In the past ten years, mesoporous silica nanoparticles have been some of the hottest materials investigated for biomedical use. Mesoporous silica nanoparticles are size-controllable and discrete particles with high surface area, large pore volume, and easy surface modification properties. These unique characteristics make mesoporous silica nanoparticles promising for biological applications. Although there is extensive literature precedent for the synthesis and applications of mesoporous silica nanoparticles, there are several critical issues resulting in limited use of multifunctional mesoporous silica nanoparticles in vitro or in vivo. For example, the large particle size (> 100-nm-diameter) and poor particle stability (aggregation) result in rapid uptake by the reticuloendothelial system, a portion of immune system which removes the nanoparticles from circulation before they reach their tumor target. Another hurdle is the possible unintentional toxicity of such nanoparticles. If the designed mesoporous silica nanoparticles cause unintentional damage to benign cells or healthy tissue and organs, their use will be greatly limited in therapeutic applications. Prior to in vivo animal experiments, unintentional cytotoxicity must be minimized and well studied. Based on the critical considerations described above, an ideal mesoporous therapeutic should possess the following characteristics prior to in vivo studies: (1) small size (<50 nm); (2) high surface area; (3) high stability; and (4) minimal unintentional cytotoxicity.
Chapter One reviews the development and use of mesoporous silica nanoparticles for biomedical use. Various components have been incorporated into mesoporus silica nanoparticles to yield various functionalities, like controlled drug release, targeting, and multimodal imaging for diagnosis. With more and more complex designs for mesoporous silica nanoparticles, practical considerations for in vivo use must be taken into account.
Chapter Two describes our novel method to synthesize highly stable, redispersible, and small mesoporous silica nanotherapeutics. This chapter discusses the particle stability of bare and modified mesoporous silica in various biological media. Critical synthetic parameters including introduction of hydrophilic and hydrophobic organosilanes and hydrothermal treatment are key to synthesize ultrastable and redispersible mesoporous silica nanoparticles. Chapter Three examines the cytotoxicity of mesoporous silica nanoparticles to human RBCs, mouse mast cells, and human endothelial cells using (1) a hemolysis assay, (2) an electrochemical assay of cell function and (3) a microfluidic device. The experimental results reveal that mesoporous silica nanoparticles have lower adverse effects on RBCs and mast cells than their similarly sized nonporous counterparts. In addition, shear stress effects on the cytotoxicity of unmodified mesoporous silica will be discussed.
In Chapter Four, a novel one-pot synthesis route was developed to fabricate size-tunable multifunctional mesoporous silica nanoparticles. Based on the experience from improving bare mesoporous silica stability, the hydrothermally assisted organosilane modification method was applied to improve the particle stability, T2 relaxivity stability, and acid resistance of magnetic mesoporous silica nanoparticles.
In the last part of my research work, Chapter Five investigates cytotoxicity of new carbon nanomaterials, graphene oxide and graphene in human erythrocytes and skin fibroblasts. The cytotoxicity results show that the physico-chemical properties, including the particle size, exfoliation extent, oxygen content, and aggregation state of graphene oxide and graphene greatly influence their cytotoxicity. This collaborative work also inspired me to consider a possible future direction involving the incorporation of graphene oxide or graphene into mesoporous silica nanoparticles to control drug release via a heat-driven route.
To conclude, Chapter Six reviews my thesis work and highlights the advances I have made in the fields of nanomedicine and nanotoxicity. In addition, possible future directions are also described.
University of Minnesota Ph.D. dissertation. April 2012. Major: Chemistry. Advisor: Christy L. Haynes. 1 computer file (PDF); xviii, 203 pages, appendix p. 198-203.
Critical considerations in development of mesoporous silica nanoparticles for biological applications..
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