Targeting Migrating Leukocytes in Drug Delivery
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Targeting Migrating Leukocytes in Drug Delivery

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Questions and Answers

What effect did the treatment with corticosteroid-loaded liposomes have on brain inflammation?

  • It had no effect on macrophage polarization.
  • It effectively reversed edema and polarized macrophages to the anti-inflammatory M2 phenotype. (correct)
  • It increased edema levels significantly.
  • It promoted an increase in pro-inflammatory cytokines.

    • Which nanoparticle engineering technique aims to prevent macrophage uptake?

  • PEGylation (correct)
  • Complement inhibitors
  • Self-mimicry
  • Endothelial cell activation

    • What role does the innate immune system play in drug delivery systems?

  • It has no impact on the pharmacokinetics of drugs.
  • It always enhances the efficacy of drug delivery.
  • It solely acts to protect against external pathogens.
  • It influences the pharmacokinetics and potential toxicities of drug delivery systems. (correct)

    • Under inflammatory conditions, what can nanoparticles be engineered to do in relation to leukocytes?

    <p>Hitchhike to sites of injury by utilizing leukocyte migration.</p> Signup and view all the answers

    Which of the following nanoparticle engineering approaches is designed to prevent anaphylaxis?

    <p>Complement inhibitors</p> Signup and view all the answers

    What is the primary response promoted by the release of anaphylatoxins such as C3a and C5a?

    <p>Complement Activation Related PseudoAllergy (CARPA)</p> Signup and view all the answers

    Which component is involved in the mechanism of complement deposits on drug delivery systems (DDS)?

    <p>Properidin</p> Signup and view all the answers

    What effect does slow infusion have on CARPA symptoms?

    <p>It reduces the severity of symptoms.</p> Signup and view all the answers

    How does Factor I help in the management of complement-associated side effects?

    <p>It reduces C3 deposition.</p> Signup and view all the answers

    Which of the following is a potential outcome of complement activation related to drug delivery systems?

    <p>Pulmonary hypertension</p> Signup and view all the answers

    What cardiovascular symptom is NOT typically associated with CARPA?

    <p>Increased heart rate</p> Signup and view all the answers

    What is an effect of anaphylatoxins released in response to complement activation?

    <p>Stimulation of smooth muscle contraction</p> Signup and view all the answers

    What strategy involves attaching Factor I to help reduce complement-associated side effects?

    <p>Engineering liposomes</p> Signup and view all the answers

    What are the primary purposes of drug delivery systems (DDS)?

    <p>To prolong pharmacokinetics and minimize off-target effects</p> Signup and view all the answers

    Which of the following is a characteristic of most clinically-used lipid-based drug delivery systems?

    <p>They are generally spherical and 50-100 nm in diameter</p> Signup and view all the answers

    What is a common feature of viruses that infect humans?

    <p>They are typically either spherical or filamentous</p> Signup and view all the answers

    What material typically coats lipid-based nanoparticles in drug delivery systems?

    <p>Polyethylene glycol</p> Signup and view all the answers

    What is the primary focus of treatment during the initial phase of ischemic stroke?

    <p>Restoring blood flow</p> Signup and view all the answers

    Which factor is responsible for the increased lung uptake of nanomaterials in the marginated neutrophil pool?

    <p>Agglutinated protein on the surface of nanomaterials</p> Signup and view all the answers

    Which therapeutic areas have nanoparticles been clinically approved to target?

    <p>Oncology and infectious diseases</p> Signup and view all the answers

    What is the approximate size of most lipid nanoparticles used in drug delivery systems?

    <p>50-100 nm</p> Signup and view all the answers

    What characteristic change occurs to the blood-brain barrier following an ischemic stroke?

    <p>Time-dependent increases in permeability</p> Signup and view all the answers

    Which of the following is NOT a feature of lipid nanoparticles used in drug delivery?

    <p>Always used to deliver solid oral doses</p> Signup and view all the answers

    What role do marginated neutrophils play under inflammatory conditions?

    <p>They are primed to respond to further danger</p> Signup and view all the answers

    How do toll-like receptors (TLR) relate to the innate immune system?

    <p>They help recognize pathogens by identifying patterns</p> Signup and view all the answers

    What is the outcome of the inflammatory processes in the acute phase following an ischemic stroke?

    <p>Activation of endothelial cells</p> Signup and view all the answers

    What is a consequence of secondary damage after an ischemic stroke?

    <p>Persistence of oxidative stress and inflammation</p> Signup and view all the answers

    What type of signal induces inflammation in trailing marginated neutrophils in research studies?

    <p>Lipopolysaccharide signals</p> Signup and view all the answers

    Which aspect of the blood-brain barrier is affected in the subacute phase after a stroke?

    <p>Continued increases in permeability</p> Signup and view all the answers

    What is the main benefit of coating nanoparticles with antibodies that bind to leukocytes?

    <p>It selectively targets migrating innate immune cells.</p> Signup and view all the answers

    Which cell types are most likely to contain nanoparticles in the brain after 24 hours?

    <p>Monocytes and neutrophils</p> Signup and view all the answers

    What percentage of recovered cells in the lungs are classified as NC+ within 2 hours?

    <p>80%</p> Signup and view all the answers

    What does a high lung uptake percentage typically indicate regarding nanoparticles?

    <p>Efficiency in targeting immune cells</p> Signup and view all the answers

    What is the significance of the data indicating lung and brain uptake percentages?

    <p>It reflects the effectiveness of nanoparticle coating.</p> Signup and view all the answers

    How does the brain uptake of nanoparticles relate to leukocyte activity?

    <p>It increases with the activation of leukocytes.</p> Signup and view all the answers

    In the context of nanoparticle delivery, what does the term 'steady delivery' imply?

    <p>Gradual increase in bioavailability in the target area.</p> Signup and view all the answers

    What challenge do researchers face when delivering nanoparticles to the brain?

    <p>Overcoming the blood-brain barrier</p> Signup and view all the answers

    Why might researchers prefer targeting innate immune cells specifically?

    <p>They facilitate faster responses in inflammatory conditions.</p> Signup and view all the answers

    How does the 24-hour data differ from the 2-hour data regarding lung uptake?

    <p>Lung uptake decreases over time.</p> Signup and view all the answers

    What role does ICAM play in the context of targeting leukocytes?

    <p>It mediates the adhesion of leukocytes.</p> Signup and view all the answers

    What can the presence of antibodies on nanoparticles contribute to?

    <p>Enhanced targeting specificity.</p> Signup and view all the answers

    How do leukocytes impact the pharmacokinetics of nanoparticles in vivo?

    <p>They enhance the retention of nanoparticles in tissues.</p> Signup and view all the answers

    What is the primary effect of endothelial cells in relation to nanoparticles?

    <p>They facilitate the transport of nanoparticles across barriers.</p> Signup and view all the answers

    Study Notes

    Targeting Migrating Leukocytes

    • Coating nanoparticles with antibodies binding to leukocytes promotes rapid uptake and elimination from the lungs, steady delivery to the inflamed brain, and makes almost all nanoparticles found in the brain located in monocytes and neutrophils.
    • Nanoparticles have been used clinically to deliver small molecules, mRNA, and siRNA.
    • Approved therapeutic areas include oncology, infectious diseases, COVID-19, and hereditary transthyretin-mediated amyloidosis.
    • Most approved carriers are lipid-based.
    • Liposomes and lipid nanoparticles are generally spherical, 50-100 nm in diameter, composed of a mix of phospholipids and cholesterol, and coated with polyethylene glycol.
    • Complement deposits on DDS by several mechanisms including properidin, antibody, and PRR.
    • Release of anaphylatoxins (C3a, C5a) can promote a significant response called Complement Activation Related PseudoAllergy (CARPA).
    • The most severe symptoms are cardiovascular in nature, including systemic hypotension, pulmonary hypertension, edema, elevated thromboxane B2, etc..
    • Slow infusions appear to reduce the severity of CARPA
    • Attaching a natural complement regulator (Factor I) to liposomes is a strategy to reduce complement-associated side effects.
    • Factor I reduces C3 deposition on liposomes
    • Factor I reduces release of C3a and C5a in plasma
    • Factor I eliminates liposome-induced cerebral hypoperfusion.

    Pattern Recognition by Marginated Neutrophils

    • Under inflammatory conditions, marginated neutrophils are primed to respond to further danger.
    • Marginated neutrophil pools respond to specific patterns following induction inflammation using lipopolysaccharide (TLR4 signal).
    • Nanomaterials displaying agglutinated protein on the surface have high levels of lung uptake.
    • This process is complement-dependent.

    Ischemic Stroke: Not Just Loss of Blood Flow

    • The initial insult in ischemic stroke is vessel occlusion, typically by a blood clot.
    • Primary treatment must focus on reperfusion (tPA, mechanical thrombectomy).
    • Secondary damage due to oxidative stress and inflammation can persist for weeks after stroke.

    The Blood-Brain Barrier in Stroke

    • The blood-brain barrier exhibits time-dependent increases in permeability following ischemic stroke.
    • Inflammatory processes in the acute and subacute phases include endothelial activation.
    • Upregulation of cell adhesion molecules that help with leukocyte migration is typical for endothelial activation.

    Targeting Migrating Leukocytes to Treat Inflammation

    • Brain inflammation is characterized by edema (fluid buildup), which can be tracked using albumin accumulation.
    • Liposomes were loaded with a corticosteroid (dexamethasone) and targeted to leukocytes.
    • Treatment effectively reversed edema and polarized macrophages to the anti-inflammatory M2 phenotype.

    Summary

    • The innate immune system (both proteins and cells) plays a critical role in the pharmacokinetics and toxicities of drug delivery systems.
    • Nanoparticles can be engineered to evade the innate immune system using several approaches:
      • Complement inhibitors - prevention of anaphylaxis and macrophage uptake
      • PEGylation - evasion from opsonization
      • Self-mimicry - ‘don’t eat me signals’ to macrophages.
    • Under inflammatory conditions, nanoparticles can be engineered to harness the innate immune response for selective delivery.
      • Marginated neutrophils – pattern response to agglutinated protein
      • Endothelial cell activation – selective delivery in stroke
      • Leukocyte migration – hitchhiking to sites of injury

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    Description

    Explore the role of nanoparticles in targeting migrating leukocytes for therapeutic delivery. This quiz covers nanoparticle composition, mechanisms of action, and their clinical applications in various diseases, including oncology and COVID-19.

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