Podcast Beta
Questions and Answers
What is a common characteristic of clinically-used lipid-based drug delivery systems?
In which therapeutic areas are nanoparticles approved for use?
What type of materials are liposomes and lipid nanoparticles primarily composed of?
How do viruses that infect humans typically differ from lipid-based nanoparticles?
Signup and view all the answers
What is a unique feature of most clinically-used lipid-based drug delivery systems?
Signup and view all the answers
Which of the following statements about drug delivery systems (DDS) is correct?
Signup and view all the answers
What type of delivery system primarily utilizes small molecule drugs?
Signup and view all the answers
What distinguishes lipid-based drug delivery systems from other types?
Signup and view all the answers
What is the primary effect of PEGylation on the pharmacokinetics of liposomal drugs?
Signup and view all the answers
How does PEGylation affect the uptake of liposomal drugs in clearance organs?
Signup and view all the answers
What effect does PEGylation have on the protein corona of nanoparticles?
Signup and view all the answers
What is a potential drawback of PEGylation in drug delivery systems?
Signup and view all the answers
What role does CD47 play in the immune system as it relates to drug delivery systems?
Signup and view all the answers
In what way does neutrophil margination affect drug delivery?
Signup and view all the answers
What effect does local inflammation have on the intravascular pool of neutrophils?
Signup and view all the answers
How might nanoparticles utilize CD47 in drug delivery approaches?
Signup and view all the answers
What is the main purpose of loading liposomes with dexamethasone in the treatment of brain inflammation?
Signup and view all the answers
Which strategy is NOT mentioned as a way to engineer nanoparticles to evade the innate immune system?
Signup and view all the answers
What phenotypic change occurs in macrophages as a result of successful treatment for inflammation in this study?
Signup and view all the answers
Under inflammatory conditions, how can nanoparticles be selectively delivered to sites of injury?
Signup and view all the answers
What role does albumin play in assessing brain inflammation?
Signup and view all the answers
What role do chemokines play in the context of stroke?
Signup and view all the answers
In which phenotype are macrophages associated with tissue repair after stroke?
Signup and view all the answers
Which statement accurately describes immune cell recruitment post-stroke?
Signup and view all the answers
What are DAMPs in the context of brain injury?
Signup and view all the answers
Which organ is first encountered by mediators after a brain injury?
Signup and view all the answers
What is the role of marginated neutrophils in response to brain injury?
Signup and view all the answers
What can be a consequence of shifting macrophages from M1 to M2 phenotype?
Signup and view all the answers
How are endothelial cells involved in immune cell recruitment?
Signup and view all the answers
What role do antibodies play in coating nanoparticles for leukocyte targeting?
Signup and view all the answers
Which aspect of leukocyte behavior is promoted by targeting with nanoparticles?
Signup and view all the answers
Which leukocyte types are predominantly found in the brain after nanoparticle targeting?
Signup and view all the answers
What does a significant lung uptake of nanoparticles indicate about their distribution strategy?
Signup and view all the answers
How long were the lungs monitored for nanoparticle interaction in the study?
Signup and view all the answers
What cellular marker is commonly associated with leukocytes in this context?
Signup and view all the answers
What percentage of recovered cells in the lungs were shown to be NC+?
Signup and view all the answers
Which outcome is NOT promoted by nanoparticle targeting of migrating leukocytes?
Signup and view all the answers
What is a potential disadvantage of high lung uptake of nanoparticles?
Signup and view all the answers
In terms of leukocyte distribution, how were brain and lung uptake levels assessed?
Signup and view all the answers
What physiological effect does the targeting of leukocytes with nanoparticles aim to achieve?
Signup and view all the answers
What is the implication of nanoparticles predominantly being found in monocytes and neutrophils post-targeting?
Signup and view all the answers
What characteristic of nanoparticles contributes to their selective targeting of leukocytes?
Signup and view all the answers
Study Notes
Clinically-Used Drug Delivery Systems
- Lipid nanoparticles are used clinically to deliver various therapeutic agents, including 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.
Liposome and Lipid Nanoparticle Characteristics
- Clinically-used liposomes and lipid nanoparticles:
- Are generally spherical.
- Have a diameter of 50-100 nm.
- Are composed of a mixture of phospholipids and cholesterol.
- Are coated with polyethylene glycol (PEG).
Viruses
- Human viruses are typically:
- Spherical or filamentous.
- Have a diameter of 20-300 nm.
- Have a protein capsid that protects nucleic acids.
- May be coated with a lipid envelope.
Effects of PEGylation on Drug Delivery Systems (DDS)
- 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.
- PEGylation alters the content of the protein corona.
- PEGylation may induce an adaptive immune response.
Self-Mimicry to Evade the Innate Immune System
- Cells express CD47 on their surface as a "don't eat me" signal to macrophages via SIRPα binding.
- Nanoparticles displaying CD47 (or a fragment) on their surface may behave similarly.
- CD47 may be an alternative to PEG for prolonging the half-life of DDS.
Harnessing the Innate Immune System
- Neutrophil Margination:
- Neutrophils transiently associate with the vessel wall in organs including the lungs.
- Approximately 50% of the intravascular pool of neutrophils are in this marginated pool.
- Local inflammation and injury can increase this pool.
Cells Involved in Post-Stroke Inflammation
- Endothelial activation and chemokine release promote immune cell migration into the brain after 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 lymphoid tissues.
Distal Organs Respond to Danger Signals
- Following local injury, chemokines, cytokines, and DAMPs emanate from the brain to recruit immune cells.
- These mediators encounter the lungs first, which contain a large number of intravascular leukocytes.
- Signaling between danger signals and marginated leukocytes primes them for response to the brain injury.
Targeting Migrating Leukocytes
- Coating nanoparticles with antibodies binding to leukocytes promotes:
- Rapid uptake and elimination from the lungs.
- Steady delivery to the inflamed brain.
- Nearly all nanoparticles in the brain are found in monocytes and neutrophils.
- This approach enables selective targeting of migrating innate immune cells.
Targeting Migrating Leukocytes to Treat Inflammation
- Brain inflammation is characterized by edema, which can be tracked using albumin accumulation.
- Liposomes loaded with a corticosteroid (dexamethasone) and targeted to leukocytes effectively reversed edema and polarized macrophages to the anti-inflammatory M2 phenotype.
Summary
- The innate immune system plays a crucial 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 to prevent anaphylaxis and macrophage uptake.
- PEGylation to evade opsonization.
- Self mimicry to provide "don't eat me signals" to macrophages.
- Nanoparticles can be engineered to harness the innate immune response for selective delivery under inflammatory conditions:
- Marginated neutrophils respond to agglutinated protein.
- Endothelial cell activation enables selective delivery in stroke.
- Leukocyte migration allows for "hitchhiking" to sites of injury.
Studying That Suits You
Use AI to generate personalized quizzes and flashcards to suit your learning preferences.
Related Documents
Description
Explore the world of lipid nanoparticles and liposomes in medicine, including their structure and function in drug delivery systems. This quiz covers various therapeutic areas and the effects of PEGylation on drug delivery. Test your understanding of these clinically-used systems and their applications in healthcare.
