[BBB/Junk Sciences] Polysorbate 80 and the BBB or how to put anti-vaxxers into a blowing cognitive dissonance

Here we go again, anti-vaxxers keeping on moving the goalpost to fit their belief instead to change to adjust it to the facts. First it was mercury, then it was formaldehyde, then aluminum, today the “ingredient du jour” is polysorbate 80 and tomorrow they will blame it to PBS saline solution.

The latest fad as I have seen is to blame polysorbate 80 as a source of “vaccine-injury” with the bold claim that it breaks down the blood-brain barrier (BBB). Lets put the fact straight and debunk this one for all. But what is even better is the “what if” counter-argument. What if polysorbate 80 was indeed a good ingredient? I will come to that later.

Polysorbate (aka Tween 80) is a amphiphile compound   as you can see the molecular structure below (source Wikipedia):
1200px-polysorbate_80

You can see the structure made of a lipophilic (loves fat) tail and a series of hydrophilic  (loves water) tails, loaded with oxygen and hydroxyl groups. This is a typical structure of a detergent: one side will mix well with water, the other will mix very well with fat and oils. The result? You can form microspheres that can dissolve well in water and dissolve fat into water. This is how a detergent works, it helps to breakdown fats into small spheres and dissolve them in the drain water.
Polysorbate 80, due to this property, is very good to dissolve drugs and medicines that under normal condition would barely dissolve into biological fluids. This is why we have it in vaccines, but we also have it in medicines. Thats the job of biopharmaceutics: finding formulations to dissolve drugs into the body and allow them to reach a concentration high enough to display their therapeutic activity.

The use of polysorbate 80 in drug delivery of anti-cancerous drug is probably the first and foremost main driving factor on investigating its effect on the BBB. Brain tumors (primary and metastatic alike) are up until now one of the most dreaded and deadliest form of cancer. For instance, the average expected lifespan upon diagnosis of a grade IV glioma (aka glioblastoma multiforme) is grim: 18-months, with less than 5% survival after 5 years. The major issue is being able to deliver drugs and chemotherapy across the BBB. As reported by Pr. William Partridge (UCLA) the BBB remains the bottleneck in drug development for the treating neurological disorders (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC539316/?fref=gc&dti=873247819461536)

The first report of the investigation of polysorbate 80 on the BBB is probably by Spiegelman and colleagues in 1984 (http://thejns.org/doi/pdf/10.3171/jns.1984.61.4.0674), investigating the effect of the solvent used in etoposide solution for treating cancer. According to their  result, they noted a statistical difference in the BBB permeability  (using Evans Blue and 99mTc as tracers) following the injection of 1.125ml/kg. According to their paper, 5mL solution contained 400mg of polysorbate 80 or a concentration of 80mg/mL. Based on this, we can assume that the BBB effect was observed for a dose of 90mg/kg. Thats a very huge dose.
If we go back to the manure anti-vaxxers say, the amount injected via vaccines is enough to cause a barrier opening. According to John Hopkins University Institute of Vaccine Safety (http://www.vaccinesafety.edu/components-DTaP.htm), the expected concentration of polysorbate is lesser or equal to 100mcg or micrograms. Thats 0.1mg per dose. If we assume such dose is injected to a newborn (average weight ~3 kgs), then the amount injected is about 0.033mg/kg. Thats 2700 times less than what has been reported to induce a BBB disruption. Also you have to factor the bioavailability of polysorbate (that is 100% upon IV route) making this number a very optimistic number.
Now, the interesting twist about polsyorbate 80 is its use to enhance some drug carriers and its widely used for finding novel formulation to enhance the delivery of anti-cancerous drugs across the BBB. You can find a list of publications on Pubmed about that aspect (https://www.ncbi.nlm.nih.gov/pubmed/?term=polysorbate+80+blood-brain+barrier). What if polysorbate 80 not only will not injure your brain, but actually may help deliver drugs to help your brain fight disease?

 

Keep in mind that polysorbate 80 is good at dissolving lipid in water solutions but it is not good to let charged molecules accross the BBB, just in case someone comes with the claims that it conjugates with aluminum. Thats some high-school chemistry level.

 

 

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4 thoughts on “[BBB/Junk Sciences] Polysorbate 80 and the BBB or how to put anti-vaxxers into a blowing cognitive dissonance

  1. “[Polysorbate-80 modified neurotoxin nanoparticle with its transport and cytotoxicity against blood-brain barrier].

    [Article in Chinese]
    Zhao YM1, Xia AX, Wei YH, Ruan YP, Li FZ.
    Author information
    Abstract
    This study was aimed at the transport across blood-brain barrier (BBB) of polysorbate-80 modified neurotoxin loaded polybutylcyanoacrylate nanoparticle (P-80-NT-NP) and its cytotoxicity. An in vitro model of BBB using rat brain microvascular endothelial cells (rBMECs) was established. The cytotoxicity of P-80-NT-NP was measured by the MTT assays, where neurotoxin (NT), nanoparticle (NP), neurotoxin nanoparticle (NT-NP) as control, and the permeability of P-80-NT-NP was determined by using of Millicell insert coculture with rBMECs and fluorescence spectrophotometry. MTT results showed that NT, NP, NT-NP and P-80-NT-NP were avirulent to rBMECs when the concentration of NT was lower than 200 ng x mL(-1). But the cytotoxicity of NP, NT-NP and P-80-NT-NP would be augmented accordingly as concentration increased (P 0.05). When the concentration of NT was 150 ng x mL(-1), the permeability on rBMECs of P-80-NT-NP and NT-NP were both significantly higher than that of NT (P < 0.01), and the permeability of P-80-NT-NP was greater than that of NT-NP (P < 0.05). In conclusion, polysorbate-80 modified neurotoxin nanoparticles can transport across the BBB, while concentration of NT is greater than 200 ng x mL(-1), P-80-NT-NP has a little cytotoxicity against rBMECs.

    https://www.ncbi.nlm.nih.gov/pubmed/21348312

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    • The article is in Chinese, unless you can read Mandarin there is little we can discuss on it except that here PS80 was used as a delivery vector to enhance the delivery of a neurotoxin across the BBB. Unless you increased the dose of NT, no cytotoxic effect of PS80 combined with NT was observed.
      That’s according to their English abstract.

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  2. “The BBB, like cell membranes in general, is subject to solvent-mediated disruption with chemicals such as ethanol, dimethylsulfoxide (DMSO), or detergents such as SDS, or Tween 80 also known as polysorbate-80.27–30 There are numerous examples in the literature where the peripheral administration of a drug, which normally should not cross the BBB, is followed by pharmacological activity in the brain. Such an observation could arise because the drug is transported across the BBB via an endogenous transport system. However, an alternative explanation is that the drug is injected in a diluent that is membrane destabilizing, and causes BBB disruption. Often the drug is solubilized in solvents such as ethanol or DMSO, or surfactants such as SDS, a Tween detergent, or other surfactants, such as polyethyleneglycol hydroxy stearate. Doses of solvents such as ethanol or DMSO at a level of 1-4 g/kg may cause solvent-mediated disruption of the BBB.27,28 This dose of DMSO or ethanol is given to animal models with surprising frequency, particularly small rodent models such as mice, which weigh only 20-30 g. The administration of just 50 μl of 50% DMSO to a 20-g mouse is equivalent to 1.25 g/kg DMSO, and there are examples in the literature of pharmacologic effects achieved in brain following systemic administration of drugs that normally do not cross the BBB. These drugs are administered in solvents such as ethanol or DMSO and the dose of solvent is such that BBB disruption may be caused by administration of the drug/solvent mixture. Tween 80, also known as polysorbate-80, is frequently administered in CNS drug formulations. A dose of polysorbate-80 of 3-30 mg/kg will cause BBB disruption in mice.30 Analgesia with kyotorphin, a oligopeptide that normally does not cross the BBB, is possible following the peripheral administration of the peptide, providing Tween 80 is coadministered.31 Low doses of another surfactant, SDS, are frequently included in CNS drug diluents. However, doses of SDS as low as 1.0 μg/kg can cause disruption of the BBB for short periods. Immune adjuvants such as Freund’s complete or incomplete adjuvant cause disruption of the BBB to circulating IgG that can persist for weeks.

    https://www.ncbi.nlm.nih.gov/pmc/articles/PMC539316/

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