PURE ZETA: PART THREE:
Surface charge (zeta) on LNP not only directs WHERE it goes in the body, but HOW it interacts w/different things. Many variables impact zeta.
Today: Smoluchowski Equation (zeta):
η = viscosity of the medium.
Viscosity is resistance to flow.
2/ Viscosity tells us how thick or "sticky" a fluid is. In simpler terms, viscosity determines how easily a liquid or gas flows. Viscosity can relate to the oil in your car. Only synthetic oil touches my cars, because synthetic oil has a higher velocity index. This means, the
3/ viscosity changes less, and is more stable, as the temperature changes during normal engine startup and operating conditions.
This has multiple components. One is called, when speaking to oil, the velocity index. Most oils become thinner, and less viscous, as they are heated.
4/ Most oils are temperature dependent. They thicken when cooled, and liquify when heated--but not all. Think of margarine as an example (yuck).
At higher temps, this is a liquid. At room temps and cooler, they are thicker. Less viscous when heat is applied. The velocity
5/ index tells us how much the viscosity of an oil changes, as temperature changes. Viscosity Index (VI) have certain ratings and specific ratings are preferred for different applications. For those of us with 4 seasons, we use different VI oils in summer vs winter.
6/ Viscosity when, it comes to the application of LNP and surface charge (zeta), is VERY important, because we have different viscosities in the human body--quite different. As an example the viscosity of our blood is quite different than that of spinal fluid (CSF).
7/ In the human body, the viscosity or resistance for blood circulation includes friction between the blood elements and between the vessel lumen and blood.
Let us take ME for example. I am a six foot tall, 48 year old ginger. I run a LOT. I do not drink or smoke. I take
8/ blood thinners. I have low resting HR of 40 from being a 40 + year distance runner and am listed as in awesome cardio shape at the doc, (elite). My blood pressure is 90/60 most days. I have some health concerns, but they do not impact this measurement. My viscosity of my
9/ blood at 37°C (98.6°F): Approx 3.0 to 4.5 centipoise (cP).
Plasma viscosity at 37°C: Approx 1.2 to 1.4 centipoise (cP).
This is much different than my cerebral spinal fluid.
CSF viscosity at 37°C: Approx 0.6 to 1.0 centipoise (cP).
THAT's a difference! Those are just three!
10/ every number in this calculation of zeta, is crucial to WHAT the surface charge (zeta) on the LNP is, because it is in RELATION to WHAT it is IN!
IT is NOT always static!
Centipoise (cP) is equal to one one-hundredth (1/100) of a poise
Water at 20°C (68°F) has a dynamic
11/viscosity of about 1.002 centipoise (cP). Dynamic means changing. Static means the same ZETA can stabilize, but it can be static. The pegylated lipids on the outside of the LNP were put there for a few reasons. But they are not a guarantee (of anything).
12/ Viscosity itself is NOT a property of the brain tissue. Bone, muscle, heart, connective tissue, organs, and other areas do not have a measurable viscosity, these are more mechanical measurements and electrical.
The EYES have different viscosities.
The cornea has low
13/ viscosity, as it needs to make tears for lubrication.
The Aqueous Humor has low viscosity to maintain pressure in the eye and nourishment. The lens is mostly protein fibers--low if any viscosity. Vitreous Humor: higher viscosity to maintain shape (in trouble if vitreous
14/ detachment, floaters, anyone?) Retina: no fluid like viscosity here. Other parts do not have much for viscosity, except for the tear film.
So, the value for viscosity, CAN influence the zeta potential, biodistribution 9where the LNP goes in the body, and how it interacts.
15/ As per the equation that is used, Higher Viscosity (η): If the viscosity of the medium in which particle is moving increases, the denominator in the equation (η) becomes larger. As a result, the calculated zeta potential (ζ) would decrease. I
16/ Higher viscosity reduces electrophoretic mobility and, consequently, the zeta potential. Higher viscosity lowers zeta.
Conversely, if the viscosity of the medium decreases, the denominator in the equation (η) becomes smaller. This would lead to an
17/ increase in the calculated zeta potential. Lower viscosity enhances the electrophoretic mobility and the zeta potential.
This means it is indirectly proportional to the final calculated zeta potential.
Let's go back to the BLOOD and SPINAL FLUID.
18/ Blood has a higher viscosity compared to CSF. The higher viscosity of blood can result in a lower zeta potential compared to CSF.
However, there is also pH to contend with in the blood versus CSF, and IONS in the blood, proteins, the endothelium, and other molecules.
19/ The zeta potential of nanoparticles can also be influenced by the local environment in different parts of the body, and
20/ cells lining blood vessels. In contrast, nanoparticles in the CSF may experience different interactions within the central nervous system.
Next up: pH and ions influencing ZETA potential biodistribution, and interactions in human body in different organs and compartments.
(correction, I DO NOT take blood thinners. DO NOT. NO ibuprofen, no aspirin, no cinnamon, no natto, none of that)
@SenatorRennick
It is going to get interesting when ions are tied in, and proteins in the body. ;)
21/ For reference, At room temperature 68 F to 77 F, the viscosity of pure ethanol is approximately 1.043 to 1.074 centipoise (cP). And again: Blood: is 3.0 to 4.5 centipoise (cP). Blood also has ions, proteins, and other molecules.
Pfizer measured zeta potential (surface charge) on an LNP, that was submitted, to the FDA, in bulk solvent (prob ethanol, no ions there) at -3 mV.