ANH Workshop 2004
NanoHealth: Bridging the Wet and Dry Divide
Richard E. Smalley, PhD
Human health has always been determined on the nanometer scale; this is where the structure and properties of the machines of life work in every one of the cells in every living thing. Now we are beginning to learn to build detectors, devices, and agents for treatment on this same length scale. The practical impact on human health of this science of the tiny will be huge.
Fullerenes are unprecedented building blocks for nano-medical applications. Concepts for chemo- and regioselective exohedral functionalizations of C60 allowing for the efficient synthesis of hydrophilic, lipophilic and amphiphilic fullerene derivatives will be presented. The programmed supramolecular aggregation of these lipophilic and amphiphilic fullerene leads to the formation of buckysomes representing a new generation of high performance vesicles. The controlled assembly and disassembly of these nano-structures can be switched by variation of the pH. At the same time the buckysomes can be loaded with lipophilic guest molecules and are accessible to chemical functionalization allowing for bio-compatibilization and docking to antibodies. Concepts for the use of buckysomes as drug delivery systems will be introduced.
The role of nitric oxide in cellular signaling in the past two decades has become one of the most rapidly growing areas in biology. Current and future research will undoubtedly expand the clinician’s therapeutic armamentarium to manage a number of important diseases by perturbing nitric oxide formation and metabolism. Such promise and expectations have obviously fueled the interests in nitric oxide research for a growing list of potential therapeutic applications. There have been and will continue to be many opportunities from nitric oxide and cyclic GMP research to develop novel and important therapeutic agents. The lecture will discuss our discovery of the first biological effects of nitric oxide and how the field has evolved since our original reports in 1977.
Carbon nanotubes are prominent artificial nanomaterials with many promising applications, but very little is yet known about their interactions with biological systems. In part, this reflects the difficulty of observing all-carbon nanostructures in complex biological environments. The discovery of near-infrared fluorescence from single-walled carbon nanotubes (SWNT) offers a powerful new approach for detecting and imaging nanotubes in cells, tissues, and organisms. Using a fluorescence microscope modified for imaging beyond 1100 nm, we have selectively and sensitively detected SWNT in biological specimens. Initial results will be presented on mouse macrophage cells incubated with nanotubes. High contrast near-infrared fluorescence images reveal intracellular nanotubes that have been actively ingested through phagocytosis. In addition, these cells show no indication of toxicity or growth inhibition from 96 hours of nanotube exposure. Future prospects for using nanotube bioconjugates as targeted diagnostic and therapeutic agents will be discussed.
Presenting a novel new minimally invasive, potentially biologically
targetable approach to cancer therapy. Nanoshell-based thermal ablation
(NBTA) holds promise as a significant new therapeutic tool for
achieving treating cancer with ablative heating therapy that is
spatially defined by the biological characteristics of tumor and/or
associated tissues. This approach may minimize patient discomfort,
allow for new innovative approaches to some surgically challenging
tumors, potentially treat regional metastatic disease even before
presentation to the physician, or provide a treatment of otherwise
inoperable tumors where surgery is accompanied by a high probability of
morbidity or mortality. The approach involves the use of a new
nanotechnology, tunable gold nanoshells, with novel biological
targeting. The biological applications of the core nanotechnology are
licensed by Nanospectra Biosciences. The proposed therapy will utilize
Nanospectra BioscienceÍs proprietary Nanoshells to convert externally
applied near-infrared light (at an otherwise non-destructive power)
into localized heat to destroy cancer cells, minimizing damage to
surrounding tissue and avoiding the systemic toxicity of other
therapies. This new therapy will offer a new opportunity to turn other
areas of cancer research (e.g., the molecular biology of cancer and the
identification of cell surface markers on cancer cells) into
The development of suitable tools for molecular imaging and targeted tissue ablation have been the focus of intense efforts in the context of many diseases. The molecular diversity of the human vasculature, and the identification of molecular addresses associated to specific vascular beds offers a unique opportunity to achieve selectivity upon systemic administration of imaging tracers and drugs. It is now recognized that blood vessels acquire abnormal molecular signatures in diseased organs. There is a clear need for improved devices that integrate targeting and sensitive imaging.Here we propose to establish strategies for the directed assembly of gold nanoparticles, which can then be targeted to receptors expressed selectively in disease sites. The strategy in our proposal is based on the application of new biotechnology platforms (i) to identify molecular receptors by in vivo and ex vivo phage display, (ii) to select specific ligands for such receptors by phage display strategies, (iii) to evaluate, validate, and prioritize biomarkers and molecular targets based on ligand-receptor and antibody-antigen pairs, (iv) to develop systems for directed assembly of gold nanoparticles (implantable and injectable) for disease surveillance and targeted delivery, (v) to develop hardware and imaging systems for the detection of nanoparticles in vivo and ex vivo, and (vi) to establish nanodevices for targeted imaging and tissue ablation. If successful, such efforts would bring advances to the management of cancer and other diseases characterized by vascular alterations.
Reinforcement of Poly(Propylene Fumarate)-Based Networks
with Surface Modified Alumoxane Nanoparticles for Bone Tissue
Andrew Barron, PhD
Slides only(low bandwidth), Speaker with slides (high bandwidth)
A new composite material has been fabricated utilizing the biodegradable polymer poly(propylene fumarate)/poly(propylene fumarate)-diacrylate and surface-modified carboxylate alumoxane nanoparticles. For this study, composites were prepared using various functional groups including: a surfactant alumoxane to enhance nanoparticle dispersion into the polymer; an activated-alumoxane to enhance nanoparticle interaction with the polymer matrix; a mixed alumoxane containing both activated and surfactant groups; and a hybrid-alumoxane containing both surfactant and activating groups within the same substituent. A sizable rise in mechanical properties of a biodegradable polymer infused with alumoxane nanoparticles marks significant progress towards a novel class of mechanically strong and biodegradable biomaterials for tissue engineering applications.
Liposomes and the Treatment of Leukemia: Does Particle Size
Gabriel Lopez-Bernstein, MD
Speaker with slides (high bandwidth)
The Gulf-Coast Consortia (GCC) is a virtual organization including six academic institutions in the Houston and Galveston Area. It links and facilitates these institutions in research and educational partnerships. We recently launched a training initiative in nano-biology with an emphasis on uniting the cross-disciplinary expertise in imaging and computing to unravel the functions and design principles of nano-materials of artificial or biological origins. The National Center for Macromolecular Imaging at Baylor College of Medicine (ncmi.bcm.tmc.edu) is a NIH supported Center which has unique electron cryomicroscopy facilities for imaging biological machines at different functional states. We have developed various image processing algorithms to retrieve the three-dimensional structures from the noisy micrographs at sub-nanometer resolutions. This technology has the promises in studying structures of nano-objects approaching atomic resolution.
Nucleation Mechanisms of Sickle Cell Hemoglobin
Peter Vekilov, PhD
Slides only(low bandwidth) , Speaker with slides (high bandwidth)
The primary pathogenic event of sickle cell anemia is the polymerization of the mutant hemoglobin (Hb) S within the red blood cells, occurring when HbS is in deoxy state in the venous circulation. Polymerization is known to start with nucleation of individual polymer fibers, followed by growth and branching via secondary nucleation, yet the mechanisms of nucleation of the primary fibers have never been subjected to dedicated tests. Nucleation is the only process in the sequence of phenomena that comprise the molecular biology, physical chemistry, and pathophysiology of the disease whose rate is an exponential function of the system parameters and as such is the easiest to suppress. We implement a technique for direct and independent determination of the rates and delay times of primary nucleation of HbS fibers, based on direct detection of emerging HbS polymers using optical differential interference contrast microscopy after laser photolysis of CO-HbS. We show that nucleation induction times agree with an a-priory prediction based on ZeldovichÍs theory and that the critical nucleus contains 11 or 12 molecules. The nucleation rates are of the order of 106 Ð 108 cm-3s-1„comparable to those leading to erythrocyte sickling in vivo„suggesting that the mechanisms deduced from in vitro experiments might provide physiologically relevant insights. The nucleation rate values are 9-10 orders of magnitude higher than those known for protein crystals and this discrepancy cannot be rationalized with the current knowledge of nucleation. We also provide evidence that the nucleation of the sickle cell hemoglobin polymers proceeds via a precursor that is likely a metastable droplet of a dense liquid phase, known to exist in hemoglobin solutions, i.e., the nucleation process can be viewed as a two-step process, or as a superposition of a density and a structure fluctuations. These findings suggest that physico-chemical tools developed to control the dynamics of phase behavior in protein and colloid solutions may be applicable to control the pathogenic polymerization of HbS.