies to treat advanced stages remains a clinical need. Laparoscopic resection of colorectal cancers has gained wide acceptance amongst surgeons and the platform for using fluorescent guided surgery has become appealing. The development of theranostic nanoparticles as a dye and drug delivery system is a promising strategy for colorectal cancer imaging and therapy. Carcinoembryonic antigen (CEA) can be utilised for the development of CEA-targeted nanotechnologies since it is overexpressed in most colorectal cancers. Targeted fluorescent imaging and therapy of primary colorectal tumours and lymph node metastases would aid stratification of the radicality of surgical resections and eradication of residual tumour cells. I aimed to develop a theranostic nanoparticle to facilitate fluorescent imaging and therapy of colorectal cancer. Methods: Affimers, non-antibody binding proteins, against carcinoembryonic antigen (CEA) were expressed and purified to be used as targeting bioreceptors. Dye-doped (NIR664) and photosensitiser-encapsulated (Foslip) silica nanoparticles were fabricated using a water-in-oil microemulsion technique. Anti-CEA or control Affimers were conjugated to nanoparticles using different chemical linkage strategies. CEA-specific fluorescent imaging and photodynamic cytotoxicity of functionalised nanoparticles was quantified in colorectal cancer cells in vitro. LS174T murine xenograft animal model was used to assess the binding specificity of the particles in vivo. Results: Anti-CEA Affimer functionalised silica nanoparticles exhibited CEA-specific fluorescence in three colorectal cancer cell lines (p < 0.0001) when compared to control particles. Cellular uptake of CEA-targeted nanoparticles was time and dose dependent. Following photo-irradiation after treatment with Foslip containing nanoparticles, significant cell death rate was observed in LoVo (70%), LS174T (80%) and HCT116 (65%) when compared to HEK293 (0%); p < 0.0001 via ROS generation. In LS174T xenografts, fluorescence in the CEA-targeted tumours was significantly greater than controls from 6 to 48 h (p < 0.0001) in 6 mice. Conclusions: Anti-CEA Affimer functionalised nanoparticles allow CEA-specific imaging and photodynamic therapy of colorectal cancer cells and have the potential to be used as an intra-operative theranostic probe. This is the first study to demonstrate live tumour-specific fluorescent imaging of colorectal cancer using Affimer -targeted nanoparticle in vivo.
Supervisor: Jayne, David ; Millner, Paul ; Hughes, Thomas Sponsor: MRC
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available