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Research Article
ISSN: 2574 -1241 DOI: 10.26717/BJSTR.2023.50.007892
Evaluation of Aqueous Nanoformulations of
Epigallocatechin-3-Gallate-Palmitate (EC16) Against
Human Coronavirus as a Potential Intervention Drug
Nicolette Frank1, Douglas Dickinson2, William Garcia1, Lucee Xiao1, Andra Xayaraj1, Lee H Lee3,
Tinchun Chu4, Mukesh Kumar5, Shannon Stone5, Yutao Liu1, Hongfang Yu1, Jingwen Cai1, Bo Yao6,
Xiaocui Jiang6 and Stephen Hsu1,2*
1Augusta University, Augusta, USA
2Camellix Research Laboratory, USA
3Montclair State University, USA
4Seton Hall University, USA
5Georgia State University, USA
6Changxing Sanju Biotech Co., Ltd. Hang Zhou, China
*Corresponding author: Stephen Hsu, Camellix Research Laboratory, Augusta, CB2404B, Augusta University, Augusta, GA
30912, USA
Copyright@ : Stephen Hsu | Biomed J Sci & Tech Res | BJSTR. MS.ID.007892. 41242
ABSTRACT
Background: Chronic neurologic diseases are common sequelae of COVID. They severely impact the
quality of life and increase the burden on healthcare systems. The long COVID neurological symptoms are
due to the robust replication of SARS-CoV-2 in the nasal neuroepithelial cells, leading to neuroinvasion,
vaccines do not inhibit SARS-CoV-2 replication in the nasal epithelial cells nor the persistent infection.
delivered drug for minimizing post-COVID neurologic symptoms. However, EC16 is a hydrophobic, water
delivery forms of EC16.
Method:
sequence.
Results: EC16 nanoformulations in normal saline, phosphate buffered saline, and cell culture medium were
Conclusion:
nasal formulations could be further developed for clinical applications to COVID-19 patients to minimize
long COVID neurological symptoms.
Keywords: COVID-19; Long COVID; EC16; EGCG-Palmitate; Formulations
ARTICLE INFO
Received: April 17, 2023
Published: April 27, 2023
Citation:
-
Epigallocatechin-3-Gallate-Palmitate
a Potential Intervention Drug. Biomed
MS.ID.007892.
Copyright@ : Stephen Hsu | Biomed J Sci & Tech Res | BJSTR. MS.ID.007892.
Volume 50- Issue 1 DOI: 10.26717/BJSTR.2023.50.007892
41243
Introduction
Following recovery from the acute infection stage of the SARS-
array of pulmonary and extrapulmonary clinical manifestations,
including nervous system and neurocognitive disorders, which include
headache, persistent loss of smell and/or taste, memory loss, brain
dizziness, anxiety, depression, earache, hearing loss, and/or ringing
Plan on Long COVID, 2022, up to 23.7 million Americans suffer from
annual loss of salary. The post-COVID chronic neurologic symptoms
have been shown to be due to the robust replication of SARS-
CoV-2 in the nasal neuroepithelial cells, leading to neuroinvasion
transmission of SARS-CoV-2 is a significant route for viral entry to
Specifically, multiciliate cells in the nasal respiratory epithelium serve
including SARSCoV-2, bypass the defensive mucus/mucin layer of the
airway by entering and exiting epithelial cells via their protruding
CoV-2, and these methods do not inhibit the robust SARS-CoV-2
replication or the persistent infection in the nasal epithelial cells.
Therefore, a significant gap exists in treatment/prevention strategies
that needs to be filled by methods to rapidly inhibit SARS-CoV-2
anti-inflammatory, antioxidant, and neuroprotective properties and
able to rapidly inhibit viral replication in nasal epithelia would be
a candidate for such a method. One such new drug candidate agent
stable lipid-soluble form of EGCG. EGCG is a water-soluble polyphenol
from green tea leaf extract with multiple beneficial properties. We
also tested the antiviral activity of EGCG against SARS-CoV-2, with
EGCG as a pharmacological agent is a rapid oxidation in solution. The
EC16 derivative is substantially more stable, and has broad virucidal,
antiviral, anti-inflammatory, antioxidant, and neuroprotective
effectively inhibit influenza virus, norovirus, and herpes simplex virus
Particularly, results from our clinical trial on herpes labialis
indicate that a lipid-soluble EGCG topical formulation possesses
that has significant potential for minimizing long COVID as a new
drug candidate is that it is an FDA categorized generally recognized
approved safe inert. The long-term goal of our study is to develop
intranasally applied EC16-containing new drugs in the form of nasal
spray to minimize long COVID symptoms either through prevention
or therapeutic approaches. However, EC16 is insoluble in water,
requiring development of an aquesous formulation. The current
study aimed to test the proof-of-concept that EC16 in aqueous
nanoformulations is able to effectively inhibit human coronavirus in
vitro, and therefore has the potential to be used in a nasally delivered
formulation.
Materials and Methods
Virus and Cell Line
ATCC.
EC16 and Other Supplies
EC16 Formulations
EC16 and EC16m were initially dispersed as stable glycerol-based
lower concentrations for the experiments.
Quantitation of EC16 Polyphenol in Mixtures
After dilution of F18 in aqueous buffers the flocculent material
Copyright@ : Stephen Hsu | Biomed J Sci & Tech Res | BJSTR. MS.ID.007892. 41244
Volume 50- Issue 1 DOI: 10.26717/BJSTR.2023.50.007892
compacted cream, and a very small amount of precipitate. The liquid
under the cream was removed by aspiration and the flocculate/cream
material reconstituted by vigorous vortexing in the same volume of
aqueous buffer. The distribution of polyphenols in the fractions from
a saline suspension was determined by the Folin-Ciocalteu reaction
ethanol as the standard.
Evaluation of Particle Size Distribution
measuring range for particle diameter is 10-2000 nm. The samples
were diluted by the same volume of 1×PBS and then loaded into the
cell. The instrument collected particle information from 11 different
positions across the cell, with two cycles of readings respectively. The
standard operating procedure was set to a temperature of 23°C, a
sensitivity of 70, a frame rate of 30 frames per second, and a shutter
speed of 100. The post-acquisition parameters were set to a minimum
bright-ness of 20, a maximum area of 1000, a minimum area of 10,
Antiviral Activity Tests
Infection of cells by OC43 virus, and viral titer: MRC-5 cells were
penicillin, streptomycin, and amphotericin B. The viral infection
assay and viral titering were performed in 96 well cell culture
dilution of OC43 virus in serum-free EMEM was loaded into wells in
quadruplicates per dilution. After a one-hour absorption, the viral
dilutions were removed and 100 µl serum-free EMEM was added,
followed by incubation at 3302
experiments were performed and results recorded.
Dose and Time Tests of Direct Contact with Virus
EC16 nasal formulations were used with different concentrations
or incubation times in direct contact with OC43 virus in serum free
EMEM. To determine the dose effect of EC16, in three independent
to a series of concentrations from 1.25 mM down to 0.05 mM, and
10 9.25/ml diluted in serum-free
mM dilution of F18 in serum-free EMEM was mixed with virus for 5,
15, 30 or 60 min, followed by rapid serial dilution with serum-free
MRC-5 cells for one-hour viral absorption, followed by media change.
The infectivity rate was determined by the TCID50 method after 4-7
days of incubation.
Pre-Infection Test
EC16m nasal formulations were incubated with MRC-5 cells in 96
well plates for 10 min, and then removed. A series dilution of OC43
in serum-free EMEM was added to the cells and incubated for 1 h.
The viral dilutions were then replaced with serum-free EMEM, and
TCID50 infection rate was determined after 4-7 days of incubation.
Post-Infection Test
To test if EC16m nasal formulations possess a post-infection
effect, MRC-5 cells in 96 well cell culture plate were infected for one
hour with the virus in series dilutions before removal. Then, 100 µl
of EC16m formulations in different concentrations were applied onto
the cells for 10 min before being replaced by serum-free EMEM. The
TCID50 values were determined after incubation for 4-7 days.
Microphotography of the Formulations
with a Zeiss Axio Imager M.2 microscope at 40x magnification under
DIC illumination, and the images were recorded.
Statistical Analysis
non-linear regression using a fit to a parabolic curve. Alpha was 0.05.
for most analyses. Reported errors are given as standard deviation
Results
Formulation F18 based on EC16
Dilution of F18 into aqueous buffers resulted in fast formation of
a flocculate precipitate that rapidly aggregated and rose to a cream
on the surface. Microscopic imaging of the vortexed samples at
the floating cream layer and the liquid underneath was removed by
aspiration. Quantitation of the polyphenol content showed that 103
cream phase, essentially all the reactive polyphenol was present in
material. The composition of the cream was not further evaluated,
for subsequent virus tests.
Copyright@ : Stephen Hsu | Biomed J Sci & Tech Res | BJSTR. MS.ID.007892.
Volume 50- Issue 1 DOI: 10.26717/BJSTR.2023.50.007892
41245
Figure 1: Light microscopy imaging of F18 stock and dilutions. The F18 glycerol stock, and 1:10 dilutions in MM, PBS and saline were examined by
transmitted light microscopy at 40x magnication using DIC illumination.
(A) Undiluted F18 stock;
(B) F18 in MM;
(C) F18 in Saline;
(D) F18 in PBS.
Size Distribution of Small Particles
After brief low-speed centrifugation of F18 in saline to separate
particle size distribution in the liquid was evaluated by nanoparticle
was 210 ±
<547 ±±0.06
x107/ml.
Antiviral Dose Effect Properties of F18
Incubation of virus with dilutions of F18 demonstrated a dose-
dependent increase in contact inhibition antiviral activity of the
formulation, as represented by an increase in the log10 reduction in
for the plateau in log10
Copyright@ : Stephen Hsu | Biomed J Sci & Tech Res | BJSTR. MS.ID.007892. 41246
Volume 50- Issue 1 DOI: 10.26717/BJSTR.2023.50.007892
Figure 2: Size distribution of particles in saline-diluted F18 determined by NTA. The size distribution prole of one representative sample is shown.
Figure 3: Dose response of contact inhibition antiviral activity of F18 EC16 nasal formulation. The formulations were diluted from an F18 glycerol
stock of EC16 (1%) into serum-free EMEM to a concentration of 0.05, 0.125, 0.25, 0.625, and 1.25 mM prior to incubation with OC43 virus at a 1:9 ratio
(virus to formulation) for 30 min, followed by a series of 10 X dilutions and TCID50 assay. The contact inhibition antiviral activity was calculated
and expressed as log10 reduction of the original titer (log10 9.25/ml), determined in a positive control on the same plate. Results are the mean from
three independent experiments (bars show standard deviation).
Copyright@ : Stephen Hsu | Biomed J Sci & Tech Res | BJSTR. MS.ID.007892.
Volume 50- Issue 1 DOI: 10.26717/BJSTR.2023.50.007892
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Time Dependent Antiviral Effect of F18
To determine the effect of time of exposure to EC16 on antiviral
EMEM and incubated with OC43 virus for different time periods
before neutralization by immediate dilution with serum-free EMEM.
antiviral activity showed a rapid increase in log10 titer reduction up
2
10
reduction, and consistent with the fold reduction observed in the dose
reduction in titer was predicted at 42.9 min. The 30 min exposure
used for dose testing was predicted to give a 3.994 log10 reduction
dose testing.
Figure 4: Time response of contact inhibition antiviral activity of F18 EC16 nasal formulation. The formulation was diluted from an F18 glycerol
stock of EC16 (1%) in serum-free EMEM, to a concentration of 1.25 mM EC16. This working formulation was incubated with OC43 virus (initial
titer log10 9.0/ml in serum-free EMEM) at a 1:9 ratio (virus to formulation) for 5, 15, 30, and 60 min before 10x serial dilutions and subjected to
TCID50 assay. The antiviral activity was calculated and expressed as log10 reduction with standard deviation. Results are from three independent
experiments.
Contact Inhibition Test of F18 in Different Diluents
The effect of the formulation diluent on direct contact log10
reduction was tested using a 30 min exposure of OC43 virus to 1.25
mM EC16. There was a significant difference between the three
10
10
Contact Inhibition by F18m Containing EC16m
The F18m formulation was diluted with serum-free EMEM to
10
then 10x serial dilutions were prepared and remaining viral titer
determined. A 30 min incubation with 1.40 mM EC16m in serum-
free EMEM resulted in a log10
viral infectivity. The reduction in titer with F18m at this dose was
somewhat modest, and significantly less than that seen with the 1.25
Copyright@ : Stephen Hsu | Biomed J Sci & Tech Res | BJSTR. MS.ID.007892. 41248
Volume 50- Issue 1 DOI: 10.26717/BJSTR.2023.50.007892
Pre-Infection Exposure to EC16m
of log10
incubation led to a log10 1.81 ±
infectivity.
Post-Infection Exposure to EC16m
To determine the post-infection dose effect of EC16m in serum-
min exposure to the diluted agent before changing to media. There
10 titer reduction of 2.19
± 10 titer reduction of 2.00 ± 0.36
10
Figure 5: Initial antiviral tests using EC16m to determine the antiviral activity on post-infection with OC43 virus. Results were obtained from four
independent experiments (bars show SD).
Discussion
The current study aimed to develop and characterize the antiviral
of using EC16 as a nasally delivered drug to provide antiviral activity
in terms of contact inactivation and pre- and post-infection inhibition
of viral replication. The human nasal cavity is made of the respiratory
consisting of olfactory sensory neurons, sustentacular cells, microvillar
neuronal cells express ACE2 and TMPRSS2, and the olfactory sensory
neurons express neuropilin-1, which facilitate SARS-CoV-2 infection
initial replication in the RE during the early stage of COVID-19, mainly
accumulation of SARS-CoV-2 in RE could cause concomitant infection
in the OE. Indeed, recent clinical and animal studies demonstrate
that SARS-CoV-2 infection of the olfactory sensory neurons and their
support cells in the OE results in local inflammation and apoptosis,
which could be the mechanisms leading to OE destruction, anosmia,
SARS-CoV-2 replication in RE, OE, and the olfactory bulb appears to
be the cause of acute anosmia, and persistent presence of the virus
in the RE and OE cells could be associated with chronic neurologic
Copyright@ : Stephen Hsu | Biomed J Sci & Tech Res | BJSTR. MS.ID.007892.
Volume 50- Issue 1 DOI: 10.26717/BJSTR.2023.50.007892
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acquired via vaccination, are not effective at reducing the SARS-
CoV-2 viral load in the nasal cavity due to robust viral replication in
nasal viral load comparable to symptomatic patients, suggesting both
Therefore, inactivation and clearance of viral particles in the nasal
delivery using nanoparticles of lipid-soluble drug or nanocarrier is
a promising method to increase the drug bioavailability with rapid
potential to treat neurologic disorders by decreasing reactive oxygen
not only performs beneficial activity in the nasal epithelia, but also
would be a first-in-class drug to prevent and minimize SARS-CoV-2
associated neurologic symptoms, including long COVID. As of today,
the US FDA have approved a number of nasal delivered drugs to
allergic rhinitis, etc.
administered drug for use against respiratory viral infection or
post-infection symptoms. The antiviral activity of EGCG has been
widely reported. In addition, EGCG has been shown to provide
neuroprotective effects to nerve cells. Results from preclinical and
improved cognitive function in 3 months, without adverse effect
tau toxicity, and inhibition of apoptosis, suggesting a potential to pre-
olfactory function could be protected. However, aqueous solutions
of EGCG rapidly oxidize. EC16 is a lipid-soluble compound mixture
derived from EGCG by esterification with palmitate. Our previous
studies showed that EC16 is able to enter epithelial cells and is
could be a preferred route to administer lipid-soluble EC16 for
neuroprotection. In comparison to water-soluble EGCG, EC16 is
significantly more potent against influenza virus, herpes simplex
In addition, the US FDA approved the use of tea polyphenol
consistent with our findings that EC16 is hydrolyzed to free EGCG
results indicate that EC16 has the potential to protect nasal epithelial
cells from SARS-CoV-2 infection as well as exerting anti-inflammatory,
antioxidant, and neuroprotective effects. Our previous in vivo studies
demonstrate that the neuroinvasion of SARS-CoV-2 occurs closely
inactivate the coronavirus in the nasal epithelial cells and be able to
deliver the multiple benefits of EC16 into the brain, bypassing the
method would overcome the well-documented poor bioavailability
of EGCG, which has a serum maximum concentration in the sub-
nasal epithelial cells, the long chain fatty acyl group would allow EC16
to attach to the cell membrane for prolonged effect against SARS-
CoV-2 and its variants.
Our long-term goal is therefore to develop an intranasally applied
prevent and treat respiratory viral infection and post-infection
symptoms. To achieve this goal, the primary property of interest is
antiviral activity, and the secondary property is anti-inflammatory,
antioxidant, and neuroprotection in both nasal neuroepithelia and the
brain. The current study aimed to test the feasibility of formulating
aqueous candidate nasal formulations containing EC16 with antiviral
properties for COVID and long COVID use. Due to the lipid-soluble
nature of EC16, the solubility of EC16 is very low in aqueous solutions.
By using our patent-pending technology, we were able to bring EC16
into aqueous suspension as particles ranging in size from nano- to
low micrometer diameter, without addition of specific nanoparticle-
forming agents or surfactants. Among 62 formulations tested thus far,
results for antiviral activity with the simplest composition. Dilution
of F18 into aqueous buffer systems resulted in rapid formation of a
flocculate precipitate, with little, if any, polyphenol in the flocculate
material, which was comprised of large aggregates of various-sized
particles that rapidly rose to form a cream. Analysis of particle size
distribution in the saline liquid phase showed a broad polydisperse
Copyright@ : Stephen Hsu | Biomed J Sci & Tech Res | BJSTR. MS.ID.007892. 41250
Volume 50- Issue 1 DOI: 10.26717/BJSTR.2023.50.007892
The F18 formulation diluted in EMEM showed potent antiviral
activity when virus was directly exposed to it, with a maximum
inhibitory effect of log10
analysis and determination of the curve constants, a concentration
of 0.225 mM was predicted to give a log10
in the saturated region. The antiviral results of F18 diluted in serum-
EC90; log10
of EC16, a 5-min direct contact with the virus reduced the viral
rapid and potent inactivation of viral infectivity is associated with a
completely different mechanism of action in comparison to antiviral
inhibition of coronavirus.
For our ongoing animal study and a future human study, the F18
formulation was tested by dilution in PBS and saline, which showed
comparable direct virus log10
10
5.41 versus log10
antiviral activity, presumably by modification of the surface charge of
particles. Of note, the difference is based on an already very high level
10 3.92-4.5 vs. log10
followed by EGCG-di-palmitates, and EGCG-tri-palmitates. Therefore,
In this report, a series of initial tests for EC16m was performed with
the F18m formulation of EC16m in serum-free EMEM dilutions. After
log10 reduction value was influenced by the titer of the virus used in
the tests, with a lower titer resulting in a lower proportionate log10
reduction. Since the F18m tests used a lower titer virus preparation
10 10 9.0 in EC16 contact inhibition
Figure 6: Contact inhibition antiviral activity of F18 EC16 suspensions in three diluents. The glycerol-based F18 EC16 nasal formulation stock (1%)
was diluted 10 X with serum-free EMEM (MM), normal saline, or phosphate buffered saline (PBS) to 1.25 mM. The working suspensions were
incubated with OC43 virus for 30 min at a 1:9 ratio (virus : formulation) prior to serial 10x dilution and subjected to TCID50 assay. Results are means
obtained from 3 independent experiments with standard deviation (the saline test result values were identical with 0 SD). The viral titer log10 was
9.75/ml determined from a positive control on the same plates.
Copyright@ : Stephen Hsu | Biomed J Sci & Tech Res | BJSTR. MS.ID.007892.
Volume 50- Issue 1 DOI: 10.26717/BJSTR.2023.50.007892
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A human study indicated that when symptoms appear during
initial SARS-CoV-2 infection, the nasal cavity viral load is less
than log10 10
tests conducted in this study have been at clinically relevant viral
subsequent viral replication in the cells. On the other hand, without
direct contact with the virus, a 10 min incubation of infected MRC-5
treatment with the cells before removal. These initial results from a
base EC16m formulation suggested that EC16m entered the cells and
the result of a single application and viral titer was observed over a
4 to 7-day incubation period. Repeated applications of EC16m may
produce a higher inhibitory effect on viral replication. According
to the characteristics of SARS-CoV-2 replication in the nasal cavity,
would assist in infection recovery. Indeed, a randomized clinical
trial using isotonic saline pressured irrigation, supplemented with
either sodium bicarbonate or povidone-iodine, significantly reduced
hospitalization rate during the early stage of COVID-19 pandemic
Saline, either isotonic or hypertonic, has been used for respiratory
conditions as an economical and effective alternative to medications
application for COVID and long COVID prevention and intervention.
A multi-mechanism of action has been reported for the inhibitory
results presented here showed that aqueous F18 base formulations
containing EC16 or EC16m similarly demonstrated antiviral activities
to either rapidly inactivate human coronavirus by direct contact or
inhibit viral entry and replication without direct contact with the
virus. These formulations therefore have the potential to be developed
into nasally applied antiviral formulations for testing.
Conclusion
We report here, for the first time according to the best of
candidate for intranasally applied aqueous formulations to minimize
COVID-associated neurologic symptoms through its strong and rapid
antiviral and other beneficial properties. Our ongoing studies are
testing the broad-spectrum of antiviral activity of EC16 on human
with significantly higher potency are being explored. These ongoing
For new drug development, the next phase studies should include
and ex vivo models, in order to collect data for pre-Investigational
regularly used in nasal irrigation/spray solutions. In conclusion,
we have developed a simple nasal nanoformulation to incorporate
lipid-soluble EC16 in saline, without surfactant, to rapidly inactivate
a single 10-min application on infected cells. These results suggest
EC16 nasal applications are potential prophylactic and therapeutic
methods to minimize respiratory virus associated, such as COVID and
post-COVID, symptoms, pending additional studies.
Acknowledgement
and Commercialization, Augusta University Research Institute.
The content is solely the responsibility of the authors and does not
Health.
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DOI: 10.26717/BJSTR.2023.50.007892
Stephen Hsu. Biomed J Sci & Tech Res
