One of the most innovative technologies to advance the field of nanomedicine has been the lipid nanoparticle delivery system in genetic medicine - and also their current use in COVID-19 vaccines from Pfizer and Moderna.
Inside a lipid nanoparticle. Illustration by Precision Nano Systems.
Lipid nanoparticles (LNPs) and Solid lipid nanoparticles (SLNs) are bioactive organic molecules that can easily penetrate cells, making them the ideal vector for cancer treatment.
Nanoparticle drug delivery in cancer treatment. Illustration from Science Direct, Journal of Advanced Research, Volume 15, Jan 2019, pp. 1-18.
Whereas in conventional cancer treatment, invasive surgery, chemotherapy or radiation treatment are often the normal modes of treatment, lipid nanoparticles can deliver drugs directly to cancer cells reducing their toxicity on the body. In addition, the cancer cells that absorb the nanoparticles can be destroyed through infrared light (which heat up the nanoparticles and hence causing cell death).
In vaccines, lipid nanoparticles can directly enter the cell and have the ability to modulate cell fate, induce or prevent mutations, initiate cell-to-cell communication and modulate cell structure, which makes them entirely powerful in their ability to affect cells at the nano-bio interface.
However, because lipid nanoparticles are bioactive organic molecules, they are easily cleared by the body through the kidneys, and prevent extending circulation throughout the body. It is through this reason the Pfizer and Moderna COVID-19 vaccines have used a method of PEGylation in order to extend the half-life of lipid nanoparticles in the bloodstream.
Nanoparticles are often coated with PEG (a non-biodegradable polymer, or plastic) in order for it to stay in the body for a longer time. Illustration from Biopharma PEG
PEGylation is a system in which lipid nanoparticles are coated with polyethylene glycol (PEG) which is a hydrophilic coating polymer, a type of water-attracting plastic, a petroleum byproduct and known human and animal carcinogen in high quantity. Despite the fact that the use of PEG has been cleared to be generally non-toxic in low doses, the long-term effect PEG coatings have on the nanoscale level on cells is largely undetermined.
Cytoplasmic vacuoles (arrows) are associated with variable levels of PEG immunoreactivity in the heart (A) kidney (B), choroid plexus (C), lung (D, E), and spleen (F, G). These vacuoles cause cell death or cancer. Image by James T. Alston, ResearchGate
Studies have shown that with the use of PEGylated therapeutics there have been multiple incidences of cellular cytoplasmic vacuolization (small vacuoles develop adjacent to cells causing cell death or cancer). PEG-induced vacuolation is especially problematic because there are no long-term effects on its toxicity on the presence of PEG in cells.
In addition, nanoparticle vaccines that utilise PEGylation have been shown to break through the blood-brain barrier (BBB) through active transcytosis, and it has been documented that the exposure to hydrophilic coating polymers on brain tissue have caused multiple brain lesions and also induces a cerebral foreign body reaction.
MRI of a brain of a 52 year old woman who developed cystic and necrotic changes in the corpus callosum of her brain after receiving the Pfizer COVID-19 vaccine; she was diagnosed with IDH-wildtype Grade IV glioblastoma. Image from Cureus.
Adverse reactions to the lipid nanoparticle COVID-19 vaccines have included fever-inducing seizures, demyelinating diseases, and other neurological conditions in which medical experts are not in consensus regarding the cause. However, these severe adverse reactions could potentially be caused by the presence of PEG in cells, subsequently breaking through the blood-brain barrier, causing vacuolization in brain tissues which could lead to long-term neurological disorders.
The delivery of lipid nanoparticles in medicine has been revolutionary, but many of the long-term effects are still yet unknown. Exposure to PEG has been shown to have cytotoxic effects, despite its rating as a non-toxic agent in vaccine delivery systems. However, we must consider in the field of medicine that much is guesswork and still unknown, but that research has definitely shown that exposure to PEG in brain tissues has been known to cause long-term neurological damage in addition to causing vacuoles in cells.
President Joe Biden, with his son, Beau, who had passed away in 2015 from glioblastoma after serving in the Iraq War. During times of pandemic, our political leaders do the best they can to ensure the safety of the population by mass vaccination campaigns. However, we must remember that our political leaders are not medical researchers, and often blindly trust the opinions of big pharma lobbyists. Recently, President Biden mandated the COVID-19 nanovaccines for US workers. Image from the New York Times.
Due to the relative expediency and unknown track record of nanovaccines utilising PEGlyation, it is imperative that we have to consider what we do not yet know. A mandate of vaccines in the past, such as the Anthrax vaccine for US military members had been entirely unsuccessful in its campaign and only served to create controversy in the harmful effects it had on service members along with fueling distrust and dissent in the population towards the government.
Mandate of vaccination campaigns in the past only led to fueling distrust and dissent amongst the population and against its government. Image from the documentary "Direct Order" (2003) which focuses on the US Military Personnel who were ordered to take the anthrax vaccine against their will and suffered life-changing adverse health effects as a result. Soldiers who refused to take the vaccine were court-martialled and dishonourably discharged.
"Youth is our future" is the motto of the people of Saudi Arabia. However, a mandatory COVID-19 nanovaccine campaign could potentially sabotage the innovative, growing nation undergoing transformation, as the long-term effects of nanoparticle vaccines on neurological functions are still yet unknown. Image of graffiti art in Saudi Arabia from commonspace.eu
The long-term effects of exposure to PEG-coated nanoparticles that are able to break through the blood-brain barrier can have severe long-term consequences not yet visible in a young population such as in Saudi Arabia, where more than 50% of the population are young people studying at universities and young people represent 2/3 of the Kingdom's population.
In the 1950s, the polio vaccine had been administered to hundreds of thousands of American youth, who decades later developed incurable cancers due to the then unknown strain of Similan virus from which the polio vaccine had been produced. Likewise, the long-term effect of PEG-coated nanoparticles which are able to break through the blood-brain barrier may take decades to unravel in its effects on neurological functions, and may unwittingly sabotage the youth in nations such as Saudi Arabia, which is at current time undergoing a Renaissance as an intellectual and cultural centre.
Despite that PEG has been labelled as a safe, inert and non-immunogenic synthetic polymer, numerous PEG-related toxicological and immunological issues have raised questions about its safety and efficacy in the delivery of nanomedicine.
The AstraZeneca and Johnson and Johnson COVID-19 vaccines utilise a traditional viral vector using viral nanoparticles as its delivery method. Although the chimp adenovirus has been reportedly utilised in order to reduce potential side effects, many serotypes of adenoviruses are able to cross the blood-brain barrier.
AstraZeneca uses an adenovirus (ChAdOx1 nCoV-19) which has been genetically edited with COVID-19 has been shown to cross the blood-brain barrier which have caused cerebral sinus venous thrombosis (ie, blood clot forms in the brain’s venous sinuses, and prevents blood from draining out of the brain) amongst some patients who have received the vaccine.
The blood-brain barrier. Stock image.
The blood-brain barrier prevents neurotoxic plasma components, blood cells and pathogens from entering the brain. However, because the COVID-19 vaccines create an antigen response, and can also cross the blood-brain barrier due to its use of nanoparticles, this may cause irreparable damage to neurological functions. Guillain-Barré Syndome, a disorder that damages the nervous system causing muscle weakness has been diagnosed in multiple case studies of those who had taken the AstraZeneca Covid-19 vaccine.
In addition, the use of nanoparticles in a microcarrier cell culture system has shown that in short-term studies, nanoparticles can cause severe problems such as cytotoxicity in both limited and chronic exposure, and its long-term effect on human health is unknown.
Radium, once thought of as “harmless” was used widely in the 1920s, and was popular due to its illuminating, glowing qualities and often used in paints and in watch dials. However, it was discovered some 30 years later of its carcinogenic qualities as people began to suffer from radiation poisoning and was finally banned in 1968. Likewise, although nanomedicine has many great potentials, the full extent of how exposure to nanoparticles affect the human body is not known but limited studies have shown that nanoparticles can cause toxicity in the human body and cause inflammatory responses.
The administration of nanoparticle vaccines may show immediate adverse effects in immunocompromised people, but may take decades before its long-term effects are fully known in healthy people. Hence, we must consider the pros and cons of what we prioritise during a pandemic whilst looking long-term into the safety and intellectual integrity of our future populations.
We must also consider that coronaviruses are relatively common and viruses will always mutate. Medical researchers have stated that at some point in our lives, everyone will eventually be infected with one or more strains of the coronavirus. Is it feasible to mandate nanovaccines in a population in which the long-term effects are unclear?
Nations like Norway have decided to “live with COVID-19” and has lifted all restrictions and has no intentions of vaccine mandates. Image from schengenvisainfo news
Google (Alphabet) has mandated vaccines for its employees in order to return to work on its campuses. Google Ventures (GV) has invested $27.1 million in Vaccitech, the startup that developed the AstraZeneca COVID-19 vaccines. Recently, Vaccitech filed an IPO for a valuation around $700 million. Sarah Gilbert, one of the founders of Vaccitech is set to receive more than a $27 million payout for her development of the AstraZeneca COVID-19 vaccine. Image from cityam
Several US states are banning a vaccine mandate by employers and educational institutions. Image from the NYTimes.
Despite the potential of nanomedicine and the revolutionary new methods of drug delivery using nanoparticles, the ultimate question we must ask is: Is the treatment worse than the disease itself?
By Sierra Choi
Disclaimer: This article is not intended as medical advice and is for educational purposes only, in order to stimulate rational dialogue and discussion. This article also represents the opinions of the author and may not necessarily reflect the opinions of the organisations she works with.