https://s3-us-west-2.amazonaws.com/secure.notion-static.com/2be03e38-0363-4c08-8bf7-da1da1a7df22/1-s2.0-S0169409X08002652-main.pdf

Bulk Viscosity of mucus is typically 1000-10000 times that of water.

Mucus gels are loaded with bacteria, cells, lipids, salts, proteins, macromolecules, and cellular debris. 90-98% of mucus is water.

Viscoelasticity is regulated by controlling water: mucin secretion ratio.

and also by controlling lipid ion content. (mucus rheology [47])

viscoelasticity increases with acidity. pH of the lung and nasal mucus is neutral

The understanding of mucus layer thickness and clearance times at various mucosal surfaces is important to the development of particles designed to overcome mucosal clearance mechanisms, since they must penetrate mucus at rates markedly faster than mucus renewal and clearance in order to overcome the barrier.

if the viscosity of the fluid that fills the pores in mucus is equivalent to that of water, the diffusion rates of particulates significantly smaller than the average mucus mesh pore size, assuming they do not adhere to mucus, are expected to be similar to their rates in water.

The obstruction scaling model assumes the average pore size to be 100 nm.

Therefore the size of the Mucus Penetrating Particles must be < 100 nm

Working of mucus as a sticky net:

• Airborne particles typically adhere to respiratory mucus before reaching the alveoli. Filtered particles are removed from the airways by mucociliary clearance and become sterilized by gastric acid
• The primary mechanism by which mucus gels efficiently trap foreign particulates is the formation of polyvalent adhesive interactions
• In addition to the negative charges imparted by the presence of carboxyl or sulfate groups on the mucin proteoglycans, there exist periodic hydrophobic “naked” globular regions along mucin strands, stabilized by multiple internal disulfide bonds
  • The high density of hydrophobic domains, coupled with the flexible nature of mucin fibers, allows efficient formation of multiple low-affinity adhesive interactions with hydrophobic regions on the surfaces of foreign particulates.
  • Although each low-affinity hydrophobic interaction can be readily disrupted by thermal energy, a large number of low-affinity adhesive interactions with the mucus mesh effectively immobilizes particles with permanent high viscidity

Foreign particles smaller than average pore size might be stopped nevertheless if the particles have high viscidity and thus are more attracted towards hydrophobic interactions. This would even dominate the effect of negative negative repulsion between proteoglycans and the foreign particles.

The dual capacity to form polyvalent adhesive interactions via both hydrophobic and anionic forces represents a particularly challenging problem for polymeric nanoparticles designed to deliver drugs and genes, since many commonly used biomaterials are either hydrophobic, such as poly (lactide–co-glycolide) and polyanhydrides, or cationic, such as polyethylenimine, chitosan and polylysine

inspiration from viruses

• coating the particles with densely charge positive-negative layer rendering the particle neutral yet hydrophilic and controlling the size of the particle such that it fits the pores.
  • instead of a high density of charge groups, we hypothesized an uncharged surface may be as muco-inert as viral capsids, provided the surface is sufficiently hydrophilic and low hydrogen bonding.

Required polymer:

• Generally regarded as safe
• strong hydrophilicity
• neutral charge

PEGylation

• PEGylation of nanoparticles may also enhance their stability in mucus. Stability is particularly important when particles must diffuse through a thick mucus layer in order to reach underlying cells.
• PEG coated large nanoparticles are OP

The rapid mucosal transport of large (200 and 500 nm) PEG- modified particles has important implications for the development of therapeutic and imaging applications in vivo.

Larger nanoparticles afford substantially higher drug encapsulation as well as reduced aggregation upon freeze drying.

As the size of drug-loaded particles increases, the drug-release kinetics are usually greatly improved as well, allowing sustained release of therapeutics over days and even months along with enhanced therapeutic efficacy