- Title
- Smart drug delivery system based on core-shell silica nanomaterials for prostate cancer
- Creator
- Tiburcius, Steffi
- Relation
- University of Newcastle Research Higher Degree Thesis
- Resource Type
- thesis
- Date
- 2022
- Description
- Research Doctorate - Doctor of Philosophy (PhD)
- Description
- Prostate cancer is the second most frequently diagnosed cancer in men and the fifth leading cause of death. Despite high morbidity associated with prostate cancer, only selected treatment options are available depending upon the progression of the disease. The most common therapies include hormone therapy, surgery, radiation, chemotherapy, phototherapy or immunotherapy. Among these treatment options, chemotherapy has been the mainstay of prostate cancer treatment especially during the advanced stages of metastatic prostate cancer. However, the use of chemotherapeutic drugs possesses serious challenges for the wider application of chemotherapy owing to the high cytotoxicity, poor absorption and non- specific mode of action. Thus, various nanostructured drug-delivery vehicles including liposomes, carbon nanotubes, dendrimers, polymeric nanoparticles and mesoporous silica nanoparticles have been widely studied for delivery of essential chemotherapeutics and increase the efficacy of the drugs. However, a low drug loading, poor ability to control size distribution of carriers, unpredictability of drug distribution, cytotoxicity and the difficulties to introduce targeting and imaging functionalities are some of their serious limitations. Moreover, a versatile platform that can load a high quantity of drug and is flexible for loading different types and combination of drugs in a single platform is highly desired to reduce the complexity of drug delivery systems. Therefore, the research and development on the design of novel drug delivery systems with simpler synthesis processes for creating uniformly sized nanoparticles that can load a large amount of different chemotherapeutic drugs with high efficiency and allow controlled drug release on the specific sites is desperately needed. The aim of this PhD project was to devise novel methods for the synthesis of advanced core- shell based mesoporous silica nanoparticles (MSN) with high specific surface area, large pore volume, tunable pore size and functionalised surface for drug-delivery applications. The advanced MSN nanostructures were used for loading different chemotherapeutic drugs with high efficiency and test their in-vitro cytotoxicity towards different prostate cancer cell lines to improve the status of the current treatment methods. The PhD Thesis also focuses on developing fundamental understanding of the various synthesis and processing parameters that tune the chemical and physical properties of MSN applicable in drug delivery systems. The deeper understanding of the structure-property correlation allowed the development of two completely new synthesis process as a part of this PhD thesis project. This thesis is divided into three chapters for fulfilling the goals of this PhD. The first chapter meticulously reviews the current state of the art on the use of silica-based nanoparticles for the treatment of prostate cancer. It critically analyses various types of silica nanoparticles that have been extensively used for the encapsulation and delivery of chemotherapy, immunotherapy and radiotherapy agents to successfully target and kill cancer cells without affecting the normal cells much. The critical analysis identifies the drawbacks of the current silica systems and gaps in current research that also serve as the motivation for the development of novel strategies and innovative ideas for development of new MSN based drug delivery system and form the backbone of the next two chapters. Chapter two is focused on the development of new method for the single-step synthesis and functionalisation of egg-yolk core-shell MSN with excellent textural properties, small and uniform particle size and extremely high drug loading capacity. This chapter proposes for the first time, the use of novel organic amines such as triethylamine and triethanolamine during the MSN synthesis that not only facilitates the development of a unique egg-yolk core-shell morphology in a single step but also decorates MSN surface with nitrogen functionalities. The uniform distribution of nitrogen accompanied by large volume from the unique structure aided in increasing the drug loading and release capacity of the optimised samples. These particles were used to deliver doxorubicin to the prostate cancer cells and illustrated promising results with high cytotoxicity towards the cancer cells owing to its rapid internalisation and delivery of the chemotherapeutic drugs. Chapter three gives details about the development of another new procedure for the synthesis of core-shell MSN using a triple surfactant system to increase surface area while limiting the particle size. The use of triple surfactant combination in this study is reported for the first time and led to the development of particles with the highest reported surface areas among several known types of MSN. The high surface area and unique size and morphological features allowed these particles to load both hydrophilic and hydrophobic drugs on its surface using model drugs, Doxorubicin and Docetaxel. Our study shows that the optimised particles not only demonstrated high drug loading and release profile, but also showed high biocompatibility when used without the drugs. The smaller size achieved for core-shell particles allowed their rapid uptake inside the cells within 12 h that translated in showing high cytotoxicity from both the drugs in two different prostate cancer cell lines. The findings of the study can be directly utilised to analyse the in vivo efficacy of these materials. Overall, this thesis reported the development two new and innovative methods for the synthesis of core shell MSN as drug delivery vehicles. These single step process and ease of synthesis suggest that the synthesis methods can be easily scaled up and can be effectively used in in vivo applications. The high biocompatibility, drug loading, and biocompatibility of the system together with excellent drug loading and release characteristics make these particles a versatile nanomaterial for large scale drug delivery application.
- Subject
- drug delivery; prostate cancer; mesoporous silica nanomaterials; thesis by publication
- Identifier
- http://hdl.handle.net/1959.13/1483273
- Identifier
- uon:51088
- Rights
- Copyright 2022 Steffi Tiburcius
- Language
- eng
- Full Text
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| Thumbnail | File | Description | Size | Format | |||
|---|---|---|---|---|---|---|---|
| View Details Download | ATTACHMENT01 | Thesis | 10 MB | Adobe Acrobat PDF | View Details Download | ||
| View Details Download | ATTACHMENT02 | Abstract | 234 KB | Adobe Acrobat PDF | View Details Download |