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Multidimensional Atomic Force Microscopy: A Versatile Novel Technology for Nanopharmacology Research

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      Abstract

      Nanotechnology is giving us a glimpse into a nascent field of nanopharmacology that deals with pharmacological phenomena at molecular scale. This review presents our perspective on the use of scanning probe microscopy techniques with special emphasis to multidimensional atomic force microscopy (m-AFM) to explore this new field with a particular emphasis to define targets, design therapeutics, and track outcomes of molecular-scale pharmacological interactions. The approach will be to first discuss operating principles of m-AFM and provide representative examples of studies to understand human health and disease at the molecular level and then to address different strategies in defining target macromolecules, screening potential drug candidates, developing and characterizing of drug delivery systems, and monitoring target–drug interactions. Finally, we will discuss some future directions including AFM tip-based parallel sensors integrated with other high-throughput technologies which could be a powerful platform for drug discovery.Electronic supplementary materialThe online version of this article (doi:10.1208/s12248-010-9232-y) contains supplementary material, which is available to authorized users.

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      Atomic Force Microscope

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        A review of stimuli-responsive nanocarriers for drug and gene delivery.

        Nanotechnology has shown tremendous promise in target-specific delivery of drugs and genes in the body. Although passive and active targeted-drug delivery has addressed a number of important issues, additional properties that can be included in nanocarrier systems to enhance the bioavailability of drugs at the disease site, and especially upon cellular internalization, are very important. A nanocarrier system incorporated with stimuli-responsive property (e.g., pH, temperature, or redox potential), for instance, would be amenable to address some of the systemic and intracellular delivery barriers. In this review, we discuss the role of stimuli-responsive nanocarrier systems for drug and gene delivery. The advancement in material science has led to design of a variety of materials, which are used for development of nanocarrier systems that can respond to biological stimuli. Temperature, pH, and hypoxia are examples of "triggers" at the diseased site that could be exploited with stimuli-responsive nanocarriers. With greater understanding of the difference between normal and pathological tissues and cells and parallel developments in material design, there is a highly promising role of stimuli-responsive nanocarriers for drug and gene delivery in the future.
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          Amyloid ion channels: a common structural link for protein-misfolding disease.

          Protein conformational diseases, including Alzheimer's, Huntington's, and Parkinson's diseases, result from protein misfolding, giving a distinct fibrillar feature termed amyloid. Recent studies show that only the globular (not fibrillar) conformation of amyloid proteins is sufficient to induce cellular pathophysiology. However, the 3D structural conformations of these globular structures, a key missing link in designing effective prevention and treatment, remain undefined as of yet. By using atomic force microscopy, circular dichroism, gel electrophoresis, and electrophysiological recordings, we show here that an array of amyloid molecules, including amyloid-beta(1-40), alpha-synuclein, ABri, ADan, serum amyloid A, and amylin undergo supramolecular conformational change. In reconstituted membranes, they form morphologically compatible ion-channel-like structures and elicit single ion-channel currents. These ion channels would destabilize cellular ionic homeostasis and hence induce cell pathophysiology and degeneration in amyloid diseases.
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            Author and article information

            Affiliations
            [1 ]Department of Bioengineering, University of California, San Diego, PFBH Room 219, 9500 Gilman Drive, MC 0412, La Jolla, California 92093-0412 USA
            [2 ]Department of Mechanical and Aerospace Engineering, University of California, San Diego, PFBH Room 219, 9500 Gilman Drive, MC 0412, La Jolla, California 92093-0412 USA
            [3 ]Department of Medicine, The University of Chicago, Chicago, Illinois 60637 USA
            Author notes

            Guest Editors: Rao Rapaka, Thomas Aigner, Joni Rutter, and David Shurtleff

            Contributors
            +1-858-8220384 , rlal@ucsd.edu
            Journal
            AAPS J
            The AAPS Journal
            Springer US (Boston )
            1550-7416
            19 October 2010
            19 October 2010
            December 2010
            : 12
            : 4
            : 716-728
            2976997
            20957528
            9232
            10.1208/s12248-010-9232-y
            © The Author(s) 2010
            Categories
            Mini-Review
            Custom metadata
            © American Association of Pharmaceutical Scientists 2010

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