- Title
- Mesoporous silica nanoparticles with 3D porous structures for biomedical applications
- Creator
- Trinh, Hoang Trung
- Relation
- University of Newcastle Research Higher Degree Thesis
- Resource Type
- thesis
- Date
- 2022
- Description
- Research Doctorate - Doctor of Philosophy (PhD)
- Description
- Porous materials are technologically important materials that find widespread use in applications ranging from catalysis and gas adsorption to water purification and drug delivery. Among different porous materials, mesoporous silica-based materials are ubiquitous in all technologically advanced applications. These materials demonstrate excellent features such as a high surface area with tunable pore size, large pore volume and tunable pore geometry (1D to 3D) and most importantly, an ordered structural arrangement of the pores. Researchers across the globe are working on tuning these properties of the mesoporous silica-based materials along with modifying their morphology for advanced drugs, proteins, genes and metal ion delivery applications. It is known in the literature that the textural properties play a major role in improving the adsorption and delivery of ions and materials in these applications; however, the role of pore geometry in controlling the materials adsorption and release from the mesoporous silica materials, especially in drug delivery is not well explored as only limited studies on their comparison in applications such as chemotherapy and antimicrobial applications are available. Thus, this thesis aimed to synthesise silica-based materials with a 3D porous structure and explore their utility for two different and challenging applications in drug and metal ion delivery. To achieve the aims, this thesis is divided into three chapters that have been published or submitted for publication. The first aim of this project was to fabricate novel spherical mesoporous silica with 3D porous structure containing large cage-like pores for encapsulation and release of a hydrophobic drug, dacarbazine (DTIC), for the treatment of skin cancer (melanoma). Skin cancer is characterised by the uncontrolled growth of abnormal cells in the skin. Among the three main types of skin cancers, melanoma is considered as the most dangerous skin cancer type owing to its high mortality rate. The highest number of skin cancer cases in the world is recorded in Australia, and hence it is vital to address skin cancer and develop novel therapies to reduce mortality and improve the long-term survival rate of the Australian population. Chemotherapy has been used as one of the most prioritised therapy for melanoma treatment. However, it has been demoted to secondary therapy mostly due to the severe side effects and poor therapeutic outcomes caused by the lack of agents to safely deliver the chemotherapeutic drugs directly to the tumour site instead of travelling through all of the body with the bloodstream. The discovery of drug delivery systems, especially the drug carriers at the nano scale, is regarded as the exact solution to help chemotherapy drugs overcome their drawbacks and make them useful for treating various cancers, including melanoma Chapter 1 of this thesis is dedicated to reviewing the field of porous silica-based drug delivery materials for skin cancer treatment. It critically analysed popular therapies for melanoma treatment such as chemotherapy, immunotherapy, targeted therapy and radiotherapy that are facilitated by silica-based drug carriers in a positive way. The critical analysis also identifies the drawbacks of the current silica systems in each therapy and then suggests the future development and the great potential of silica nanoparticles as drug carriers not only in drug delivery of chemotherapeutic drugs but also as a versatile material covering other fields of medical applications. Based on a thorough literature review published as a part of this thesis, it is found that DTIC, is the only FDA-approved drug for the treatment of melanoma; however, its direct administration to patients is accompanied by major side effects. Despite several trials for delivering DTIC using various porous materials including lipids, polymers and 2D mesoporous silica nanomaterials (MSN), the low drug loading achieved in these materials has hampered their use and further application as a drug delivery material for treatment of melanoma. In Chapter 2, we hypothesised that the large 3D cage-like pores of MSN can not only enhance the drug loading of 3D drug molecules, but the interconnected porosity can also control its sustained release from the MSN. Thus in this study, 3D porous MSNs were synthesised with spherical morphology and less than 250 nm size for loading and controlled release of the DTIC. To achieve this unique structure with spherical morphology and small particle sizes, a novel combination of three surfactants (pluronic (P-127), fluorocarbon (FC- 4)and cetyltriethyl ammoniumbromide (CTEABr)) with a unique synthesis process wasestablished as a part of this thesis. This combination has never been reported for the synthesis of spherical mesoporous silica for drug delivery applications and is a unique contribution of this thesis to the research community. The high surface area of 825 m2/g and a large pore volume ~0.9 cm3/g of the spherical 3D porous structure of MSN helped in achieving the highest reported encapsulation of DTIC in MSN with more than 23% drug loading capacity. The sustained release of up to 60% within 48 h in an acidic medium facilitated high cytotoxicity of the drug released from the MSN on the B16-F10 cancer cells as compared to the direct DTIC treatment. Together, these results indicated a high potential for spherical 3D mesoporous MSNs as a novel drug delivery material and can be extended for encapsulation and release of multiple drugs for the treatment of various cancers. Chapter 3: Mesoporous silica-based materials have also become a substitute for calcium and magnesium silicate-based biomaterials for bone regeneration. MSNs have been shown to be incorporated into the musculoskeletal system to support bone tissue regeneration by promoting osteoinduction, osteoconduction and osteointegration, similar to the popular bioceramics-based bone scaffold materials and supporting rapid bone healing. However, the induction of severe immune reaction to the artificial scaffold-based bone regenerating material has been the Achilles heel of most bone replacement materials. Moreover, the surgical implantation of these materials also results in bacterial infections that further exacerbate the inflammatory reaction. Thus, porous silica-based nanomaterials loaded with antibiotics and anti-inflammatory materials have been explored for promoting bone regeneration. Previous work has reported the role of zinc-loaded mesoporous silica-based materials as antimicrobial materials that have the potential to act as bone regeneration materials. However, most of these reports were focused either only on the antimicrobial properties or the bone regeneration promoted by the zinc ions released from mesoporous silica materials. Thus, another aim of this thesis was to study the effect role pore size, pore geometry, and structural order on the zinc loading and release kinetics of mesoporous silica and how it affects the osteogenic activity of mesoporous silica materials while retaining its antimicrobial activity. At first, the effect of zinc loading on the textural properties of two different mesoporous silica materials – SBA-1 having a high surface area of 956 m2/g and a 3D porous structure with a small pore size ~ 2 nm, and SBA-15 having a smaller surface area of 490 m2/g and 2D pore structure and large pore size ~11 nm, was evaluated. At the same zinc loading, the 3D porous SBA-1 showed lower antimicrobial activity as compared to 2D SBA-15 materials due to the slower release of zinc from the SBA-1. However, the osteogenic activity showed that higher zinc release from SBA-15 was toxic to avianized bone marrow- derived stromal cells. In contrast, the slower zinc release kinetics of SBA-1 resulted in a better cyto-compatibility. It was also noted that both SBA-15 and SBA-1 could promote osteogenic differentiation of the TVA-BMSC that is promoted further by incorporation of zinc. Taken together, these results indicated a huge role of pore size, pore geometry and structural order in imparting better osteogenic activity and high antimicrobial activity. Overall, this thesis emphasises the role that mesoporous silica materials with a 3D ordered porous structure can play in the development of technologically advanced applications such as drug delivery and bone regenerative materials. Scientifically, it provides 2 major contributions to the field of mesoporous silica 1) Synthesis of spherical MSN with a 3D pore structure using triple-surfactant assisted methodology capable of loading a large amount of drug while ensuring a sustained release and 2) Elucidation of the role pf pore structure, pore size and pore geometry in controlling the loading and release of zinc to impart antimicrobial and osteogenic activity. Owing to the versatile, biocompatible, and degradable nature of mesoporous silica, it has been deemed safe for the human body, and these results will push the development of mesoporous materials further. Overall, a deeper understanding of different kinds of 3d-porous MSNs and their properties and more and wider application potential of these materials will facilitate their translation in various fields of medical treatment.
- Subject
- silica nanoparticle; mesoporous silica; skin cancer; drug delivery; melanoma
- Identifier
- http://hdl.handle.net/1959.13/1506979
- Identifier
- uon:55942
- Rights
- Copyright 2022 Hoang Trung Trinh. This thesis is under embargo and will be released 12.10.2024
- Language
- eng
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