Thesis (Ph. D.)--Dept. of Chemistry and School of Computing and Engineering. University of Missouri--Kansas City, 2004. / "A dissertation in chemistry and software architecture." Advisor: Yan-Ching Jean. Typescript. Vita. Description based on contents viewed Feb. 27, 2006; title from "catalog record" of the print edition. Includes bibliographical references (leaves 205-218). Online version of the print edition.

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Doctor of Philosophy / Department of Chemistry / Stefan Bossmann / A novel type of supramolecular aggregate, named "nanosponge" was synthesized through the interaction of novel supramolecular building blocks with trigonal geometry. The cholesterol-(K/D)[subscript n]DEVDGC)₃-trimaleimide unit consists of a trigonal maleimide linker to which homopeptides (either K or D) of variable lengths (n = 5, 10, 15, 20) and a consensus sequence for executioner caspases (DEVDGC) are added via Michael addition. Upon mixing in aqueous buffer, cholesterol-(K)[subscript n]DEVDGC)₃-trimaleimides, as well as a 1:1 mixture of cholesterol-(K/D)[subscript n]DEVDGC)₃-trimaleimides form stable nanosponges, whereas cholesterol-(D)[subscript n]DEVDGC)₃-trimaleimide is unable to form supramolecular aggregates by itself. The structure of the novel nanosponges was revealed through explicit solvent and then coarse-grained molecular dynamics (MD) simulations. The nanosponges are between 80nm and several micrometers in diameters and virtually non-toxic to monocyte/macrophage-like cells. Furthermore, the structure of novel binary nanosponges consisting of cholesterol-(K/D)[subscript n]DEVDGC)₃-trimaleimide units possessing a trigonal maleimide linker, to which either lysine (K)₂₀ or aspartic acid (D)₂₀ are tethered, has been elucidated by means of TEM. A high degree of agreement between these findings and structure predictions through explicit solvent and then coarse-grained molecular dynamics (MD) simulations has been found. Based on the nanosponges’ structure and dynamics, caspase-6 mediated release of the model drug 5(6)-carboxyfluorescein has been demonstrated. Moreover, the binary (DK20) nanosponges have been found virtually non-toxic in cultures of neural progenitor cells. Additionally, DK20 nanosponges were taken up efficiently by leucocytes (WBC) in peripheral blood within 3h of exposure. The percentage of live cells among the WBC was not significantly decreased by the DK20 nanosponges. Therefore, this novel material holds great promise for improved cell-mediated therapy. Two different nanosponges loaded with the anticancer agent perillyl alcohol (POH) were developed to test the suitability of nanosponges for cell-based cancer therapy. Drug-loaded nanoshuttles featuring trigonal supramolecular building blocks, type (D-POH)₁₀K₂₀ and (D-POH)₁₀R₂₀ were synthesized, purified, and characterized by Dynamic Light Scattering (DLS) and Atomic Force Microscopy (AFM). They were then tested in cell cultures of murine glioma cells (GL26) and murine neural progenitor cells (NPC). The two nanosponges exhibited significantly different biophysical properties (size distribution and zeta potentials). Consequently, different efficacies in killing GL26 and NPC were observed in both, serum free and serum containing culture media. The results from these experiments confirmed that type (D-POH)₁₀K₂₀ nanosponge is an excellent candidate for the cytotherapy of glioblastoma.

Membrane sacs, known as vesicles and liposomes have been widely used as stores for bioactive materials both in vitro and in vivo. The vesicles are biocompatible and in vitro experiments often use them in conjunction with magnetic nanoparticles. The magnetic nanoparticles allow the liposomes to be magnetically located and act as a trigger for release of the encapsulated materials. However, these magnetic vesicles or 'magnetoliposomes' as they are also known have not mananged to cross the barrier into clinical use. The work in this thesis aims to develop a novel system of magnetoliposomes for use in a biological environment. Magnetoliposomes are created from phospholipid suspensions extruded to give a spherical bilayer membrane. This membrane is doped with biotinylated lipids. These lipids are key to allowing the system to work in vitro. The magnetic nanoparticles are formed from iron and are coated with a novel synthetic linker to allow them to interact with the liposomes. When the liposomes and the nanoparticles are mixed in the presence of the protein avidin, large heirarchacal structures are formed which are stable under physiological conditions. The magnetoliposomes are held in an alginate hydrogel scaffold which acts as a support for the liposomes and as an adherent cell scaffold for tissue culture. This work demonstrates that this system can be used to encapsulate and release a range of bioactive molecules such as nickel chloride as a mimic for cytotoxic cancer drugs, ascorbic acid-2-phosphate for the upregulation of collagen production in chondrocytes and SB 431542 for the differentiation of mouse embryonic stem cells. The results shown in this work demonstrate that it is possible to use this novel linking system to create a new form of magnetoliposomes which are stable, biocompatible and easy to form and use. This work also demonstrates a strong model for possible drug delivery in vivo.

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<p> Photoresponsive polymers can act as controllable drug delivery systems that may revolutionize ophthalmic drug delivery for disease treatment in the posterior segment of the eye. Localized, controlled drug delivery devices have significant therapeutic advantages for treating diseases of back of the eye by increasing patient compliance and maintaining therapeutic levels of drug in the tissue. Sustained-release delivery systems that respond to light/laser stimuli are under development to control the rate of delivery resulting in a tuneable treatment profile ideal for retinal diseases. The use of light as a crosslinking mechanism has the potential to create unique materials with controllable swelling, degradation and diffusion properties. </p> <p> This thesis investigates the synthesis and development of universal, graftable PEG-anthracene molecules and their applications in photosensitive alginate and hyaluronate (HA) "photogels". Anthracene undergoes reversible dimerization with wavelengths above 300 nm and de-dimerization/dissociation below 300 nm; due to its well-understood chemistry and symmetry, it was used as a starting point and proof-ofconcept for the synthesis of reversible dimerizing crosslinkers that may be generically grafted to different polymers to cause crosslinking/decrosslinking. After synthesis, watersoluble PEG-anthracene macromolecules were grafting via carbodiimide chemistry to the carboxyl groups along the polymer backbone of alginate and HA at various densities to create viscous liquids or gels with good handling properties. </p> <p> Light irradiation can be used to control the swelling and effective crosslinking density of the photogels which in tum can control drug delivery from photocrosslinked hydro gels as illustrated through the decrease or increase in the delivery of a variety of low molecular weight (<1000 Da) and high molecular weight (>10,000 Da) model drug compounds from both alginate and HA photogels with various light treatments. Novel loading mechanisms were developed through the loading of compounds into uncrosslinked gels followed by crosslinking 365 nm exposures to "lock" in the model drug compounds. Diffusion coefficients effectively compared the different systems showing increase exposures of 365 nm resulted in greater decrease in release of compounds demonstrating the ability to fine-tune release rates. Different formulations and control gels demonstrate a variety of different release profiles. The photogels were valuable long-term controlled release systems (>80 days) that also demonstrate high cytocompatibility when grown with ophthalmic cell lines. </p> <p> Novel photoresponsive biomaterials for smart delivery of therapeutics which use light-controlled crosslinking and decrosslinking mechanisms have been developed. The PEG-anthracene graftable photocrosslinkers show the ability to introduce photocontrolled crosslinking into hydrogel systems. While anthracene as the photodimerizer and alginate and HA as the bulk materials are used as a proof-of-concept in this work, this grafting system can be further manipulated to include new photosensitive dimerizers and other applicable polymers. The ability to use light stimuli to control release rates in a continual fashion, rather than having delivery that is strictly on or off, is a valuable finding that may lead to the development of drug delivery systems that can be catered towards individuals and the progression of their disease. </p> / Thesis / Doctor of Philosophy (PhD)

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