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Glycyrrhiza glabra: An Insight to Nanomedicine

Article  in  Journal of Nanoscience and Nanotechnology · January 2021

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 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3367 Spain, Sicily, and England) and small scale (India, Iran,
2. Botanical Description . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3369 Afghanistan, etc.) [2, 3]. The dried, peeled or unpeeled
3. Medicinal Uses and Phytoconstituents . . . . . . . . . . . . . . . . . . . . 3369
4. Nanomedicine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3370
underground stems and roots constitute the drug known
5. Applications of G. glabra in Nanomedicine . . . . . . . . . . . . . . . 3370 in the trade as Liquorice. It is used in medicine for more
5.1. Green Synthesis of NPs Using G. glabra and than 4000 years [4]. The dried rhizome and root have
Their Therapeutic Potential . . . . . . . . . . . . . . . . . . . . . . . . 3370 been used by Indian, Chinese, Egyptian, Greek and Roman
5.2. Formulation of Nanoparticles with G. glabra civilizations. The use of licorice preparations to relieve
Extract or Major Constituents and Their Use in
Different Disease Conditions . . . . . . . . . . . . . . . . . . . . . . . 3371
throat and bronchial infection was known for more than
5.3. Surface Modification of Nanoparticulate Carriers by 2000 years [5]. The Indian traditional medicinal system
Constituents of Licorice Extract . . . . . . . . . . . . . . . . . . . . . 3372 (Ayurveda, Unani, and Siddha) uses more than 7500 plant
6. Conclusion and Future Outlook . . . . . . . . . . . . . . . . . . . . . . . . . 3375 species [6]. More than 1250 preparations in Ayurvedic sys-
Acknowledgment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3375 tem contains licorice as one of its constituents [7] and
References and Notes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3375
used in the treatment of respiratory and digestive system
diseases mainly.
1. INTRODUCTION This immense potential of Mulahatti opens several
Glycyrrhiza glabra Linn. is a traditional medicinal plant doors in medicine and is capable of revolutionizing
over the globe due to its high ethnopharmacological value, it [65, 66]. Medicine has nowadays become more adaptive
it can cure diverse illnesses. This plant is commonly dis- towards new techniques and technology like nanotechnol-
tributed in the subtropical and warm temperate regions [1] ogy, which leads to a new frontier in the health care system
like Southern Europe, Syria, Iran, Afghanistan, Russia, that is “Nanomedicine.” Nanomedicine offers promising
China, Pakistan and Northern India (Punjab, Haryana and improvements in diagnostic utilities, preventive medicine,
Sub Himalayan tracts). The plant is cultivated in Rus- tissue regeneration, targeted pharmacotherapy, etc. by
sia, China, Spain, Germany, France, UK, USA, Italy, and operating at molecular, intracellular and intercellular levels
as compared to conventional medicine [8]. Formulations
∗
Author to whom correspondence should be addressed. 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, the G. glabra plant. It involves the synthesis of metal
liposomes, nanocrystals, etc. [9]. Even surface modifi- NPs using various plant extracts [19, 20, 24–26, 54–56],
cation of synthesized nanomaterials leads to effective loading of extract or constituent in nanoformula-
drug delivery, increased cellular uptake, lesser cytotoxicity, tions [21–23] and surface modification of different NPs
increased drug deposition, biocompatibility [10–18]. using constituents [10–18]. In the green synthesis of metal
Extensive research in the field of nanomedicine is going NPs, the different plant parts like roots, leaves, rhizome,
on using the phytoconstituents or different extracts of 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. Glycyrrhiza glabra: An Insight to Nanomedicine

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

(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. Figure 2. Phytoconstituents of G. glabra.

J. Nanosci. Nanotechnol. 21, 3367–3378, 2021 3369

Glycyrrhiza glabra: An Insight to Nanomedicine Rani et al.

NPs, dendrimers, nanocrystals, emulsions, liposomes, solid

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].
Figure 3. Applications of G. glabra.
5. APPLICATIONS OF G. GLABRA
eczema [98], hemorrhoids [28], epilepsy [99, 100], IN NANOMEDICINE
chronic hepatitis [101], heart diseases and oro dental Phytoconstituents of licorice can be used as good bioana-
diseases [49, 102], regulate the estrogen-progesterone lytical tools for nanomedicines and can provide the alter-
ratio [44, 45], to protect low density lipoprotein (LDL), native and may be better solutions for disease prevention,
red blood cells from oxidative damage [28, 49] and free diagnosis and treatment [110–112]. The potential of this
radical scavenging activity [50, 103–107]. 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 Their Therapeutic Potential
including human health and changing the tools, techniques, The green synthesis of NPs is an eco-friendly and cost
ideas, therapies, etc. at present level. The new concept of effective biological method as no toxic chemicals are
nanomedicine arose from merging nanoscience and nan- used in this approach. The phytoconstituents of plant
otechnology with the medicine [51, 120]. Nanomedicine help in reduction and stabilization of the synthesized
is a branch of medicine that applies the knowledge and nanoparticles.
tools of nanotechnology to the prevention and treatment To date, various kinds of metal-based NPs (silver, zinc
of disease. It involves the use of nanoscale materials, oxide, and copper oxide, see Table I) have been synthe-
such as biocompatible nanoparticles and nanorobots, for sized using G. glabra by many research groups. Most of
diagnosis, delivery, and sensing or actuation purpose in them used the root extract of this plant. Various instru-
a living organism. There are various forms in which ments like UV–Vis, DLS, XRD, FTIR, Vis-NIR, TEM,
nanomedicines are evolved like engineered NPs, polymeric 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. Glycyrrhiza glabra: An Insight to Nanomedicine

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

Table II. Silver NPs exhibiting important bio-activities.

NP Activity Tested organism/cell line The method used to check activity Reference

Silver Antibacterial Enterococcus faecalis and Candida Kirby and Bauer [19]
Antifungal albicans Disc diffusion assay
Silver Antiulcer Helicobacter pylori Agar disc diffusion assay [25]
Silver Antibacterial Gram positive-Stayphylococcus Agar disc diffusion method [55]
Antifungal aureus, Bacillus subtillis MTT assay
Anticancerous Gram negative-Escherichia coli,
Pseudomonas aeruginosa,
Salmonella typhi
Trichoderma, rhizopus, Aspergilslus
niger, Candida spp.
On Hela cell line
Silver Antibacterial Bacillus cereus, Staphylococcus Disc diffusion method [24]
Antifungal aureus, Escherichia coli,
Pseudomonas aeruginosa
Fusarium oxysporum

J. Nanosci. Nanotechnol. 21, 3367–3378, 2021 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 mucoadhesive NPs by encapsulating the root extract con-
(see Table III) [57]. taining Glabridin with alginate [61], polylactic acid (PLA)
Glycyrrhizin-loaded NPs have been prepared and and polylactic-co-glycolic acid (PLGA) [62]. The antifun-
evaluated for anti-diabetic activity in nicotinamide- gal efficacy of each formulation with ethanolic root extract
streptozotocin-induced diabetic rats [21]. This is the first was accessed [22] and even included in an oral gel, an oral
study to assess the antidiabetic effects of NFs of gly- film, and toothpaste.
cyrrhizin in a type-II diabetes model. They synthesized the For the tuberculosis treatment, gelatin based NPs of
NPs using biocompatible polymers, chitosan, and gum ara- licorice extract were prepared by double desolvation tech-
bic by ionotropic gelation method. The size of spherical nique, and then conjugated with mannose for active tar-
Glycyrrhizin-loaded chitosan-gum arabic NPs (GL-loaded geting to the macrophages. The particle size of optimized
CSGA-NPs) was in range of 140–200 nm [58]. Then the formulation was around 300 nm. The in vitro drug release,
NFs of both glycyrrhizin and metformin were prepared by in vitro uptake by the cell, in vivo pharmacokinetics and
loading these onto the NPs. They compared their effec- in vivo anti-tubercular efficacy of the mannosylated NPs in
tiveness on type-II diabetes by administrating the NF to murine tuberculosis model were checked. A statically sig-
diabetic rats for 21 successive days and it was found that nificant reduction in bacterial counts in lungs and spleen
glycyrrhizin loaded NPs showed significant antidiabetic of Mycobacterium tuberculosis H37Rv infected mice was
effect [21, 121]. observed as compared to untreated ones [23].
Glabridin is a phenylated isoflavonoid compound found
in the roots of G. glabra, and is responsible for its anti- 5.3. Surface Modification of Nanoparticulate Carriers
fungal activity against Candida albicans which causes by Constituents of Licorice Extract
candidiasis [49, 59, 60]. Different scientists have uti- There are various studies regarding surface modification
lized this property by developing bioadhesive NFs or of NPs using constituents of licorice extract, mainly the

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

Rani et al. Glycyrrhiza glabra: An Insight to Nanomedicine

Table III. Nanoformulations and disease targeting.

Nanoformulation Disease-targeted The material used to prepare NPs The substance used in loading The type of study involved Reference

Polymeric NPs Type II diabetes Chitosan and gum Glycyrrhizin In vivo [21, 58]
arabic
Mannosylated Tuberculosis Gelatin Root extract In vivo and in vitro [23]
gelatin NPs (acetone)
Bioadhesive NF Oral candidiasis Alginate, Root extract In vitro [22]
polylactic acid (Ethanolic)
(PLA) and
polylactic-co-
glycolic acid
(PLGA)
Polymeric NPs Inflammation Chitosan and Glycyrrhizic acid In vivo and in vitro [57]
Katira gum

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

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

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

Rani et al. Glycyrrhiza glabra: An Insight to Nanomedicine

6. CONCLUSION AND FUTURE OUTLOOK 12. Du, H., Yang, X., Pang, X. and Zhai, G., 2014. The synthesis,
This review summarizes the nanomaterials synthesized self-assembling, and biocompatibility of a novel O-carboxymethyl
chitosan cholate decorated with glycyrrhetinic acid. Carbohydrate
using Glycyrrhiza glabra and their therapeutic potential
Polymers, III, pp.753–761, DOI: 10.1016/j.carbpol.2014.04.095.
especially antifungal and antibacterial activities. It also 13. Yao, Z., Zheng, X., Hua, X., Rong, X., He, G., Fang, W. and Yu, S.,
provides information about nanoformulations and surface 2010. Development of glycyrrhetinic acid-modified stealth cationic
modification of different NPs done by using G. glabra con- liposomes for gene delivery. International Journal of Pharmaceu-
stituents. Furthermore, the clinical efficacy of NPs needs tics, 397, pp.147–154, DOI: 10.1016/j.ijpharm.2010.06.029.
14. Shi, L., Tang, C. and Yin, C., 2012. Biomaterials glycyrrhizin-
to be explored and discussed with the component of nano-
modified O-carboxymethyl chitosan nanoparticles as drug vehicles
toxicity studies. There is a need for a more in-depth study targeting hepatocellular carcinoma. Biomaterials, 33(30), pp.7594–
on various model animal systems for their reliability and 7604, DOI: 10.1016/j.biomaterials.2012.06.072.
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On the basis of the therapeutic potential of G. glabra and Synthesis, characterization and liver targeting evaluation of self-
its use in NP synthesis, this plant could be a potential can- assembled hyaluronic acid nanoparticles functionalized with gly-
cyrrhetinic acid. European Journal of Pharmaceutical Sciences, 96,
didate for the development of nanomedicine. pp.255–262, DOI: 10.1016/j.ejps.2016.09.036.
16. Wang, X., Gu, X., Wang, H., Yang, J. and Mao, S., 2018. Enhanced
Acknowledgment: The authors acknowledge the delivery of doxorubicin to the liver through self-assembled nanopar-
help rendered by Dr. Anuj Nehra, Centre for Bio- ticles formed via conjugation of glycyrrhetinic acid to the hydroxyl
Nanotechnology, Chaudhary Charan Singh Haryana Agri- group of hyaluronic acid. Carbohydrate Polymers, 195, pp.170–
cultural University, Hisar. 179, DOI: 10.1016/j.carbpol.2018.04.052.
17. Liu, F., Yang, D., Liu, Y., Cao, Q., Sun, Y., Wang, Q.
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Received: 16 April 2019. Accepted: 9 July 2020.

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

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