Browsing by Subject "Drug Delivery"
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Item Chemistry and Applications of Metal-Organic Materials(2012-02-14) Zhao, DanDeveloping the synthetic control required for the intentional 3-D arrangement of atoms remains a holy grail in crystal engineering and materials chemistry. The explosive development of metal-organic materials in recent decades has shed light on the above problem. Their properties can be tuned by varying the organic and/or inorganic building units. In addition, their crystallinity makes it possible to determine their structures via the X-ray diffraction method. This dissertation will focus on the chemistry and applications of two kinds of metal-organic materials, namely, metal-organic frameworks (MOFs) and metal-organic polyhedra (MOP). MOFs are coordination polymers. Their permanent porosity makes them a good ?gas sponge?. In the first section, an isoreticular series of MOFs with dendritic hexacarboxylate ligands has been synthesized and characterized structurally. One of the MOFs in this series, PCN-68, has a Langmuir surface area as high as 6033 m2 g-1. The MOFs also possess excellent gas (H2, CH4, and CO2) adsorption capacity. In the second section, a NbO-type MOF, PCN-46, was constructed based on a polyyne-coupled di-isophthalate linker formed in situ. Its lasting porosity was confirmed by N2 adsorption isotherm, and its H2, CH4 and CO2 adsorption capacity was examined at 77 K and 298 K over a wide pressure range (0-110 bar). Unlike MOFs, MOP are discrete porous coordination nanocages. In the third section, a MOP covered with bulky triisopropylsilyl group was synthesized, which exhibits a thermosensitive gate opening property. This material demonstrates a molecular sieving effect at a certain temperature range, which could be used for gas separation purpose. In the last section, a MOP covered with alkyne group was synthesized through kinetic control. The postsynthetic modification via click reaction with azide-terminated polyethylene glycol turned them into metallomicelles, which showed controlled release of an anticancer drug 5-fluorouracil. In summary, two kinds of metal-organic materials have been discussed in this dissertation, with the applications in gas storage, gas separation, and drug delivery. These findings greatly enrich the chemistry and applications of metal-organic materials.Item Design, synthesis, and evaluation of dendrimers based on melamine as drug delivery vehicles(2009-05-15) Lim, Jong DooA variety of dendrimers based on melamine are designed, synthesized, and evaluated for drug delivery systems. The synthesis of a dendrimer, including multiple copies of four orthogonally reactive groups, is described. The three groups on the surface are nucleophilic and include four free hydroxyl groups, four tert-butyldiphenylsilyl (TBDPS) ether groups, and sixteen amines masked as tert-butoxycarbonyl (BOC) groups. The core of the dendrimer displays two electrophilic monochlorotriazines. The dendrimer above is further manipulated for in vivo biodistribution: incorporation of the reporting groups Bolton-Hunter and DOTA (1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid); PEGylation for biocompatibility and size tuning. In preliminary biodistribution studies, dendrimers circulate in the blood for a longer time as the molecular weight increases, which is important to passively target tumor tissues via the EPR effect. Also, high uptake by the tumor tissues was observed in mice bearing prostate cancer xenografts. A drug delivery vehicle for the anticancer agent paclitaxel is described. This drug delivery vehicle contains sixteen molecules of paclitaxel via acid-labile ester linkage, two Bolton-Hunter groups, and sixteen monochlorotriazine groups for PEGylation. The in vitro drug release studies shows faster release of paclitaxel at lower pH in PBS.Item Effect of shape on cell internalization of polymeric hydrogel nanoparticles(2013-05) Agarwal, Rachit, Ph. D.; Roy, KrishnenduRecent progress in drug discovery has enabled us to target specific intracellular molecules to achieve therapeutic effects. These next generation therapeutics are often biologics which cannot enter cells by mere diffusion. Therefore it is imperative that drug carriers are efficiently internalized by cells before releasing their cargo. Nanoscale polymeric carriers are particularly suitable for such intra-cellular delivery. Although size and surface-charge has been the most studied parameters for nanocarriers, it is now well appreciated that particle shape also plays a critical role in their transport across physiological barriers. Hence there is increasing interest in fabricating shape-specific polymeric nano and microparticles for efficient delivery of drugs and imaging agents. Nanoimprint lithography methods, such as Jet-and-flash imprint lithography (J-FIL), provide versatile top-down processes to fabricate shape-specific, biocompatible nanoscale hydrogels that can deliver therapeutic and diagnostic molecules in response to disease-specific cues. However, the key challenges in top-down fabrication of such nanocarriers are scalable imprinting with biological and biocompatible materials, ease of particle-surface modification using both aqueous and organic chemistry as well as simple yet biocompatible harvesting. Here we report that a biopolymer-based sacrificial release layer in combination with improved nanocarrier-material formulation can address these challenges. The sacrificial layer improves scalability and ease of imprint-surface modification due to its switchable solubility through simple ion exchange between monovalent and divalent cations. This process enables large-scale bio-nanoimprinting and efficient, one-step harvesting of hydrogel nanoparticles in both water- and organic-based imprint solutions. We also show that when shape is decoupled from volume, charge and composition, mammalian cells preferentially internalize disc-shaped nanohydrogels of higher aspect ratios over nanorods. Interestingly, unlike nanospheres, larger-sized hydrogel nanodiscs and nanorods are internalized more efficiently. Uptake kinetics, efficiency and internalization mechanisms are all shape-dependent and cell-type specific. Although macropinocytosis is used by all cells, epithelial cells uniquely internalize nanodiscs using caveolae pathway. On the other hand, endothelial cells use clathrin-mediated uptake along with macropinocytosis for all shapes and show significantly higher uptake efficiency compared to epithelial cells. We also study the effect of shape and surface properties for their tissue uptake and penetration using spheroids as a 3D tumor model and show that hydrophobic particles show no difference in penetration inside such models even after 125 fold reduction in volume. These results provide a fundamental understanding of how cell and tissue behavior is influenced by nanoscale shape and surface properties and are critical for designing improved nanocarriers and predicting nanomaterial toxicity.Item Functionalized Zirconium Phosphate Nano Platelets - From Surface Design to Drug Delivery(2014-05-30) Mukherjee, AtashiThe chemical characterization of nanomaterials in the realm of drug delivery and surface modification is on the current frontiers of analytical chemistry. A drug delivery vehicle must be able to carry therapeutic cargo and be able to reach the intended target or compartment. This dissertation will focus on the analytical characterization of zirconium phosphate (ZrP) in both alpha and theta phases as a drug delivery matrix utilizing multiple unique and novel analytical techniques. In the first area we present for the first time, a methodology for the characterization of individual drug loaded 150 nm ZrP nanoparticles (NPs) by obtaining molecular information from single massive cluster impacts. The clusters used in this secondary ion mass spectrometry (SIMS) technique are Au_(400)^(4+) and C_(60)^(+/2+). The ionized ejecta from each impact are recorded individually which identifies ions emitted from a surface volume of ~10 nm in diameter and 5-10 nm in depth. The mode of analyzing ejecta individually from each single cluster impact gives insight into chemical homogeneity within nanodomains. The in vitro biological release profile was investigated in simulated biological environment for the drug-ZrP nanocomposites. The release profiles reveal a direct dependency with the pH of the medium for the release of the complexes indicating targeting opportunities. Additionally the NP matrix breaks down in the artificial lysosomal fluid medium at pH ? 4.5 indicating good bio-clearance possibilities, a major issue that plagues several alternative drug delivery carriers. This project is expected to give rise to a facile drug delivery matrix that is highly biocompatible and leads to greater targeted gentoxicity for cancerous cells. The second area of research presented in this dissertation investigates the surface modification of 150 nm ?-ZrP NPs utilizing a host of different organo modifiers. ?-ZrP was surface modified by reacting surface P-OH groups with 3-(triethoxysilyl)propyl isocyanate(TEPI), dichloromethyl(phenyl)silane(DCMPS) and lauryl methacrylate(LMA). SIMS in the event-by-event bombardment detection mode was utilized to calculate the degree of surface coverage for a brand new platform in conjunction with TGA, FTIR and XRPD to detail the surface confinement of the molecular assemblies. New discoveries continue to be made by creative scientists? everyday pushing what we know about inorganic layered materials and the analytical chemistry that drives this field.