Drug Delivery Systems in Immunology

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Questions and Answers

What is a primary benefit of coating nanoparticles with antibodies binding to leukocytes?

Rapid uptake and elimination from lungs (correct)

Direct targeting of infectious agents

Enhanced immune response against pathogens

Increased size of nanoparticles

Which immune cells are primarily responsible for the uptake of nanoparticles in the brain?

B lymphocytes and plasma cells

Basophils and eosinophils

Natural killer cells

Monocytes and neutrophils (correct)

In the context of nanoparticle use, what does the term 'steady delivery' refer to?

Consistent release of nanoparticles to inflamed brain regions (correct)

Continuous delivery of nanoparticles without external forces

Immediate targeting of all immune cells

Rapid movement of nanoparticles through bloodstream

Which factor is likely NOT a benefit of targeting migrating innate immune cells with nanoparticles?

Potential for all nanoparticles to enhance healing Signup and view all the answers

What percentage of recovered cells were identified as NC+ from the lungs after 2 hours?

60% Signup and view all the answers

What does 'Lung Uptake (%ID/g)' imply about the performance of nanoparticles?

Amount of nanoparticles successfully taken up by the lungs Signup and view all the answers

What type of response is promoted by the release of anaphylatoxins like C3a and C5a?

Complement Activation Related PseudoAllergy (CARPA) Signup and view all the answers

What is one strategy mentioned to engineer drug delivery systems (DDS) to eliminate CARPA?

Attachment of a natural complement regulator (Factor I) Signup and view all the answers

Which of the following is NOT a symptom associated with CARPA?

Cerebral hyperperfusion Signup and view all the answers

What effect do slow infusions have on CARPA symptoms?

Reduce the severity of CARPA Signup and view all the answers

What role do chemokines play in post-stroke inflammation?

They promote migration of immune cells into the brain. Signup and view all the answers

How can macrophages influence tissue repair after a stroke?

By shifting from M1 to M2 phenotype. Signup and view all the answers

What does Factor I do to liposomes during the interaction with complement?

Reduces C3 deposition Signup and view all the answers

What is elevated during severe CARPA symptoms?

Thromboxane B2 Signup and view all the answers

Which statement about the recruitment of immune cells is accurate?

Recruitment can occur from circulating pools and lymphoid tissues. Signup and view all the answers

Which of the following best describes the nature of the most severe symptoms of CARPA?

Cardiovascular Signup and view all the answers

What initial site do danger signals encounter following local brain injury?

The lungs Signup and view all the answers

What is the function of marginated neutrophils in response to brain injury?

They become primed for response to brain injury. Signup and view all the answers

What is one outcome of attaching Factor I to liposomes?

Reduction of C3a and C5a release in plasma Signup and view all the answers

Which component is NOT involved in the recruitment of immune cells after stroke?

Oxygen levels Signup and view all the answers

What triggers the pulmonary marginated neutrophil pool to respond to specific patterns?

Lipopolysaccharide induction Signup and view all the answers

What is the primary treatment focus during an ischemic stroke?

Reperfusion Signup and view all the answers

How does the blood-brain barrier respond to ischemic stroke over time?

It exhibits time-dependent increases in permeability Signup and view all the answers

What is a characteristic of the marginated neutrophils under inflammatory conditions?

They become primed to respond to further danger Signup and view all the answers

What mechanism is suggested to be involved in the uptake of nanomaterials by the lungs?

Complement-dependence Signup and view all the answers

Which of the following contributes to secondary damage post-stroke?

Oxidative stress and inflammation Signup and view all the answers

What process is enhanced in the acute and subacute phases of ischemic stroke?

Endothelial activation and upregulation of adhesion molecules Signup and view all the answers

What is NOT a typical initial insult in an ischemic stroke?

Oxidative stress Signup and view all the answers

What type of material shows high levels of lung uptake by marginated neutrophils?

Nanomaterials with agglutinated protein Signup and view all the answers

During which phase of stroke does the blood-brain barrier primarily increase in permeability?

Both acute and subacute phases Signup and view all the answers

Study Notes

Targeting Migrating Leukocytes

Coating nanoparticles with antibodies specific for leukocytes promotes rapid uptake and elimination from the lungs, steady delivery to the inflamed brain, and selective targeting of migrating innate immune cells.
Essentially all of the nanoparticles in the brain are found in monocytes and neutrophils.
The percentage of nanoparticles in the lungs and brains varies depending on the presence of antibodies.

Complement-Associated DDS Toxicities

Complement deposits on drug delivery systems (DDS) via multiple mechanisms, including properidin, antibody, and pattern recognition receptors (PRR).
Complement activation can lead to the release of anaphylatoxins (C3a, C5a), which trigger a response known as Complement Activation Related PseudoAllergy (CARPA).
CARPA is characterized by cardiovascular symptoms like systemic hypotension, pulmonary hypertension, edema, and elevated thromboxane B2.
Slow infusions can reduce CARPA severity.

Engineering DDS to Eliminate CARPA

Attachment of a natural complement regulator (Factor I) to liposomes can effectively mitigate complement-associated side effects.
Factor I reduces C3 deposition on liposomes, minimizes release of C3a and C5a in plasma, and eliminates liposome-induced cerebral hypoperfusion.

Pattern Recognition by Marginated Neutrophils

Under inflammatory conditions, marginated neutrophils become primed to respond to danger signals.
Upon lipopolysaccharide (TLR4) stimulation, the pulmonary marginated neutrophil pool responds to specific patterns.
Nanomaterials displaying agglutinated protein on their surface exhibit high levels of lung uptake through a complement-dependent mechanism.

Ischemic Stroke: Not Just Loss of Blood Flow

The initial insult in ischemic stroke is vessel occlusion, commonly due to a blood clot.
Primary treatment should focus on reperfusion using strategies like tissue plasminogen activator (tPA) and mechanical thrombectomy.
Secondary damage stemming from oxidative stress and inflammation can persist for weeks after stroke.

The Blood-Brain Barrier in Stroke

The blood-brain barrier exhibits time-dependent permeability increases following ischemic stroke.
Inflammatory processes during acute and subacute phases involve endothelial activation.
This includes upregulation of cell adhesion molecules, facilitating the recruitment of immune cells.

Cells Involved in Post-Stroke Inflammation

Endothelial activation and chemokine release facilitate the migration of immune cells into the brain after stroke.
These immune cells can either promote tissue repair or exacerbate damage based on their phenotype.
Shifting macrophages from the pro-inflammatory M1 phenotype to the anti-inflammatory M2 phenotype can promote tissue repair.
Immune cells can be recruited from circulating pools or from lymphoid tissues.

Distal Organs Respond to Danger Signals

After local injury, chemokines, cytokines, and damage-associated molecular patterns (DAMPs) emanate from the brain to recruit immune cells.
The lungs, containing a large number of intravascular leukocytes (marginated neutrophils), are the first organ to encounter these mediators.
Signaling between danger signals and marginated leukocytes primes them for a response to brain injury.

Targeting Migrating Leukocytes to Treat Inflammation

Brain inflammation is characterized by edema (fluid buildup), which can be tracked using albumin accumulation.
Liposomes loaded with dexamethasone, a corticosteroid, and targeted to leukocytes can effectively reverse edema and polarize macrophages towards 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 through diverse strategies:
- Complement inhibitors prevent anaphylaxis and macrophage uptake.
- PEGylation evades opsonization.
- Self-mimicry utilizes "don't eat me signals" to macrophages.
Under inflammatory conditions, nanoparticles can be engineered to leverage the innate immune response for selective delivery:
- Marginated neutrophils respond to patterns, such as agglutinated protein.
- Endothelial cell activation enables selective delivery in stroke.
- Leukocyte migration allows for hitchhiking to sites of injury.

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Description

Explore the mechanisms of targeting migrating leukocytes using nanoparticles and the associated toxicities of complement activation in drug delivery systems. This quiz covers concepts such as the impact of antibodies on nanoparticle distribution and the cardiovascular effects related to complement activation. Test your understanding of these advanced topics in immunology and drug delivery systems.