Theses and Dissertations from UMD
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Item PREPARATION OF A NANOSUSPENSION OF THE PHOTOSENSITIZER VERTEPORFIN FOR PHOTODYNAMIC AND LIGHT-INDEPENDENT THERAPY IN GLIOBLASTOMA(2024) Quinlan, John Andrew; Huang, Huang-Chiao; Bioengineering; Digital Repository at the University of Maryland; University of Maryland (College Park, Md.)Photodynamic therapy (PDT) using verteporfin (VP) has treated ocular disease for over 20 years, but recent interest in VP’s light-independent properties has reignited interest in the drug, particularly in glioblastoma (GBM) (NCT04590664). Separate efforts to apply PDT to GBM using 5-aminolevulinic acid (5-ALA)-induced protoporphyrin IX (PpIX) have also garnered attention (NCT03048240), but, unfortunately, clinical trials using 5-ALA-induced PpIX-PDT have yet to yield a survival benefit. Previous studies have shown VP to be a superior PDT agent than 5-ALA-induced PpIX. Our lab has shown that 690 nm light activates VP up to 2 cm into the brain, while 635 nm light only activates PpIX at depths <1 cm into the brain. Additionally, VP is a more effective photosensitizer than PpIX because it has a higher singlet oxygen yield and is active in the vasculature as well as target tumor cells. However, the hydrophobicity of VP limits effective delivery of the drug to the brain for treatment of GBM.In this context, this thesis aims to re-evaluate the delivery method for VP. VP traditionally requires lipids for delivery as Visudyne. Recent shortages of Visudyne and potential drawbacks of liposomal carriers motivated our development of a carrier-free nanosuspension of VP, termed NanoVP. Previous work has shown that cellular uptake of VP is greater when delivered as NanoVP rather than liposomal VP, resulting in improved cell killing after light activation. This thesis builds on this previous work by (1) evaluating synthesis and storage parameters for NanoVP, (2) determining the pharmacokinetics, biodistribution, and brain bioavailability of NanoVP, and (3) evaluating the potential efficacy of NanoVP as a PDT and a chemotherapy agent, and by supporting development of a zebrafish model of the blood-brain barrier (BBB) for mechanistic studies of improved drug delivery to the brain.Item BIOMATERIALS REPROGRAM ANTIGEN PRESENTING CELLS TO PROMOTE ANTIGEN-SPECIFIC TOLERANCE IN AUTOIMMUNITY(2023) Eppler, Haleigh B; Jewell, Christopher M; Bioengineering; Digital Repository at the University of Maryland; University of Maryland (College Park, Md.)The immune system is tightly regulated to balance the killing of disease-causing organisms while protecting host tissue from accidental damage. When this balance is disrupted, immune dysfunctions such as autoimmune diseases occur. Autoimmune diseases like type 1 diabetes and multiple sclerosis (MS) develop when self-tissue is mistakenly attacked and damaged by immune cells. For example, during MS, the immune system mistakenly attacks the myelin sheath that insulates neurons, causing loss of motor function and burdening patients and caregivers. Recent advances in immunotherapies offer exciting new treatments; however, even monoclonal antibody therapies cannot differentiate between healthy and disease-causing cells. Biomaterials provide powerful capabilities to help address these shortcomings. In particular, control over the concentration, duration, location, and combination of signals that are received by immune cells could be transformative in developing more selective immunotherapies that are safe and promote antigen-specific tolerance during autoimmune disease. This dissertation uses two biomaterial approaches to deliver regulatory cargo to antigen presenting cells (APCs). An important APC function is to detect disease-causing organisms by sensing pathogen associated molecular patterns (PAMP) through motif-specific receptors. CpG rich motifs are PAMPs that activate toll-like receptor 9 (TLR9) on DCs and B cells. TLR9 signaling activates B cells and DCs. In MS, TLR9 signaling is aberrantly elevated on certain DCs contributing to systemic inflammation. In MS, B cells signaling through the TLR9 pathwway induced the expression of more inflammatory cytokines as compared to B cells from healthy controls. Controlling this overactive TLR signaling restrains inflammation and is a possible tolerogenic therapeutic approach in MS. The first part of this dissertation uses biomaterials-based polyelectrolyte multilayers (PEMs) to deliver tunable amounts of GpG – an oligonucleotide that inhibits TLR9 signaling – to dendritic cells (DCs). These studies demonstrate that PEMs inhibit DC activation and reduce pathway-specific inflammatory signaling. Furthermore, this work demonstrates that these changes to DCs promote tolerance in downstream T cell development as shown by increasing regulatory T cells. These studies demonstrate this biomaterial delivery system selectively inhibits TLR signaling and DC activation. These changes to DCs promote myelin-specific T cells to adopt a regulatory phenotype, demonstrating a potential approach to developing tolerance inducing antigen-specific immunotherapies for MS. The second part of this dissertation uses a degradable polymer microparticle (MP) system to control the local microenvironment of lymph nodes (LNs). LNs are key sites in the development of immune responses. LNs are composed of different microdomains that coordinate immune cell interactions such as germinal centers (GCs), where B cells develop. These MPs are loaded with myelin self-antigen (MOG35-55) and an mTOR inhibitor, rapamycin (rapa). The MPs are designed to be too large to passively diffuse from the LNs; instead, they slowly degrade releasing encapsulated immune cues to immune cells within the lymph node (LN). Our previous work demonstrates this treatment approach induces antigen-specific tolerance in a preclinical model of MS, but the role of APCs – including DCs and B cells - has not been elucidated. This dissertation reveals that MP treatment alters key LN structural components responsible for interactions between cells in GCs. In addition, MPs alter interactions between B cells/DCs and T cells, as measured by presentation of encapsulated antigen and inhibition of T cell costimulatory molecules by encapsulated rapa. These changes inhibit myelin-specific T cell proliferation and promote regulatory T cells. Finally, B cells from MOG/rapa and MOG MP treated lymph nodes transfer myelin-specific efficacy to mice induced with EAE. These findings illustrate how LN and cellular processes can be regulated by MPs to promote myelin-specific tolerance informing the development of myelin-specific immunotherapies for MS. Together, this body of work provides insight into how biomaterials can be designed to exploit native LN and immune cell functions in the design of next-generation approaches to safely induce myelin-specific tolerance during MS or other autoimmune diseases.Item LIGHT ACTIVATABLE PURE PORPHYRIN NANOPARTICLES FOR THE PHOTODYNAMIC OPENING OF THE BLOOD-BRAIN BARRIER AND GLIOBLASTOMA TREATMENT(2022) Inglut, Collin Thomas; Huang, Huang Chiao; Bioengineering; Digital Repository at the University of Maryland; University of Maryland (College Park, Md.)Glioblastoma (GBM) consistently recurs due to infiltrating cancer cells that cannot be removed by surgery and chemotherapy. The diffusive nature of GBM makes complete surgical resection unsafe, and the intact blood-brain barrier (BBB) prevents the penetration and accumulation of nearly all chemotherapy in infiltrative GBM cells. Existing BBB opening strategies are often associated with increased risk of edema, hemorrhage, or neurotoxicity and thus have limited clinical success. Photodynamic therapy (PDT) is a photochemistry-based treatment modality that has shown promise in treating GBM and opening the BBB in the clinic. In fact, a single adjunctive dose of PDT has been shown to add as much as 18 months to patient survival. However, the full potential of PDT is limited by the light activation depth of the ‘gold standard’ pro-drug photosensitizer, 5-aminolevulinic acid (5-ALA). In addition, large doses of PDT can result in edema and neurotoxicity. To address these issues, our lab has developed a photodynamic priming (PDP) strategy using the verteporfin (VP) photosensitizer, which operates at low optical energy to enhance intratumoral drug accumulation without damaging the healthy brain tissues. Unfortunately, VP is hydrophobic and requires liposomal encapsulation for intravenous administration, which can alter the photosensitizers cellular pharmaceutics. Here, we develop and compare a novel carrier-free pure-photosensitizer nanoparticle to a clinically relevant liposomal formulation.This dissertation covers a complementary, four-pronged approach to enhance drug delivery to brain tumors and treat GBM: (1) Understand the photoactivation depth of clinically relevant photosensitizers in the rodent brain for the targeting of infiltrative GBM cells. (2) Explore the mechanisms of photochemistry-induced BBB opening. (3) Engineer light-activable nanotechnology that can open the BBB, improve drug delivery, and eradicate GBM cells. And (4) develop a high-throughput model to examine the BBB integrity and efflux transporter function. The central hypothesis of this dissertation is the delivery of photoactivatable pure-photosensitizer nanoparticles can eradicate GBM cells and enhance drug delivery to microscopic GBM tumors.Item GENETICALLY ENGINEERED PROBIOTICS FOR DIAGNOSTICS AND DRUG DELIVERY: APPLICATIONS FOR CROHN’S DISEASE(2018) McKay, Ryan; Bentley, William E; Bioengineering; Digital Repository at the University of Maryland; University of Maryland (College Park, Md.)In the history of medicine, therapies have evolved while their mode of delivery has remained largely static. Generally, the active ingredient is formulated with an excipient to confer stability, and is ultimately delivered orally or intravenously in most applications. Crohn’s disease (CD), an illness with increasing global prevalence characterized by chronic inflammation of the intestines, is commonly treated with intravenously administered biologics. When these medicines spread throughout the body, only a small percentage acts at the desired site and side effects often arise. Thus, a targeted system is desired to localize treatment at sites of colonic inflammation. There is an entire field dedicated to localized delivery that typically employs drug-laden particles or capsules that can respond to local chemical or physical cues. We believe that bacteria can be “programmed” to respond analogously, and ultimately synthesize and deliver therapeutics. Nitric oxide (NO) levels are elevated at sites of intestinal inflammation, and thus serves as a targeting molecule that can attract programmed bacteria via a process called pseudotaxis. This is achieved by rewiring the native motility circuits of bacteria to respond to high NO levels. Additionally, localized treatment is attained by an NO- specific response whereby the designed bacteria produce and secrete a human protein reported to reduce inflammation in CD patients. This system may improve CD treatment via: 1) site-specific targeting to minimize side effects and increase efficacy, 2) in situ synthesis of the therapeutic avoids payload loss in the digestive tract and manufacturing obstacles associated with biologics, 3) probiotics are reported to provide innate benefits to CD patients, and 4) oral delivery is preferred by patients versus intravenous. We have also developed probiotics that fluoresce in response to NO which may serve as an ingestible biosensor for CD. We believe these reporter probiotics can assist in the diagnosis of CD by utilizing visualization of bacteria in a stool sample to reduce the need for invasive colonoscopies and biopsies. Overall, we have developed a platform of probiotic cells that respond to NO with applications for Crohn’s disease in mind, translating to noninvasive methods for both the diagnosis and treatment of CD.Item Molecular Routes to Sorting Carbon Nanotubes(2017) Meany, Brendan; Wang, YuHuang; Chemistry; Digital Repository at the University of Maryland; University of Maryland (College Park, Md.)Carbon nanotubes are molecular cylinders of graphene that are synthesized as heterogeneous mixtures consisting of an assortment of structures. Because the optical and electronic properties of nanotubes are strongly dependent on their atomic structure and bundling states, effectively dispersing and separating the nanotubes by the different structures is of great importance for their applications ranging from personal electronics and sensors to bioimaging and drug delivery systems. In this thesis, we describe new molecular approaches to address the challenge of dispersing and sorting carbon nanotubes. First, an open-ring molecular container, acyclic cucurbit[n]uril, clips onto small diameter nanotubes stabilizing them in water leaving the remaining larger diameter nanotubes to agglomerate. At a concentration 1000 times lower than typically required for surfactants, these C-shaped molecules complex with carbon nanotubes creating large exposed surface areas along the tube outerwall. Simple addition of surfactant, sodium dodecylbenzene sulfonate, patches the exposed areas creating a nanotube fluorescent turn-on effect. A second approach to dispersing carbon nanotubes uses ammonium laurate, a previously unused surfactant though similar in structure to the popular sodium dodecylsulfate. When compared to sodium dodecylsulfate, we observe selectivity towards small diameter nanotubes and cleaner substrate deposition which is important for future applications. Lastly, a gel chromatography method is designed utilizing diazonium chemistry to improve the selectivity allowing nearly identical structures to be sorted in high purity. The surface chemistry disrupts the typical interaction between surfactant dispersed nanotubes and gel resin leading to differences in flow rates based on nanotube structure and therefore significantly improve the capability to sort nanotubes. Finally, we show that optical excitation of individual single-walled carbon nanotubes in the semi-dilute concentration regime is capable of melting double-stranded DNA on the excited nanotubes. These molecular approaches open new opportunities to dispersing and sorting carbon nanotubes in cleaner and highly selective manners.Item Self-assembly of inorganic nanoparticle amphiphiles for biomedical applications(2015) Liu, Yijing; Nie, Zhihong; Chemistry; Digital Repository at the University of Maryland; University of Maryland (College Park, Md.)Ensembles of interacting nanoparticles (NPs) can exhibit novel collective properties ─ arising from the coupling between NPs ─ that can be radically different from individuals. Realizing the enormous potential of NPs in biomedical applications requires the organization of NPs into hierarchically ordered structures. My dissertation is focused on the design of NP amphiphiles (NPAMs) and the use of NPAMs as building blocks to construct polymer-inorganic hybrid materials. The NPAMs are made from NPs surface-grafted with amphiphilic block copolymers (BCPs). In this way, the NPAMs synergistically combine the properties of both inorganic NPs and grafted BCPs, such as optical and magnetic properties of NPs, and flexibility of BCPs. First, we demonstrated that NPAMs with relatively low polymer ligand densities (~0.03 chain/nm2) self-assembled into vesicular nanostructures composed of a single layer of NP chains in the membrane. The decrease in the interparticle distance between NPAMs in the chain vesicles led to strong plasmon coupling of NPs and hence enhanced efficiency in photoacoustic imaging. Second, we fabricated hybrid vesicles with well-defined shapes and surface patterns by co-assembling amphiphilic BCPs and NPAMs, which include Janus-like vesicles (JVs) with different shapes, patchy vesicles, and homogeneous vesicles. Third, we prepared magneto-plasmonic hybrid vesicles with various structures through concurrent self-assembly of NPAMs, free BCPs, and hydrophobic magnetic NPs. The hybrid vesicles were demonstrated for both light-triggered release of payload and magnetic resonance imaging. Particularly, the magnetic manipulation of vesicles to specific location can be used to enhance the photothermal effect of the vesicles in cancer imaging and therapy. Finally, we reported that the use of a microfluidic flow-focusing device for the self-assembly of JVs that can act as vesicular motors. The vesicles can be used to encapsulate active compounds, and the release of this payload can be effected using near-infrared light. This systematic study will help us gain deeper understanding of the self-assembly of NPAMs into controllable nanostructures and control the collective properties of NP ensembles for various applications. This research will also provide new insights into the fundamental questions that must be overcome before the hybrid materials can be utilized in effective cancer imaging and treatment.Item ROLE OF ICAM-1-MEDIATED ENDOCYTOSIS IN ENDOTHELIAL FUNCTION AND IMPLICATIONS FOR CARRIER-ASSISTED DRUG DELIVERY(2014) Serrano, Daniel; Muro, Silvia; Biology; Digital Repository at the University of Maryland; University of Maryland (College Park, Md.)Intercellular adhesion molecule 1 (ICAM-1) is a transmembrane protein found on the surface of vascular endothelial cells (ECs). Its expression is upregulated at inflammatory sites, allowing for targeted delivery of therapeutics using ICAM-1-binding drug carriers. Engagement of multiple copies of ICAM-1 by these drug carriers induces cell adhesion molecule (CAM)-mediated endocytosis, which results in trafficking of carriers to lysosomes and across ECs. Knowledge about the regulation behind CAM-mediated endocytosis can help improve drug delivery, but questions remain about these regulatory mechanisms. Furthermore, little is known about the natural function of this endocytic pathway. To address these gaps in knowledge, we focused on two natural binding partners of ICAM-1 that potentially elicit CAM-mediated endocytosis: leukocytes (which bind ICAM-1 via β2 integrins) and fibrin polymers (a main component of blood clots which binds ICAM-1 via the γ3 sequence). First, inspired by properties of these natural binding partners, we varied the size and targeting moiety of model drug carriers to determine how these parameters affect CAM-mediated endocytosis. Increasing ICAM-1-targeted carrier size slowed carrier uptake kinetics, reduced carrier trafficking to lysosomes, and increased carrier transport across ECs. Changing targeting moieties from antibodies to peptides decreased particle binding and uptake, lowered trafficking to lysosomes, and increased transport across ECs. Second, using cell culture models of leukocyte/EC interactions, inhibiting regulatory elements of the CAM-mediated pathway disrupted leukocyte sampling, a process crucial to leukocyte crossing of endothelial layers (transmigration). This inhibition also decreased leukocyte transmigration across ECs, specifically through the transcellular route, which occurs through a single EC without disassembly of cell-cell junctions. Third, fibrin meshes, which mimic blood clot fragments/remnants, bound to ECs at ICAM-1-enriched sites and were internalized by the endothelium. Inhibiting the CAM-mediated pathway disrupted this uptake. Following endocytosis, fibrin meshes trafficked to lysosomes where they were degraded. In mouse models, CAM-mediated endocytosis of fibrin meshes appeared to remove fibrin remnants at the endothelial surface, preventing re-initiation of the coagulation cascade. Overall, these results support a link between CAM-mediated endocytosis and leukocyte transmigration as well as uptake of fibrin materials by ECs. Furthermore, these results will guide the future design of ICAM-1-targeted carrier-assisted therapies.Item Building Block Approach to the Synthesis of a Cucurbit[7]uril Derivative Bearing Sulfonate Functional Groups(2014) Brownlow, Lorene Elizabeth; Isaacs, Lyle; Chemistry; Digital Repository at the University of Maryland; University of Maryland (College Park, Md.)Low aqueous solubility prevents 40-70% of new pharmaceutical agents from reaching their full potential. The use of molecular containers as solubilizing agents is one solution currently under development. Chapter 1 introduces molecular containers under investigation as drug delivery excipients. Synthetic approaches, properties and important derivatives of cyclodextrins and cucurbiturils are briefly reviewed. Chapter 2 describes the tested hypothesis that the addition of sulfonate functional groups to CB[7] will enhance the aqueous solubility of the CB[7] derivative as compared to CB[7] itself. The building-block approach to obtain a difunctionalized CB[7] derivative by the condensation of glycoluril hexamer (21) and ((¬CH2)4SO3Na)2 glycoluril bis(cyclic ether) (30) is described. The new CB[7] derivative had surprisingly low aqueous solubility (20.2 mM), but very similar molecular recognition properties to those of CB[7]. The CB[7] derivative was investigated for its use as an excipient for drug solubilization and found to have no enhancement compared to CB[7].Item Blueprinting Self-Assembled Soft Matter: An `Easy' Approach to Advanced Material Synthesis in Drug Delivery and Wound Healing(2010) Dowling, Matthew Burke; Raghavan, Srinivasa R; Bioengineering; Digital Repository at the University of Maryland; University of Maryland (College Park, Md.)From Jello to mayonnaise to silly putty to biological cells, our world is replete with "soft matter" - materials that behave as soft, deformable solids or highly viscoelastic liquids. Living systems, in particular, can be thought of as extremely sophisticated `soft' machines, with each cellular unit representing a touchstone for the functional potential of soft materials built via self-assembly. Drawing inspiration from biology, we blueprint soft biomaterial designs which rely upon self-assembly to achieve enhanced functionality. As opposed to complex synthesis schemes often used to develop improved biomaterials, we take an `easy' approach by allowing relatively simple molecules orchestrate themselves into advanced machines. In this dissertation, we describe four separate "soft" systems, all constructed by self-assembly of amphiphilic molecules under designed and/or triggered conditions in aqueous media. These systems revolve around a common theme: the structural tandem of (1) vesicles and (2) biopolymers, and the resulting interactions between the two. Our blueprints show promise in several important biomedical applications including controlled drug release, tissue engineering, and wound care. In the first part of this study, we blueprint a biopolymer gel that entraps pH-sensitive vesicles. The vesicles are formed by the self-assembly of a single-tailed fatty acid surfactant. We show that the gel has pH-responsive properties imparted upon it via the embedded vesicle nanostructures. Specifically, when the gel is brought in contact with a high pH buffer, the diffusion of buffer into the gel disrupts the vesicles and transforms them into micelles. Accordingly, a vesicle-micelle front moves through the gel, and this can be visually seen by a difference in color. The disruption of vesicles means that their encapsulated solutes are released into the bulk gel, and in turn these solutes can rapidly diffuse out of the gel. Thus, we can use pH to tune the release rate of model drug molecules from these vesicle-loaded gels into the external solution. In the second part, we have blueprinted hybrid biopolymer capsules containing drug-loaded vesicles by means of a one-step self-assembly process. These capsules are called "motherships" as each unit features a larger container, the polymer capsule, carrying a payload of smaller vesicular containers, or "babyships," within its lumen. These motherships are self-assembled via electrostatic interactions between oppositely charged polymers/surfactants at the interface of the droplet. Capsule size is simply dictated by drop size, and capsules of sizes 200-5000 µm are produced here. Lipid vesicles, i.e. the babyships, are retained inside motherships due to the diffusional barrier created by the capsule shell. The added transport barrier provided by the vesicle bilayer in addition to the capsule shell provides sustained drug release from the motherships. Furthermore, this one-step drop method allows for the rapid synthesis of soft materials exhibiting structural features over a hierarchy of length scales, from nano-, to micro- to macro-. Thirdly, we have therapeutically functionalized biopolymer films by simply passing a solution of vesicles over the film surface. We deposit films of an associating biopolymer onto patterned solid substrates. Subsequently, these polymer films are able to spontaneously capture therapeutically-loaded vesicles from solution; this is demonstrated both for surfactant as well as lipid vesicles (liposomes). Importantly, it is verified that the vesicles are intact - this is shown both by direct visualization of captured vesicles (via optical and cryo-transmission electron microscopy) as well as through the capture and subsequent disruption of drug filled vesicles. Such therapeutically-functionalized films may be of use in the treatment of chronic wounds and burns. Lastly, we have demonstrated that the addition of a certain biopolymer transforms a suspension of whole blood into a gel. This blueprint is inspired from previous research in our group on the biopolymer-induced gelation of vesicles, which are structurally similar to cells. Upon mixture with heparinized human whole blood, this amphilic biopolymer rapidly forms into an "artificial clot." These mixtures have highly elastic character, with the mixtures able to hold their own weight upon vial inversion. Moreover, the biopolymer shows significant hemorrhage-controlling efficacy in animal injury models. Such biopolymer-cell gelation processes are shown to be reversed via introduction of an amphiphilic supramolecule, thus introducing the novel concept of the "revesible hemostat." Such a hemostatic functionality may be of large and unprecedented use in clinical the treatment of problematic hemorrhage both in trauma and routine surgeries.Item Synthesis of Magnetic Nanotubes as Magnetic Resonance Contrast Agents and Drug Carriers and the Study of Their Cytotoxicity(2008-11-20) Bai, Xia; Lee, Sang Bok; Chemistry; Digital Repository at the University of Maryland; University of Maryland (College Park, Md.)The increasing interest in the medical application of nanotechnology has heightened the need for synthesizing nanoparticles with well-defined dimensions and multifunctionalities. Studies on template synthesis demonstrate relatively reliable reproducibility of the nanostructures. Moreover, differential modification can be achieved with template synthesis method. Based on template synthesis method, magnetic nanotubes (MNT), silica nanotubes (SNT) loaded with superparamagnetic iron oxide nanoparticles (SPION), were successfully prepared. The magnetic properties of MNTs including saturation magnetization (Msat) and magnetic resonance (MR) relaxivities were investigated. Results revealed that Msat of MNTs is as high as 95 emu/gFe, which is on the highest side of reported value for magnetite nanoparticles. The MR study showed that MNTs enhanced proton MR relaxation considerably, especially transverse relaxation T2 (*). The transverse relaxivities (r2(*)) of MNTs are higher than that of Feridex, a FDA approved MR contrast agent, indicating that MNTs could potentially act as efficacious T2(*)-weighted MR contrast agents. MNTs were also studied as drug carriers to control the loading and release of Doxorubicin (Dox: a cancer drug model). The inner surfaces of MNTs were modified with C18- and pyridine-silane with various ratios. The results showed that Dox molecules held in the MNTs were stable at pH 7.2, and released at pH 4.5. With proper modification, MNTs can be used to control drug release profiles. The magnetic nanoparticles in MNTs helped in loading drug molecules due to barrier effect. Cytotoxicity and cellular uptake of SNTs with two different sizes and surface charges were investigated for two cell models, primary (non-malignant) and cancer cells. The nanotubes showed limited toxicity which was concentration-, surface charge-, and length- dependent. The internalization was confirmed with both confocal microscopy and TEM studies. Confocal microscopic images demonstrated that endocytosis was one of the main mechanisms for internalization of nanotubes. A novel method was developed in this thesis to improve multifunctionality of SNT as a drug delivery system by modifying the nanotubes segmentedly between the entrance and the remainder. Ideally, we can make a universal delivery vehicle with SNTs as the constitute structure which can be filled with therapeutic and imaging payloads and have biological surface modifiers for targeting.