Mucosal membrane Flashcards
what is the mucosal membrane function?
hydrate , lubricate
protective barrier
describe the composition of mucus?
unevenly distributed within the body
depends on disease state
It is a viscoelastic hydrogel
what is a viscoelastic hydrogel composed of?
Cross-linked mucin fibres (swell in water)
Cells/ cell debris
Microbiota and secretions (e.g. vaginal lactic acid)
DNA, proteins, Ig, lysozyme, lactoferrin * Lipids, polysaccharides
what are the properties of mucus?
- Variable pH
* Neutral (respiratory tract)
* Slightly basic (ocular, colonic (distal), endo- cervical)
* Slightly acidic (vaginal)
* Very acidic to almost neutral (gastric)
* luminal vs epithelial pH - Variable layer thickness
* Anatomical site: relatively thin in the nasal
cavity, thick in stomach and colon
* May vary depending on digestive activity
* Healthy vs. disease state (e.g. cystic fibrosis)
why does mucus act as a barrier?
Due to dynamic properties High Mucus turnover
* Nasal cavity and respiratory tract replenished every 10-20 min
* Gastro-intestinal tract: 50-270 min turnover
* Eyes: turnover rate 13-20% per minute
Due to composition
- Strong adhesive forces
- Electrostatic
- Negative charge
- hydrophobic
- due to lipids -Presence of hydrophobic domains
how can we design NPs to overcome mucus as a barrier?
adhere to mucus - mucoadhesive
penetrate the muscus - much-penetrating
how can NPs modified to be mucoadhesive?
1.non-specific binding using electrostatic interaction
anionic - poly(acrylic acid) or sodium alginate /gellan gum (-)
cationic - chitosan (+)
neutral - cellulose
2. covalent bonds
- disulphide bridges
3. lectins
- carbohydrate-bindomg (glycol)proteins - attached/coated to NPs
- active targeting NPs
risk of immunogenicity and toxicity
how do lectins promote mucoadhesion?
- cytoadhesion - bind to receptors that line the mucus
- cytoinvasion - promote invasion
- transcytosis - invade and cross the cells
how can NPs increase mucopentration?
be small adhesive/non-adhesice molecules = penetrate mucosal membrane
AND
V Small <100nm non adhesive molecules = penetrate the epithelium (OPTIMUM)
what are ideal mucus penetrating particle properties?
small enough to fit through pores in mucus
inert to avoid binding to mucus
how can Mucus-penetrating particles overcome adhesive and steric barriers? and how?
can be achieved by PEGylation
by masking the surface charge and hydrophobicity on surface particle
what is a disadvantage of PEG masking properties?
it can also allow molecules to be mucoadhesive too
impact of MW and density of PEG?
increase MW= increase adhesion = decrease penetration
low coverage = increase hydrophobic interaction = decrease penetration
what is Pluronic F-127 surface modification?
Triblock copolymer
Mechanism of action: Similar to PEG
Requires a poly(propylene oxide) segment > 3 kDa
what is the Adv/dis-adv of Pluronic F-127 surface modification vs. PEG?
- Physical adsorption on NP surface
- Stability of coverage is an issue
what are the issues with PEG?
- anti-PEG antibodies
- intracellular accumulation
what are mucolytic agents?
disrupt the mucus membrane via protein degradation (e.g. papain)/ entangled DNA degradation/ reduction of disulphide bonds
whats the difference between local and systemic lung administration?
how can we target different regions of the lung?
using size of NPs
Microparticles are larger= block smaller capillaries = embolism
what type of NPs are used for inhalation for pulmonary drug delivery?
lipid and polymer-based:
- Liposomes
- Polymeric nanoparticles
-Solid lipid nanoparticles
- Protein nanoparticles
what is HIC index?
measure of surface hydrophobicity
Higher HIC value = increase hydrophobic surfaces = increase adverse effects in the lung = toxic/inflammation
how can you increase alveolar macrophage uptake?
- passive targeting
increase MW - active targeting
- mannose coated NPs = affinity for mannose receptor = increase uptake -found in all macrophages (non-specific)
- lactoferrin coated NPs = increase uptake by epithelial cells
what Is lactoferrin?
80 kDa iron (Fe3+) binding glycoprotein, related to transferrin
**Ubiquitous distribution - secreted by epithelial cells into most exocrine fluids
both antibacterial and antiviral.**
what is the disadvantage of lactoferrin
its a glycoprotein that can undergo degradation by proteases
why is mucosal vaccination used?
Route of entry for pathogens
Ease of administration - no need to train / no needles
Local AND systemic immunity
what are the two sites in the mucosal immune system?
inductive site - where the immune response starts
effector site - effector cell mediate the immune response from the inductive site
what are some examples of inductive site?
mucosal-associated lymphoid tissue (MALT)
- G(ut)ALT - appendix / solitary lymph nodes
- B(roncheal)ALT
- N(asal)ALT - tonsil/ adenoid lymph nodes
what is type 1 MALT ?
- respiratory region
- GIT
- upper female reproductive tract
gIgA effector molecules
microfilm cells in epithelium mediate transport antigen/pathogens from the lumen to immune structures
what is type 2 MALT ?
Type 2 MALT (Mucosa-Associated Lymphoid Tissue) plays a crucial role in immune surveillance and defense against pathogens that enter the body through the respiratory mucosa.
what is the ideal vaccine delivery system?
Protective
* Prevents degradation of the vaccine
Targeted
* Increased accumulation at inductive sites * Avoid entrapment in mucus layer
Effective
* Able to stimulate immune response to pathogen
Safe and not immunogenic in itself
how can you improve mucosal vaccines?
use adjuvants by reducing the dose and enhancing immune response
what are common adjuvants?
aluminimum salts
emulsions
example ISCOM for mucosal delivery
what is ISCOM?
Mixture of:
* Phospholipids
* Cholesterol
* Quil A (soap bark tree extract) – immunoadjuvant that punctures holes in membranes
Antigen incorporation into lipid network
how to passively target M cells?
large size
Importance of surface chemistry
* Charge
* Hydrophobic surface
* Adhesion to M-cells
how to actively target M cells?
- Cholera toxin B
* Adjuvant properties
* Risk of CNS inflammation - UEA (Ulex europaeus agglutinin I)
* Selective binding to M cells in Peyer’s patches
how to trigger innate immunity?
adjuvants
hydrophobic surface
DAMPs
how can targetting dendritic cells improve mucosal vaccines?
found in type 2 mucosa
lectin ligand, antibody, mannose receptors
= inc uptake
