PURE ZETA: PART SEVEN: LNP: How Zeta Changes in the Human Body (layman's), and Why Pharma Companies are Incorrect
PURE ZETA: PART SEVEN: LNP: How Zeta Changes in the Human Body (layman's), and Why Pharma Companies are Incorrect Stating their Calculation of Zeta Potential (surface charge) is Accurate, much less, that it will not do harm.
Zeta is the starting point for most adverse events.
2/ (read previous threads for full explanations on LNP/Colloids/lipids/Zeta)
Zeta is calculated by physical means, and also equations (Smoluchowski/Henry), as previously explained in these threads, in depth (for X). Zeta is the kickoff point to adverse events. It is the ignition.
3/ Fact: the measured zeta that drug companies said would not bind, -3.13 mV, was measured in a bulk solvent, and had NOTHING to do with the human body. DNA plasmid contamination, changes in PEG, both correlated to specific batches in adverse events, PROVEs this (next thread).
4/ THEY ARE WRONG. The data inputs used for calculating the surface charge CHANGES depending on WHERE in the body the NLP IS, what it interacts with, and again, zeta changes immediately more negative with the DNA plasmid contamination. This is not hypothesis. This is factual.
5/Key factors that change and impact surface charge of LNP (zeta), determining WHERE it goes in body (biodistribution) and WHAT it does (the starting point behind where spike is expressed, where mutations would occur (if they did), and al of the bad things, beings with ZETA:
6/Debye length is CRITICAL in Smoluchowski equation. DEBYE is influenced by ionic strength. In fluids like blood or interstitial fluid, ionic strength is lower compared to highly ionic solutions, resulting in a larger Debye length in biological fluids. This changes zeta.
7/ Changes in ionic strength of biological fluids changes Debye length and zeta. An increase in ionic strength results in a shorter Debye, which changes zeta--changing strength (and possibly direction) of surface charge, changing where the LNP goes, and what it is about to do.
8/ Changes in pH changes the surface charge of the LNP. Many biological fluids have specific pH values that can influence the zeta potential. Variations in tissue pH changes the surface charge of the LNP in specific body compartments, changing what it does and where it goes.
9/Biological fluids contain proteins, like albumin and immunoglobulins, that can adsorb onto the surface of the LNP. The adsorption of proteins can change surface charge (zeta) of the LNP. This phenomenon is known as protein corona formation. And it can cause adverse events.
10/LNPs interact with cells and tissues in body, which can alter local environment and ionic strength. Cellular responses, such as release of cytokines, can lead to changes in pH or ionic strength, impacting the zeta potential, causing an IMUNE SYSTEM CASCADE (cytokine storm).
11/ Different tissues and body compartments have varying ionic strengths, pH levels, and protein compositions. Ionic strength in the blood is different than that of interstitial fluid, or the CSF. These differences impact zeta as they traverse different body compartments.
12/ BLOOD: ionic strength is relatively constant and tightly regulated to maintain conditions. The electrolyte composition in blood plasma (sodium, potassium, calcium, and chloride ions, is well-controlled, resulting in a stable ionic strength. HOWEVER, the presence of plasma
13/proteins and cellular components can changes in zeta potential due to protein corona formation and interactions with blood cells, leading to a cascade of possible effects.
Interstitial fluid is the fluid that surrounds cells in tissues. It contains a similar electrolyte
14/composition to blood plasma, but ionic strength depends on the tissue type. Ionic strength in interstitial fluid around muscle tissue may differ from that in interstitial fluid around adipose tissue. These variations change zeta of LNP as they move between tissues.
15/Inside cells, ionic composition and strength are VERY different from extracellular fluids. intracellular environment has high concentrations of potassium ions (K+) and low concentrations of sodium ions (Na+). LNPs entering cells change in ionic strength and zeta. Every time.
16/Mucous Membranes:gastrointestinal tract or respiratory system, ionic strength changes by secretion of mucus, which contains specific electrolytes. The interaction of LNP w/ mucous membranes CHANGES THE LNP ZETA, and what it will do. The cerebrospinal fluid (CSF) that
17/surrounds brain and spinal cord has a different ionic composition compared to blood plasma. The ionic strength in CSF is lower, creating a longer Debye length. This difference changes LNP surface charge when entering the CENTRAL NERVOUS SYSTEM, INCLUDING THE BRAIN.
18/ The bloodstream is not the only place LNP can come in contact with proteins and form protein coronas. Protein corona formation can also occur in extracellular fluids, such as interstitial fluid or the fluid surrounding cells in tissues. When LNPs are introduced into these
19/ environments, they can adsorb proteins from the local milieu, chaning the surface charge and behavior--causing them to bind with certain tissues, cause clots, cause internal inflammation, bind with endothelium, react with antibodies, and enter areas like the pituitary.
20/ Mucous Membrane: LNP can interact w/ proteins in mucus secretions. This interaction can result in protein corona formation and impact the LNP interactions with mucous membranes and cells, leading to adverse events. Cerebral spinal fluid--the LNP can form coronas here too.
21/Existing CANCER and TUMORS: The environment in tumors is different as well, and the zeta potential can change when LNP comes in contact with tumors and growth, it does not matter if they are benign or malignant.
Inside cells, particularly immune cells such as macrophages
22/and dendritic cells, nanoparticles may encounter a different set of proteins during endocytosis and cellular uptake. This can influence the particles' intracellular fate.
Back to ions: MUSCLES have a different ionic strength, and this can change zeta and the interactions.
23/ Adipose tissue (fat), has a distinct microenvironment. It contains a variety of adipokines and fatty acids, which can interact with LNP and change ZETA. Yes, your FAT!
The CSF surrounding brain and spinal cord has a lower ionic strength than blood plasma. This results in a
24/longer Debye length, allowing for more spatial distribution of LNP, and can impact their behavior at interfaces, making them more accessible to certain areas of the CNS.
Next thread ties everything together. Citations exist in previous threads, breaking down everything.