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Glycyrrhiza glabra: An Insight to Nanomedicine

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DOI: 10.1166/jnn.2021.19007

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Copyright © 2021 American Scientific Publishers
Nanoscience and Nanotechnology
All rights reserved Vol. 21, 3367–3378, 2021
Printed in the United States of America www.aspbs.com/jnn

Glycyrrhiza glabra: An Insight to Nanomedicine

Kanika Rani1 , Nisha Devi1 ∗ , Vinod Saharan2 , and Pushpa Kharb1
1
Department of Molecular Biology, Biotechnology & Bioinformatics, Chaudhary Charan Singh Haryana Agricultural University,
Hisar 125004, Haryana, India
2
Department of Molecular Biology and Biotechnology, Maharana Pratap University of Agriculture and Technology,
Udaipur 313004, Rajasthan, India

Glycyrrhiza glabra Linn (Fabaceae), commonly known as Licorice/Liquorice, Mulahatti; is an under-

shrub. The dried, peeled or unpeeled underground stems and roots are used for the treatment of
upper respiratory tract ailments, immunodeficiency, endocrine disorders, skin, liver, joint and heart
diseases. Medicinal properties of this plant are enormous and offer it as one of the greatest can-
didates in the field of Nanomedicine. The Nanomedicine has dedicated to safeguard and upgrade
human health using the nanotechnology. Bioactive constituents of this plant perform versatile phar-
macological actions and can be used as good Bioanalytical tools. Therefore, an updated overview
on current knowledge of green synthesis of nanoparticles (NPs), nanoformulations and surface
modification using G. glabra is provided here in order to explore its therapeutic potential especially
antifungal and antibacterial activities. In our lab, we have synthesized silver nanoparticles (Ag NPs)
using leaves and rhizome parts of G. glabra.
Keywords: Glycyrrhiza glabra, Nanomedicines, Nanoparticles, Plant Extract.

CONTENTS Northern India. Actually, cultivation is at both large (in

1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
2. Botanical Description . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
3. Medicinal Uses and Phytoconstituents . . . . . . . . . . . . . . . . . . . .
4. Nanomedicine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
5. Applications of G. glabra in Nanomedicine . . . . . . . . . . . . . . .
5.1. Green Synthesis of NPs Using G. glabra and
Their Therapeutic Potential . . . . . . . . . . . . . . . . . . . . . . . .
5.2. Formulation of Nanoparticles with G. glabra
Extract or Major Constituents and Their Use in
Different Disease Conditions . . . . . . . . . . . . . . . . . . . . . . .
5.3. Surface Modification of Nanoparticulate Carriers by
Constituents of Licorice Extract . . . . . . . . . . . . . . . . . . . . .
6. Conclusion and Future Outlook . . . . . . . . . . . . . . . . . . . . . . . . .
Acknowledgment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
References and Notes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
1. INTRODUCTION
Glycyrrhiza glabra Linn. is a traditional medicinal plant
over the globe due to its high ethnopharmacological value,
it can cure diverse illnesses. This plant is commonly dis-
tributed in the subtropical and warm temperate regions [1]
like Southern Europe, Syria, Iran, Afghanistan, Russia,
China, Pakistan and Northern India (Punjab, Haryana and
Sub Himalayan tracts). The plant is cultivated in Rus-
sia, China, Spain, Germany, France, UK, USA, Italy, and
∗
Author to whom correspondence should be addressed.
3367 Spain, Sicily, and England) and small scale (India, Iran,
3369 Afghanistan, etc.) [2, 3]. The dried, peeled or unpeeled
3369
3370
underground stems and roots constitute the drug known
3370 in the trade as Liquorice. It is used in medicine for more
than 4000 years [4]. The dried rhizome and root have
3370 been used by Indian, Chinese, Egyptian, Greek and Roman
civilizations. The use of licorice preparations to relieve
3371
throat and bronchial infection was known for more than
2000 years [5]. The Indian traditional medicinal system
3372 (Ayurveda, Unani, and Siddha) uses more than 7500 plant
3375 species [6]. More than 1250 preparations in Ayurvedic sys-
3375 tem contains licorice as one of its constituents [7] and
3375
used in the treatment of respiratory and digestive system
diseases mainly.
This immense potential of Mulahatti opens several
doors in medicine and is capable of revolutionizing
it [65, 66]. Medicine has nowadays become more adaptive
towards new techniques and technology like nanotechnol-
ogy, which leads to a new frontier in the health care system
that is “Nanomedicine.” Nanomedicine offers promising
improvements in diagnostic utilities, preventive medicine,
tissue regeneration, targeted pharmacotherapy, etc. by
operating at molecular, intracellular and intercellular levels
as compared to conventional medicine [8]. Formulations
of nanomedicine could be engineered nanoparticles (NPs),

J. Nanosci. Nanotechnol. 2021, Vol. 21, No. 6 1533-4880/2021/21/3367/012 doi:10.1166/jnn.2021.19007 3367

Glycyrrhiza glabra: An Insight to Nanomedicine Rani et al.

polymeric NPs, lipid nanosystems, dendrimers, micelles,
liposomes, nanocrystals, etc. [9]. Even surface modifi-
cation of synthesized nanomaterials leads to effective
drug delivery, increased cellular uptake, lesser cytotoxicity,
increased drug deposition, biocompatibility [10–18].
Extensive research in the field of nanomedicine is going
on using the phytoconstituents or different extracts of
the G. glabra plant. It involves the synthesis of metal
NPs using various plant extracts [19, 20, 24–26, 54–56],
loading of extract or constituent in nanoformula-
tions [21–23] and surface modification of different NPs
using constituents [10–18]. In the green synthesis of metal
NPs, the different plant parts like roots, leaves, rhizome,
and seeds, are used for extraction purpose. The major

Kanika Rani has obtained B.Sc. degree in Life Sciences from D.N. College, Hisar in 2013
and M.Sc. degree in Molecular Biology and Biotechnology from Chaudhary Charan Singh
Haryana Agricultural University, Hisar in 2015. Currently, she is pursuing Ph.D. degree
from the Department of Molecular Biology, Biotechnology and Bioinformatics, Chaudhary
Charan Singh Haryana Agricultural University and working under the guidance of Dr.
Pushpa Kharb, Professor and Head, Department of Molecular Biology, Biotechnology and
Bioinformatics, COBS&H, CCS Haryana Agricultural University, Hisar, Haryana, India.
She is working on, ‘Green synthesis of nanoparticles and their biomedical applications.’

Nisha Devi has obtained B.Sc. degree in Biotechnology from Feroze Gandhi Memorial
P.G. College, Mandi Adampur, Hisar in 2010 and M.Sc. degree in Biotechnology from
Guru Jambheshwar University of Science and Technology, Hisar in 2012. Currently, she
is pursuing Ph.D. degree from the Department of Molecular Biology, Biotechnology and
Bioinformatics, Chaudhary Charan Singh Haryana Agricultural University and working
under the guidance of Dr. Pushpa Kharb, Professor and Head, Department of Molecular
Biology, Biotechnology and Bioinformatics, COBS&H, CCS Haryana Agricultural Uni-
versity, Hisar, Haryana, India. She is working on, ‘Green synthesis of nanoparticles and
their biomedical applications.’

Pushpa Kharb is currently working as Head, Department of Molecular Biology and

Biotechnology, CCS Haryana Agricultural University, Hisar. She obtained her M.Sc. and
Ph.D. (Genetics) from CCS Haryana Agricultural University, Hisar. She was a Rockefeller
Foundation Post-Doctoral Fellow for two years (1997–1999) at Texas A&M University,
College Station Texas, USA. A recipient of ICAR sponsored Best Teacher award, she has
filed ten patents (of which three have been granted) in the area of Biotechnology. She held
the position of Director (T), Centre for Plant Biotechnology, New Campus, CCS HAU,
Hisar for three years (2011–2014). She has handled several National and International
research projects and has a number of publications in National and International journals
of repute to her credit.
Vinod Saharan currently serves as Scientist and Head, Department of Molecular Biology
and Biotechnology at Maharana Pratap University of Agriculture and Technology, Udaipur.
He is recipient of HRD-Israel government fellowship (2003) for Ph.D. research at Ben-
Gurion University, Israel. Further he did his Post Doc in 2007 at Agricultural Research
Organization (ARO) Volcani centre, Israel. He has guided 20 Master’s student and 6
Ph.D. students. Dr. Saharan has completed 7 R&D projects in Biotechnology field. His
laboratory is pioneer in development of chitosan/biopolymer based nano-materials for
various applications in plants. His research group is specialized in slow/protective release
of bioactive compounds through nano-encapsulation. Currently he is heading 02 research
projects funded by Department of Biotechnology and one International-bilateral project
funded from Department of Science and Technology in collaboration with Republic of
Iran. His laboratory is also collaborating with Washington University in stain Louis, United States. Dr. Saharan is
reviewer of many Elsevier, Springer and ACS journals. He has published 60 research papers, 20 book chapters and
one Springer book on nanotechnology. He has many academic-research visits to countries like Israel, China, Dubai,
Singapore, Sweden etc.

3368 J. Nanosci. Nanotechnol. 21, 3367–3378, 2021

Rani et al.
solvent for extraction is water and then ethanol is also
used. During bioactivity checks, the silver NPs showed
antibacterial, antifungal, antiulcer and anticancerous activ-
ity [19, 24–26]. The nanoformulations (NFs) loaded either
with extract or bioactive constituent of the plant are pre-
pared by using chitosan, gum arabic, gelatin, alginate,
polylactic acid (PLA), polylactic co-glycolic acid (PLGA),
etc. These NFs are further used for targeting various
ailments [21–23].
The therapeutic potential of this plant offers several
possibilities which can further be elevated and impro-
vised with the use of nanotechnological approaches.
To the best of our knowledge, no review has been
published on this plant, particularly in the context of
nanomedicine. The objective of this was to reveal about
importance and potential of this plant in the field of
Nanomedicine.
2. BOTANICAL DESCRIPTION
It is commonly known as Licorice/Liquorice, Sweetwood,
Yastimadhu, Mulahatti. Glycyrrhiza word is made from
ancient Greek words glykos (meaning sweet) and rhiza
(meaning root) [27]. It is a dicotyledonous angiosperm
which belongs to family Fabaceae (also known as Legumi-
nosae), a diploid plant with chromosome no. 16 [28]. It is
a hard herb or undershrub attaining a height up to 2.5 m;
leaves are multifoliate, imparipinnate; flowers are papil-
ionaceous, in axillary spikes, lavender to violet in color;
pods are compressed and containing reniform seeds [29].
Flowering occurs in June–July (late spring and early sum-
mer). The stem is underground that grow horizontally up
to 2 m length, highly branched consisting of short taproot
system with a large number of rhizomes [30]. The taproot
subdivides into subsidiary roots, from which horizontal
woody stolons arise (see Fig. 1) [31]. Figure 1 depicts the
Glycyrhiza glabra var. H.M-1 plants in the research farm
and net house at CCS HAU, Hisar.
(a)
(b)
(c)
Figure 1. (a) G. glabra plants in the field of CCS HAU, Hisar (b) single
plant in the net house (c) rhizome along with plant.
J. Nanosci. Nanotechnol. 21, 3367–3378, 2021
Glycyrrhiza glabra: An Insight to Nanomedicine
3. MEDICINAL USES AND
PHYTOCONSTITUENTS
The root of G. glabra contains alkaloids, glycosides, car-
bohydrates, starches, phenolic compounds, flavonoids (dif-
ferent classes, including flavanones, flavones, flavanonols,
chalcones [67], isoflavans, isoflavenes, isoflavones and
isoflavanones) [32, 33], proteins, pectin, mucilage,
saponins (responsible for sweet taste), lipid, tannins,
sterols and steroids (Fig. 2) [34, 35]. It is rich in sec-
ondary metabolites. It contains nearly 300 flavonoids
and more than 20 triterpenoids [36]. The flavonoids
(liquirtin and formomonetin) and triterpenes (glycyrrhizin,
glycyrrhetinic acid, and liquirtic acid) are responsible
for the medicinal properties of G. glabra [37, 68–70].
Glycyrrhizin is the main constituent (10% of licorice),
which is a primary active ingredient and 50 times
sweeter than sucrose [38, 71]. Eleven new phenolic
compounds, glycybridins A-K (1–11), along 47 knowns,
have been identified recently on the basis of NMR
and MS analysis [39]. The compounds, 6-aldehydo-
isoophiopogonone, and liquiritigenin [72–75] have been
identified for the first time. These compounds have
shown potent activity against multidrug-resistant (MDR)
human bacterial pathogens (Escherichia coli, Acinetobac-
ter baumannii, Staphylococcus aureus, and Pseudomonas
aeruginosa) [40].
Licorice is a good source of nutrition because it contains
proteins, carbohydrates, mineral salts (Ca, P, Na, K, Fe, Si,
Se, Mn, Zn, Cu), vitamins (B1, B2, B3, B5, E, and C) [33].
It is used for the treatment of upper respiratory tract
ailments including coughs [76], hoarseness, sore throat
and bronchitis [77]. Roots have demulcent, antacid, anti-
ulcer [41], anti-inflammatory [78–80], expectorant [81],
tonic, diuretic, laxative, sedative [42,43], antipyretic [29],
antimicrobial [82–90], antiviral [91], anti-herpes [44] and
anxiolytic [45] activities. It is also used in the treatment
of liver diseases, joint diseases, arthritic conditions [92],
immunodeficiency [46,93], diabetes [94–96], endocrine
disorders [47], kidney diseases [48], psoriasis [97],
Figure 2. Phytoconstituents of G. glabra.
3369
Glycyrrhiza glabra: An Insight to Nanomedicine Rani et al.

NPs, dendrimers, nanocrystals, emulsions, liposomes, solid

Figure 3. Applications of G. glabra.
eczema [98], hemorrhoids [28], epilepsy [99, 100],
chronic hepatitis [101], heart diseases and oro dental
diseases [49, 102], regulate the estrogen-progesterone
ratio [44, 45], to protect low density lipoprotein (LDL),
red blood cells from oxidative damage [28, 49] and free
radical scavenging activity [50, 103–107].
lipid nanoparticles.
Nanomedicines can efficiently transport through fine
capillary blood vessels and lymphatic endothelium. They
have higher binding capacity to certain biomolecules,
longer blood concentration and circulation duration, bet-
ter accumulation in target tissues and reduced immune
response and oxidative stress in tissues [9, 52, 53].
These provide advantages over the conventional medicines
including superior efficacy, safety, physicochemical prop-
erties and pharmacokinetics/pharmacodynamics profiles of
pharmaceutical ingredients [9, 108, 109]. This can be help-
ful in treatment of various diseases which can’t be effi-
ciently controlled by conventional medicines [9, 53].
5. APPLICATIONS OF G. GLABRA
IN NANOMEDICINE
Phytoconstituents of licorice can be used as good bioana-
lytical tools for nanomedicines and can provide the alter-
native and may be better solutions for disease prevention,
diagnosis and treatment [110–112]. The potential of this
plant can be exploited as (see Fig. 3).

4. NANOMEDICINE 5.1. Green Synthesis of NPs Using G. glabra and

Nanotechnology is now revolutionizing every sector
including human health and changing the tools, techniques,
ideas, therapies, etc. at present level. The new concept of
nanomedicine arose from merging nanoscience and nan-
otechnology with the medicine [51, 120]. Nanomedicine
is a branch of medicine that applies the knowledge and
tools of nanotechnology to the prevention and treatment
of disease. It involves the use of nanoscale materials,
such as biocompatible nanoparticles and nanorobots, for
diagnosis, delivery, and sensing or actuation purpose in
a living organism. There are various forms in which
nanomedicines are evolved like engineered NPs, polymeric
Their Therapeutic Potential
The green synthesis of NPs is an eco-friendly and cost
effective biological method as no toxic chemicals are
used in this approach. The phytoconstituents of plant
help in reduction and stabilization of the synthesized
nanoparticles.
To date, various kinds of metal-based NPs (silver, zinc
oxide, and copper oxide, see Table I) have been synthe-
sized using G. glabra by many research groups. Most of
them used the root extract of this plant. Various instru-
ments like UV–Vis, DLS, XRD, FTIR, Vis-NIR, TEM,
SEM, SEM-EDX, AFM and TGA were used for the

Table I. Synthesis of NPs by green approach.

NPs Size (nm) Shape Plant part used The solvent used for extraction Characterization using instruments Reference

Silver 20–30 Spherical Root Aqueous UV-Vis, TEM, SEM, XRD, [54]
EDX, FTIR
9 Spherical Root Ethanol Vis-NIR, TEM, FTIR, DLS, [19]
TGA, XRD
7–45 Spherical Root Aqueous UV-Vis, TEM, XRD, FTIR [25]
41.5–45.6 Face centered cubic Root Aqueous UV-Vis, TEM, SEM, XRD, [26]
Zeta potential, FTIR and
AFM
46 – Rhizome Aqueous UV-Vis, FTIR, SEM [55]
5–45 Spherical Leaves Aqueous UV-Vis, FTIR, SEM, XRD [24]
Copper 28.21 Leaves UV-Vis, SEM, XRD [56]
Zinc oxide 35 Spherical Seed Aqueous XRD, TEM, Zeta potential, [20]
particle size histogram
Notes: Where UV-visible spectrophotometer (UV–Vis), dynamic light scattering (DLS), X-ray diffraction (XRD), fourier transform infrared spectroscopy (FTIR), visible
near infrared (Vis-NIR), transmission electron microscopy (TEM), scanning electron microscopy (SEM), energy dispersive X-ray (EDX), atomic force microscopy (AFM),
thermogravimetry analysis (TGA).

3370 J. Nanosci. Nanotechnol. 21, 3367–3378, 2021

Rani et al.
characterization of NPs. The size of the NPs ranged from
9–46 nm and most of NPs were spherical in shape [19, 20].
Dinesh and co-workers synthesized silver NPs (AgNPs)
using the aqueous root extract with 0.5 mM AgNO3 .
The UV-Vis spectrum gave SPR band at 440 nm and
SEM and TEM images confirmed about 20–30 nm size,
spherical shape and good crystalline nature of NPs which
was further confirmed by 5 diffraction peaks. The FTIR
results showed characteristic IR bands of terpenoid and
flavonoids. The colloidal solution of the NPs was sta-
ble for more than 2 months [54]. Hydro-ethanolic root
extract of the plant (1:1 ratio) with 1 mM AgNO3 showed
antibacterial and antimycotic activities against Entero-
coccus faecalis and Candida albicans respectively. The
AgNPs synthesized with lesser AgNO3 conc. (1 mM)
showed better results as compared to higher conc. (10 mM)
as the size of the particles confirmed by TEM were 9.7 ±
3.8 nm and 9.5 ± 2.9 nm respectively and zeta potential
was −42.5 ± 11.2 mV and −31.9 ± 9.12 mV respectively
and also the lesser cytotoxicity on HeLa cell lines (see
Table II) [19].
The cytotoxicity of AgNPs was also checked on human
CD34 +ve stem cells. The SEM analysis of CD34 +ve
stem cells along with AgNPs showed that differentiation
and multiplication of cells were very good as there was
no toxicity. The FTIR data of these particles showed C–O
stretching of alcohols, hydroxyl group, carboxylic acids,
ester and ether groups. The XRD data revealed their face
centered cubic structure and PSA determined the average
size of 41.8 nm. The particle morphology and topology
was spherical as depicted by AFM. The zeta potential of
NPs was −34.1 mV. Thus, shape, size, charge, nature, etc
of NPs played crucial role in the toxicity analysis [26].
The ZnO NPs prepared by aqueous seed extract of the
plant were subjected to treat human glioblastoma cells
with the the help of temozolomide (TMZ) a commer-
cially available drug by the MTT cell viability assay. These
spherical NPs of 35 nm size (TEM analysis) and zeta
Table II. Silver NPs exhibiting important bio-activities.
NP Activity Tested organism/cell line
Silver Antibacterial Enterococcus faecalis and Candida
Antifungal albicans
Silver Antiulcer Helicobacter pylori
Silver Antibacterial Gram positive-Stayphylococcus
Antifungal aureus, Bacillus subtillis
Anticancerous Gram negative-Escherichia coli,
Pseudomonas aeruginosa,
Salmonella typhi
Trichoderma, rhizopus, Aspergilslus
niger, Candida spp.
On Hela cell line
Silver Antibacterial Bacillus cereus, Staphylococcus
Antifungal aureus, Escherichia coli,
Pseudomonas aeruginosa
Fusarium oxysporum
J. Nanosci. Nanotechnol. 21, 3367–3378, 2021
Glycyrrhiza glabra: An Insight to Nanomedicine
potential of −56.3 mV were highly stable and significantly
resulted in IC50 (inhibitory concentration) value around
30 micro g/ml [20].
Our group has synthesized Silver NPs (50–120 nm)
using G. glabra leaf and root extract and characterized
AgNPs with the dynamic light scattering (DLS) tech-
nique and root extract with the Fourier transform infrared
spectroscopy (FTIR). The size distribution of synthe-
sized particles ranged from 50–120 nm Figure 4(A). The
FTIR spectra of root powder revealed strong spectral
peaks of different functional groups at several positions
Figure 4(B). This data can be compared with that of syn-
thesized NPs as their stability depends upon the capping
done by corresponding functional groups (kotakadi 2016).
The further work is in progress.
Researchers have come up with many therapeutic activi-
ties of the silver NPs synthesized using G. glabra extracts.
These show antibacterial, antifungal, antiulcer and anti-
cancerous activities [122]. These are effective against
gram-positive as well as gram-negative bacteria.
5.2. Formulation of Nanoparticles with G. glabra
Extract or Major Constituents and Their Use in
Different Disease Conditions
Nanoformulations are formulations of nanomedicines.
These can be engineered NPs, polymeric NPs, dendrimers,
micelles, nanocrystals, emulsions, liposomes, solid lipid
nanoparticles etc. [113]. These can control the pharma-
cokinetics and pharmacodynamics of nanomedicines [9].
Recently, many researchers have prepared the nanoformu-
lations (NFs) of G. glabra and targetted them against sev-
eral diseases. The anti-inflamatory activity of glycyrrhizic
acid was amplified by its encapsulation in chitosan-katira
gum NPs. During in vivo study in Wistar rats, a com-
parative evaluation between glycyrrhizic acid chitosan-
katira gum NPs and solution of glycyrrhizic acid was done
in which modified NPs showed greater anti-inflamatory
efficacy than the solution of glycyrrhizic acid, thereby
The method used to check activity Reference
Kirby and Bauer [19]
Disc diffusion assay
Agar disc diffusion assay [25]
Agar disc diffusion method [55]
MTT assay
Disc diffusion method [24]
3371
Glycyrrhiza glabra: An Insight to Nanomedicine Rani et al.

(A)

(B)

Figure 4. (A) Dynamic light scattering image of silver NPs. The size distribution by intensity of NPs in solution. (B) FTIR spectra of the root powder
of the plant.

indicating increased bioavailability of glycyrrhizic acid
(see Table III) [57].
Glycyrrhizin-loaded NPs have been prepared and
evaluated for anti-diabetic activity in nicotinamide-
streptozotocin-induced diabetic rats [21]. This is the first
study to assess the antidiabetic effects of NFs of gly-
cyrrhizin in a type-II diabetes model. They synthesized the
NPs using biocompatible polymers, chitosan, and gum ara-
bic by ionotropic gelation method. The size of spherical
Glycyrrhizin-loaded chitosan-gum arabic NPs (GL-loaded
CSGA-NPs) was in range of 140–200 nm [58]. Then the
NFs of both glycyrrhizin and metformin were prepared by
loading these onto the NPs. They compared their effec-
tiveness on type-II diabetes by administrating the NF to
diabetic rats for 21 successive days and it was found that
glycyrrhizin loaded NPs showed significant antidiabetic
effect [21, 121].
Glabridin is a phenylated isoflavonoid compound found
in the roots of G. glabra, and is responsible for its anti-
fungal activity against Candida albicans which causes
candidiasis [49, 59, 60]. Different scientists have uti-
lized this property by developing bioadhesive NFs or
mucoadhesive NPs by encapsulating the root extract con-
taining Glabridin with alginate [61], polylactic acid (PLA)
and polylactic-co-glycolic acid (PLGA) [62]. The antifun-
gal efficacy of each formulation with ethanolic root extract
was accessed [22] and even included in an oral gel, an oral
film, and toothpaste.
For the tuberculosis treatment, gelatin based NPs of
licorice extract were prepared by double desolvation tech-
nique, and then conjugated with mannose for active tar-
geting to the macrophages. The particle size of optimized
formulation was around 300 nm. The in vitro drug release,
in vitro uptake by the cell, in vivo pharmacokinetics and
in vivo anti-tubercular efficacy of the mannosylated NPs in
murine tuberculosis model were checked. A statically sig-
nificant reduction in bacterial counts in lungs and spleen
of Mycobacterium tuberculosis H37Rv infected mice was
observed as compared to untreated ones [23].
5.3. Surface Modification of Nanoparticulate Carriers
by Constituents of Licorice Extract
There are various studies regarding surface modification
of NPs using constituents of licorice extract, mainly the

3372 J. Nanosci. Nanotechnol. 21, 3367–3378, 2021

Rani et al.
Table III. Nanoformulations and disease targeting.
Nanoformulation Disease-targeted The material used to prepare NPs
Polymeric NPs Type II diabetes Chitosan and gum
arabic
Mannosylated Tuberculosis Gelatin
gelatin NPs
Bioadhesive NF Oral candidiasis Alginate,
polylactic acid
(PLA) and
polylactic-co-
glycolic acid
(PLGA)
Polymeric NPs Inflammation Chitosan and
Katira gum
glycyrrhizin (GL) and glycyrrhenitic acid (GA). The sur-
face modified NPs provide advantages over the unmod-
ified NPs like increased uptake by cells [10, 12, 14],
increased encapsulation efficiency [12], targeted drug
delivery [10, 12, 14, 16], slow release of drug from encap-
sulated polymeric NPs so that drug becomes effective for
a longer time [12], enhanced biocompatibility [17, 63, 64]
and gene transfection efficiency [13] of NPs to the cells
(see Table IV).
The cellular uptake of NPs could be enhanced by the
attachment of glycyrrhizin to the surface reactive amino
group (SRAG) present over the surface of calcein-loaded
bovine serum albumin nanoparticles (Cal-BSA-NP) result-
ing in the formation of calcein-loaded bovine serum
albumin glycyrrhizin attached nanoparticles (Cal-BSA-
NP-GL). In the comparative study, it was found that uptake
of Cal-BSA-NP-GL by rat hepatocytes was 4.43 fold
higher than that of Cal-BSA-NP (in terms of amount),
because a binding site for GL is present over the sur-
face of rat hepatocytes through which BSA-NP-GL may
be internalized [10]. Similar kind of results are obtained
when glycyrrhizin was conjugated to Chitosan nanoparti-
cles (CS-NPs) by sodium peroxide oxidation leading to
the formation of glycyrrhizin attached chitosan nanoparti-
cles (CS-NPs-GL). The drug encapsulation efficiency and
drug release profile of CS-NPs and CS-NPs-GL were com-
pared using the drug Adriamycin (ADR). It was found
that encapsulation efficiency of CS-NPs and CS-NPs-GL
were 65.5%±2.1% and 91.7%±3.2% respectively and the
release profile of ADR from CS-NPs and CS-NPs-GL over
72 hr were 70% and 28% respectively. Moreover, by label-
ing Chitosan with rhodamine B isothiocyanate (RBITC),
the interaction between NPs and rat hepatocytes was exam-
ined using flow cytometer and confocal length microscopy.
It was found that CS-NPs-GL were significantly deposited
in the hepatocyte, and the uptake amount of modified NPs
(CS-NPs-GL) in hepatocytes was 4.9 times greater than
that in nonparenchymal cells, while CS-NPs showed sim-
ilar uptake level in both cell types [11, 12, 114, 115].
Glycyrrhizin modified O-carboxymethyl chitosan
nanoparticles (CMCNP-GL) were used as a drug delivery
J. Nanosci. Nanotechnol. 21, 3367–3378, 2021
Glycyrrhiza glabra: An Insight to Nanomedicine
The substance used in loading The type of study involved Reference
Glycyrrhizin In vivo [21, 58]
Root extract In vivo and in vitro [23]
(acetone)
Root extract In vitro [22]
(Ethanolic)
Glycyrrhizic acid In vivo and in vitro [57]
vehicle for the targeting of paclitaxel (PTX) drug in hep-
atocellular carcinoma. The drug was loaded into modified
NPs (PTX/CMCNP-GL) with a maximal encapsulation
efficiency of 83.7%. There was increased accumulation
of PTX in hepatic tumor tissue and targeted delivery to
hepatocarcinoma cells in case of (PTX/ CMCNP-GL)
as compared to injecting unmodified CMCNP and PTX
separately [14, 116, 117]. Recently, a group of scien-
tists developed chitosan coated-glycyrrhizic acid loaded
and encapsulated-poly-(E)-caprolactone NPs (CS-GA-
PCL-NPs) by double emulsification solvent evaporation
method for the treatment of cerebral ischemia. These
CS-coated-GA-loaded-PCL-NPs showed greater mucoad-
hesive property, in comparision to conventional and
homogenized NFs with average particle size of 201.3 ± 4.6
nm, 77.94 ± 5.01% entrapment efficiency and with PDI
(polydispersity index) of 0.253 ± 0.019. Also, an elution
time of 0.37 min and m/z of 821.49/113.41 for GA along
with an elution time of 1.94 min and m/z of 363.45/121.40
were observed for hydrocortisone i.e., Internal standard
(IS). Similarly, %CV i.e., inter and intra assay i.e., 0.49–
4.41%, linear dynamic range (10–2000 ng/mL) and %
accuracy of 90.00–99.09% were also observed. AUC0–24
with augmented Cmax was noted (∗∗ p < 01), in Wistar
rat brain as compared to i.v. treated group during phar-
macokinetics studies. In MCA-occluded rats, enhanced
neurobehavioral activity i.e., locomotor and grip strength
along with a decrease in cytokines level (TNF-a and
IL-1b) was observed, following i.n. administration. When
these NPs were administered intranasally, the bioavailabil-
ity of the drug in the brain of Wistar rat was elevated as
compared to intravenous administration. Also, these were
safe and free of any health associated risk [18].
The gene transfection capacity has been improved by
the glycyrrhetinic acid (GA). Researchers developed gly-
cyrrhetinic acid modified stealth cationic liposome (GA-
PEG-CLs) loaded with green fluorescent protein plasmid
DNA (pDNA). Initially, they synthesized the GA-PEG-
Chol conjugates by covalently linking GA to the PEG-
Chol, which was formed from the covalent linkage
3373
Glycyrrhiza glabra: An Insight to Nanomedicine Rani et al.

Table IV. Surface modification of nanoparticles using G. glabra constituents.

Surface modified Average size of NPs

NPs used by using after modification Drug or gene loaded Results Reference

Bovine serum Glycyrrhizin 77 nm Calcein Increase in uptake by rat [10]

albumin hepatocytes
nanoparticles
(BSA-NP)
Chitosan NPs Glycyrrhizin 147.2 nm Adriamycin Increase in encapsulation efficiency, [11, 12]
increase in drug release time and
increase in uptake by hepatocytes
Stealth cationic Glycyrrhetinic acid _ Green fluorescent Increased transfection efficiency and [13]
liposome protein plasmid lower cytotoxicity to normal
(GA-PEG-CLs) DNA (pDNA) hepatocyte cells
O-carboxymethyl Glycyrrhizin 100–205 nm Paclitaxel Increased accumulation of PTX in [14]
chitosan hepatic tumor tissue and targeted
nanoparticles delivery of PTX drug to
(CMCNP) hepatocarcinoma cells
Hyaluronic acid Glycyrrhetinic acid 152.6–260.7 nm DiR (NIR fluorescent Superior targeting efficiency and no [15]
nanoparticles cyanine dye) significant cytotoxicity
Hyaluronic acid Glycyrrhetinic acid 180–280 nm Doxorubicin (DOX) Increased deposition of drug in the [16]
nanoparticles liver resulting in a decrease in
nephrotoxicity and cardiotoxicity
of DOX
Graphene oxide (GO) Glycyrrhetinic acid 160 nm pEGFP-N1 gene The improved dispersive property, [17]
(GA) and (plasmid DNA of biocompatibility and gene
polyamidoamine enhanced green transfection capacity
(PAMAM) fluorescent protein)
dendrimer
poly-(E)- Glycyrrhizic acid and 201.3 ± 4.6 Glycyrrhizic acid Enhanced mucoadhesive property, [18]
caprolactone chitosan improved neurobehavioural
(PCL) activity and decrease in level of
cytokines

between cholesterol (Chol) and PEG 2000. Then GA-PEG-
Chol, cholesterol and 1,2-dioleoyl-3-trimethylammonium
propane (DOTAP) were used to prepare glycyrrhetinic
acid modified stealth cationic liposome (GA-PEG-CLs).
A mixture of liposomes were produced comprising of
ordinary cationic liposome (CLs), steric cationic liposome
(PEG-CLs) and GA modified stealth cationic liposome
(GA-PEG-CLs). Then pDNA was added in the suspen-
sion of all the three types of cationic liposomes and incu-
bated for 30 min which resulted in loading of pDNA
in the cationic liposomes. The GA-PEG-CLs loaded with
green fluorescent protein plasmid DNA (pDNA) were
used to investigate toxicity as gene vector and in vitro
transfection efficiency on HCC HepG2 and HEK 293
cell lines. It was reported that 5% GA-PEG-CLs having
DOTAP/Chol/GA-PEG-Chol at a molar ratio of 50:45:5
had higher gene transfection efficiency and lower cytotox-
icity to normal hepatocytes. The amount of GA affected
the gene entrapment and transfection efficiencies of GA-
PEG-CLs positively [13].
Surface modification of the Hyaluronic acid NPs by
glycyrrhetinic acid showed the superior targeting effi-
ciency and lesser or no cytotoxicity. Wang and the co-
workers synthesized a multifunctional drug delivery carrier
i.e., hyaluronic acid glycyrrhenitic acid succinate (HSG)
copolymer. From this copolymer, HSG self-aggregating
NPs and DiR (NIR fluorescent cyanine dye) loaded NPs
were prepared. During in vivo study, HSG NPs showed
superior targeting efficiency to the liver cells. In vitro study
revealed HSG NPs were stable and exhibited no significant
cytotoxicity [15]. For further studies, they used these self-
assembled HSG NPs for delivery of doxorubicin (DOX)
drug into liver cells. The tissue distribution study was also
performed along with the cytotoxic analysis, which exhib-
ited that the HSG/DOX NPs significantly intensified the
deposition of drug in the liver resulting in a decrease in
nephrotoxicity and cardiotoxicity of DOX [16].
Similar findings were observed in case of GO-
PAMAM-GA hybrids formulated by covalent cross-
linking of polyamidoamine (PAMAM) dendrimer and
glycyrrhetinic acid (GA) to the graphene oxide (GO).
These hybrids elevated the biocompatibility of hepato-
carcinoma (SMMC-7721) and human embryonic kidney
(HEK-293) cell lines. At the concentration of 200 g
mL−1 of hybrids, the viability of SMMC-7721 cells was
still 98%. They also transferred pEGFP-N1 gene (plasmid
DNA of enhanced green fluorescent protein) into human
hepatocarcinoma (SMMC-7721) and human embryonic
kidney (HEK-293) cells through GA-PAMAM and GO-
PAMAM-GA hybrids. The gene transfection capacity was
improved up to 50% through GA functionalization of
GO-PAMAM [17, 63, 64, 118, 119].

3374 J. Nanosci. Nanotechnol. 21, 3367–3378, 2021

Rani et al.
6. CONCLUSION AND FUTURE OUTLOOK
This review summarizes the nanomaterials synthesized
using Glycyrrhiza glabra and their therapeutic potential
especially antifungal and antibacterial activities. It also
provides information about nanoformulations and surface
modification of different NPs done by using G. glabra con-
stituents. Furthermore, the clinical efficacy of NPs needs
to be explored and discussed with the component of nano-
toxicity studies. There is a need for a more in-depth study
on various model animal systems for their reliability and
safety to translate the technology in the health care sector.
On the basis of the therapeutic potential of G. glabra and
its use in NP synthesis, this plant could be a potential can-
didate for the development of nanomedicine.
Acknowledgment: The authors acknowledge the
help rendered by Dr. Anuj Nehra, Centre for Bio-
Nanotechnology, Chaudhary Charan Singh Haryana Agri-
cultural University, Hisar.
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Received: 16 April 2019. Accepted: 9 July 2020.
J. Nanosci. Nanotechnol. 21, 3367–3378, 2021