Nanoparticles and Immune Cell Interactions

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Questions and Answers

What characteristic of brain inflammation is primarily indicated by albumin accumulation?

Fluid buildup (edema) (correct)

Increased neuronal activity

Decreased blood flow

Reduction of leukocyte activity

Which drug was loaded into liposomes for targeted therapy in the context of brain inflammation?

Prednisone

Ibuprofen

Aspirin

Dexamethasone (correct)

What strategy is used to prevent macrophages from uptake of nanoparticles?

Polarization to M1 phenotype

Inhibition of neutrophil marginating

Enhanced opsonization

Complement inhibitors (correct)

Under inflammatory conditions, how can nanoparticles be designed to enhance drug delivery?

By harnessing leukocyte migration Signup and view all the answers

What is the desired macrophage phenotype targeted by treatment in the study?

M2 macrophage Signup and view all the answers

What is the primary site for the elimination of drug delivery systems (DDS) from circulation?

Liver Signup and view all the answers

What type of liposomes are designed to evade recognition by the innate immune system?

Stealth liposomes Signup and view all the answers

Which component of the innate immune system is slowed down by grafting PEG onto liposomes?

Opsonization Signup and view all the answers

What does the reticuloendothelial system (RES) primarily consist of?

Macrophages and the bloodstream Signup and view all the answers

Which organ takes a large fraction of injected DDS, accounting for more than 90%?

Liver Signup and view all the answers

What is one of the key mechanisms through which PEG slows elimination of DDS?

Reducing complement activation Signup and view all the answers

In addition to the liver, which other locations represent sites of DDS elimination?

Spleen and lungs Signup and view all the answers

What significant challenge does the macrophage-dependent elimination of DDS pose?

Reduced therapeutic efficacy Signup and view all the answers

What role do endothelial activation and chemokine release play following a stroke?

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

Which macrophage phenotype shift is associated with promoting tissue repair?

From M1 to M2 Signup and view all the answers

Where can immune cells be recruited from in response to brain injury?

From circulating pools and lymphoid tissues Signup and view all the answers

What are the initial mediators that recruit immune cells following local brain injury?

Chemokines, cytokines, and DAMPs Signup and view all the answers

Which organ is primarily encountered by danger signals following brain injury?

Lungs Signup and view all the answers

What type of leukocytes are found in high numbers within the lungs and can respond to brain injury?

Marginated neutrophils Signup and view all the answers

What is a key function of signaling between danger signals and marginated leukocytes?

Priming them for response to brain injury Signup and view all the answers

What type of immune cells participate in post-stroke inflammation and can influence damage or repair?

Immune cells of various phenotypes Signup and view all the answers

What is one significant effect of PEGylation on liposomal drugs?

Prolongs the pharmacokinetics of liposomal drugs Signup and view all the answers

How does PEGylation affect the uptake of nanoparticles in clearance organs?

It reduces uptake in spleen and liver Signup and view all the answers

What effect does PEGylation have on the protein corona around nanoparticles?

It reduces the amount of protein that opsonizes nanoparticles Signup and view all the answers

What could be a consequence of PEGylation in drug delivery systems?

Increased adaptive immune response Signup and view all the answers

What role does CD47 play in immune evasion for nanoparticles?

Acts as a 'don’t eat me' signal to macrophages Signup and view all the answers

What is the process termed when neutrophils associate transiently with the vessel wall?

Margination Signup and view all the answers

What percentage of the intravascular pool of neutrophils is typically in the marginated pool?

50% Signup and view all the answers

What can lead to dramatic increases in the marginated pool of neutrophils?

Local inflammation and injury Signup and view all the answers

What effect do antibodies on nanoparticles have on leukocyte behavior?

Promote steady delivery to the inflamed brain Signup and view all the answers

Which of the following is primarily responsible for the uptake and elimination of nanoparticles from the lungs?

Surface coating with specific antibodies Signup and view all the answers

What percentage of recovered cells are represented in the lung uptake after 2 hours?

20% Signup and view all the answers

What is the lung uptake percentage for nanoparticles coated with antibodies at the highest measured level?

80% Signup and view all the answers

Which cells predominantly house nanoparticles after entering the brain?

Neutrophils and monocytes Signup and view all the answers

In the target areas (lungs and brain), which type of immune cells are the nanoparticles designed to selectively target?

Migrating innate immune cells Signup and view all the answers

What is the impact on endothelial cells when nanoparticles are targeted to leukocytes?

They enhance uptake of leukocytes Signup and view all the answers

What is the characteristic uptake pattern observed in the brain after 24 hours?

Steady increase in uptake Signup and view all the answers

How do leukocytes behave in response to nanoparticles within the lungs?

They are quickly absorbed and eliminated Signup and view all the answers

What does a high binding efficacy of nanoparticles to leukocytes imply for therapeutics?

Enhanced delivery of therapeutic agents Signup and view all the answers

The percentage of follicles that are NC+ in the brain after nano-uptake demonstrates what type of distribution?

Localized concentration Signup and view all the answers

At 2 hours, what can be inferred about the translocation efficiency from the lungs to the brain?

Insufficient translocation occurs Signup and view all the answers

Why is selective targeting important when designing nanoparticles for leukocyte delivery?

To avoid targeting healthy cells 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 and steady delivery to the inflamed brain.
Essentially all nanoparticles in the brain are found in monocytes and neutrophils, suggesting selective targeting of migrating innate immune cells.

Macrophages Eliminate DDS from Circulation

Macrophages in contact with the bloodstream are the primary elimination site for drug delivery systems (DDS). This is known as the reticuloendothelial system (RES).
Kupffer cells in the liver take a large fraction (>90%) of injected DDS.
The spleen, lungs, and bone marrow also represent sites of elimination.

Polyethylene Glycol (PEG) Slows Elimination

Grafting PEG onto the surface of liposomes helps evade recognition by the innate immune system.
One key mechanism is slowing of opsonization—reduced complement activation.
These liposomes are referred to as ‘stealth’ liposomes.

Effects of PEGylation on DDS Behavior

PEGylation significantly prolongs the pharmacokinetics of liposomal drugs.
PEGylation reduces uptake in clearance organs, particularly the spleen and liver.
PEGylation reduces the amount of protein that opsonizes nanoparticles and alters the content of the protein corona.
However, PEGylation may induce an adaptive immune response.

Self-Mimicry to Evade the Innate Immune System

Cells display CD47 on their surface as a “don’t eat me” signal to macrophages via SIRPα binding.
Nanoparticles displaying CD47 (or a fragment thereof) on their surface may behave similarly.
CD47 may be a viable alternative to PEG for prolonging the half-life of DDS.

Neutrophil Margination

Neutrophils transiently associate with the vessel wall in organs including the lungs in a process termed margination.
Approximately 50% of the intravascular pool of neutrophils are in this marginated pool.
Local inflammation and injury can lead to dramatic increases in this pool.

Cells Involved in Post-Stroke Inflammation

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

Distal Organs Respond to Danger Signals

Following local injury, chemokines, cytokines, and DAMPs emanate from the brain to recruit immune cells.
The first organ these mediators encounter is the lungs, which contain a large number of intravascular leukocytes (marginated neutrophils).
Signaling between danger signals and marginated leukocytes primes them for response to the brain injury.

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 plays a critical role in the pharmacokinetics and toxicities of DDS.
Nanoparticles can be engineered to evade the innate immune system using several approaches:
- Complement inhibitors: Prevent 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

This quiz explores the relationship between nanoparticles and the body's immune system, focusing on how targeting these particles can influence their uptake and elimination by leukocytes. Learn about the roles of macrophages, PEG modification, and the reticuloendothelial system in drug delivery systems.