User talk:Hannah Kempton

Overview: siRNA Delivery Across the Blood Brain Barrier to treat Huntington's Disease

• Overview Sentence

Background

Blood Brain Barrier

• The blood brain barrier (BBB) plays a crucial role in modulating cerebral homeostasis and directing neuronal functions. It separates circulating blood from cerebrospinal brain fluid and prevents harmful toxins from reaching the brain.
• In other parts of the body, the thin endothelial cells lining vessel and capillary walls overlap at leaky junctions that are flexible enough to allow larger molecules like hormones, viruses, and bacteria to squeeze through the junctions or diffuse directly through the cells into the surrounding tissue.
• However, the endothelial cells lining blood vessels in the brain overlap at tight junctions and are surrounded by a thick basal membrane containing contractile pericytes as well as astrocytic glial cells that provide nutrients and play a role in brain and spinal cord repair. These cells are collectively known as the BBB.
• The BBB only allows small, essential hydrophobic molecules like O2 and glucose and essential ions like Na+, K+, and Cl- to pass from the blood to the brain and central nervous system (CNS), but prevents the passage of molecules greater than about 500 Da.

Nanodelivery

• Recently, the use of nanoparticles (NPs) has become increasingly common in solving environmental and medical problems, particularly in targeted drug delivery systems, among others
• Due to their size, NPs are unique in that their chemical, physical, and biological properties differ from that of their bulk materials, so they can be considered “new” material
• Significance of Nanoscience in Medicine
  • Higher surface area:volume ratio → nanomaterials have higher reactivity, mechanical strength, and magnetic or electrical properties
  • NPs able to cross BBB and mediate repair of BBB damage that may be responsible for diseases like Alzheimer’s
  • For our purposes, NPs may serve as an effective vector, containing siRNA or other drugs, for targeted drug delivery across the BBB

Significance

Central Idea: Bridging the Gap

• talk about our idea and its scientific context: combining developing field of nanotechnology to deliver siRNAs
• Typically, viruses are used: talk about why bad
• Will have many applications once the nanodelivery is optimized: for this study we will focus on delivering siRNAs for the purpose of therapeutics in Huntington's Disease, but the optimized siRNA delivery technique will be widely applicable

Huntington's Disease

• stuff about disease: why we selected Huntington's (social context: any improvement on current treatment is good)

Experimental Overview

siRNA

• explain we're not designing them just taking them from another paper that successfully used viral delivery

in vitro BBB mode

• explain justification for doing in vitro
• briefly describe selected model

References

• Nanobiotechnology-Based Strategies for Crossing the Blood–Brain Barrier
  • http://www.medscape.com/viewarticle/770396
  • Intro
    • Issues with some existing methods: damage bbb
    • “ The ideal method for transporting drugs across the BBB should be controlled and should not damage the barrier. Among the various approaches that are available, nanobiotechnology-based delivery methods provide the best prospects for achieving this ideal. This review describes various nanoparticle (NP)-based methods used for drug delivery to the brain and the known underlying mechanisms.”
    • “Some strategies require multifunctional NPs combining controlled passage across the BBB with targeted delivery of the therapeutic cargo to the intended site of action in the brain.”
    • Fig 1 could be useful to base a figure off of in background info
    • macromolecules can pass via receptor-mediated process (ex transferrin (Tf), insulin, immunoglobulin G)
    • also remember some disorders increase BBB permeability as part of pathogenesis
    • The upper limit of pore size in the BBB that enables passive flow of molecules across it is usually <1 nm; however, particles that have a diameter of several nanometers can also cross the BBB by carrier-mediated transport
  • Ideal Method of Transport
    • It should be controlled;
    • It should not damage the barrier;
    • The carrier system should be biodegradable and not toxic;
    • Transport of drugs across the BBB should be selective;
    • Systemic delivery should be targeted to the BBB and the site of intended action in the brain;
    • The drug load transported through the BBB should be adequate for reaching therapeutic concentrations in the brain;
    • Therapeutic concentrations should be maintained for a sufficient duration of time for the desired efficacy.
  • NPs used
    • Various factors that influence the transport include: type of polymer or surfactant used, NP size and the drug molecule.
    • lipid NPs
    • liposomes
    • polymeric NPs (put Tf receptors on outside so can cross via Tf receptors) “molecular trojan horse”
      • chitosan, dendrimers, nanogels, plga
    • delivering siRNAs?
    • lots on brain tumor treatment

• In vitro blood-brain barrier models: current and perspective technologies
  • http://www.ncbi.nlm.nih.gov/pubmed/22213383
• Gene Therapy for Huntington’s Disease
  • http://www.ncbi.nlm.nih.gov/pubmed/22222669
• Using non-coding small RNAs to develop therapies for Huntington's disease
  • http://www.nature.com/gt/journal/v18/n12/full/gt2011170a.html
• Self-assembling Modified β‑Cyclodextrin Nanoparticles as Neuronal siRNA Delivery Vectors: Focus on Huntington’s Disease
  • http://pubs.acs.org/doi/abs/10.1021/mp3003946
  • This paper is the closest to what we plan to do, but they only used their nanoparticles to get into neurons and did not account for BBB: They used a nanodelivery method that could deliver the siRNA across neuronal membranes, but then injected that directly into the brain, bypassing BBB completely