Review

Recent Advances in Nanomedicine for Antimalarial Drug

Delivery
Manashjit Gogoi*

Department of Biomedical Engineering, North-Eastern Hill University, Shillong–793022, India

Malaria is one of the major public health problems caused by parasites belonging to plasmodium genus
in the tropical and subtropical countries. Advancement of nanotechnology is opening up a window of
huge opportunities for better treatment of malaria. Different nano drug delivery systems such as
liposomes, solid lipid nanoparticles, dendrimer, nano-emulsion and polymeric nanoparticles are widely
investigated for treating malaria. In this review, the recent advances in nanomedicine for antimalarial
drug delivery are summarised.

INTRODUCTION
Malaria is one of the major public health
problems in tropical and subtropical
countries. Malaria parasites are
transmitted from infected host to
susceptible host by the bite of an infected
Anopheles mosquito. As per the World
Health Organization’s (WHO) Malaria
Report 2016, nearly 148–304 million
people suffered from acute malaria
globally and 0.235–0.639 million among
the infected died. In 2015, it was
estimated that globally 429,000 people
died due to malaria, most of them in
WHO African Region (92%), followed
by the WHO South-East Asia Region
(6%) and WHO Eastern Mediterranean
Region (2%) (WHO, 2016). One of the
reasons behind the large number of
malaria associated deaths in WHO Africa
region and WHO South-East Asia
Region is the emergence of drug
resistance parasites especially in East
Africa (Korenromp et al., 2003) and
Greater Mekong Subregion (Imwong et
al., 2017). Artemisinin combination
therapies (ACTs) are leading options for
treatment of malaria caused by
Plasmodium falciparum in the malaria
prevalent regions of the world. But, the
emergence and spread of artemisinin
resistant P. falciparum across the Greater
Mekong Subregion possess a serious

Key words: Nanomedicine, malaria, nano drug delivery system, nanoparticles.

*Corresponding Author: Manashjit Gogoi, Department of Biomedical Engineering, North-Eastern Hill University,
Shillong–793022, Meghalaya, India.
Email: manash.aec@gmail.com

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Gogoi 152

threat to global malaria control and Malaria and Conventional Therapy

elimination drive. The artemisinin Malaria is an ancient disease and has
resistance evolved in the Thailand- been troubling the mankind since
Myanmar border due to the E252Q thousand years. The Italian word malaria
PfKelch mutation; later it was overtaken means “bad air”. Traits of malaria were
by C580Y as ACTs began to fail reported in ancient history from India,
(Imwong et al., 2017). China, and Egypt. Greek and Roman
Due to lack of funding, limited work medical literature contain accurate
was carried out in the field of malaria descriptions about malaria (Nayak et al.,
research in last few decades; and hence 2013). Malaria is caused by four
limited progress is achieved in Plasmodium species, i.e., P. falciparum,
eradication of malaria. In recent years, P. vivax, P. malariae and P. ovale cause
due to infusion of money from several malaria in humans. P. falciparum and P.
public and private organizations e.g. Bill vivax are the two major species
and Melinda Gates Foundation, responsible for malaria globally (Duong
Medicines for Malaria Venture, Drugs for et al., 2004). Almost all deaths i.e. 99%
Neglected Diseases initiative (DNDi) and resulted from P. falciparum malaria
the Institute for One World Health whereas P. Vivax was estimated to cause
(IOWH), the situation improved to some 3100 deaths in 2015 and most of the
extent. However, as no new drug is deaths (86%) occurred outside Africa
discovered during last several years and (WHO, 2016).
discovery of drug is an expensive and Malaria is a complex disease and the
time consuming affair; nanomedicine has life cycle of protozoan parasite
been explored for eradication of malaria. responsible for malaria is divided
Nanomedicines have the potentials to between a vertebrate host and an insect
increase the therapeutic potency of vector. Plasmodium parasites (except P.
existing drugs by improving their malariae) enter the human blood in the
adsorption, distribution, metabolism and form of sporozoites through mosquito
excretion (ADME) and reducing over bite. These sporozoites infect the liver
drug toxicity (Nayak et al., 2013). cells and proliferate into thousands of
merozoites (Tuteja, 2007). The

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153
Figure 1: The life cycle of the parasite (adapted from Murambiwa et al., 2011).
merozoites released from the liver enter
the red blood cell (RBC) and start an
asexual cycle consisting
trophozoites, schizonts and merozoites
for multiplication of parasites. These
parasites again become ready to infect
fresh RBCs. In this process, a few
gametes are also formed which enter the
mosquito midgut during bite; their sexual
cycles start in the mosquito and it leads
to production of sporozoites. Asexual
cycle in human is divided into the exo-
erythrocytic cycle in liver and intra-
erythrocytic cycle in RBC. The intra-
erythrocytic phase elicits the clinical
manifestations of malaria (Garnham,
1966; Jarcho, 1968). The life cycle of the
Biomed Res J 2017;4(2):151-161
Nanomedicine for antimalarial drug delivery
parasite is shown in Fig. 1.
At present, quinine related drugs,
of rings, Artemisinin derivatives, anti-folates
derivatives and new class of combination
drugs are extensively used to treat
malaria. These drugs are used in
combination for better malaria treatment.
Quinine related drugs are highly potent
in treating malaria. Chloroquine (CQ)
has been used for treatment of malaria
for over eight decades due to its excellent
pharmacokinetic and pharmacological
advantages over all other antimalarial
drugs. CQ is known for its fast action in
blood parasite stages, low toxicity, good
bioavailability from oral dosage, water
solubility, high volume of distribution in
Gogoi 154

the body and lower cost (Santos- administrations (Murambiwa et al.,

Magalhães and Mosqueira, 2010). 2011).
Primaquine (PQ) is a very toxic drug
used in the prophylaxis against all types Nanomedicine for Drug Delivery
of malaria. Nevertheless, quinine related Nanocarriers with prolong blood
drugs are effective against malaria; P. circulation time i.e. stealth nanocarriers
falciparum is developing resistance have been used for delivering
against these classes of drugs. antimalarial drugs in order to increase the
ACT is the frontline treatment against resident time in the human body and to
malaria. Artemisinin and its derivatives increase the probability of drug
have the ability to kill a broad range of molecules to interact with infected red
asexual parasite stages at safe blood cells and parasites (Mosqueira el
concentrations (Santos-Magalhães and al., 2004). In addition to this, nano-drug
Mosqueira, 2010). In 2005–06, ACTs delivery systems (NDDs) provide
were deployed as first-line treatment in protection to unstable drugs, cell
several endemic countries in Africa, as a adhesion properties, and ability to
result, the malaria cases and deaths were conjugate specific ligands on their
reported to be declining (O'Meara et al., surface (Date et al., 2007; Kayser and
2008). There were reports of high failure Kiderlen, 2003). NDDs such as
rates of ACT along Thai-Cambodian liposomes, polymeric nanoparticles, solid
border (Noedl et al., 2008; Vijaykadga et lipid nanoparticles, dendrimers, nano-
al., 2006). Data showed the development emulsions are extensively studied for
of possible artemisinin resistance. antimalarial drug delivery. These NDDs
Moreover, artemisinin derivatives were are used to deliver encapsulated
reported to show dose, time and route therapeutic agents either by passive or
dependent neurotoxicity in laboratory active targeting strategy. Brief accounts
animals (Petras et al., 2000). of studies done using different NDDs are
Nevertheless, no report is available given below.
regarding the toxicity of artemisinin and
its derivatives in human. The observed Passive targeting
discrepancy between animal and human Malaria infected erythrocytes and
studies may be due to different routes of occasionally hepatocytes are targeted

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155 Nanomedicine for antimalarial drug delivery

using NDDs either by active or passive using passive targeting strategy.

targeting (Santos-Magalhães and Liposomes are spherical vesicles made
Mosqueira, 2010) strategy. In passive up of lipid bilayers. Liposomal drug
targeting, conventional NDDs or surface delivery systems are widely used for
modified long circulating NDDs their biocompatibility, biodegradability
preferentially accumulate at targeted site and their ability to encapsulate both
due to physiochemical and hydrophilic and hydrophobic therapeutic
pharmacological factors (Barratt, 2003; agents. Nayak et al. (2012) investigated
Garnett, 2001). Once these NDDs come the therapeutic efficacy of curcuminoids
into contact with hepatocytes or loaded liposomes alone and in
mononuclear phagocyte system and then combination with α/β arteether following
they internalize these NDDs. It is intravenous administration in P. berghei
difficult to target infected RBCs using infected mice. Animals treated with
conventional NDDs as the RBCs are curcuminoids-loaded liposomes showed
phagocytically and endocytically lower parasitemia and higher survival in
inactive. The main strategy of the passive comparison to control group (no
targeting is to increase the plasma treatment). The combination therapy of
maximum concentration (Cmax) of a drug curcuminoids-loaded liposomes (40
which is proportional to the toxicity of mg/kg b.w.) along with α/β arteether (30
drug and the efficacy is proportional to mg/kg b.w.) was able to cure infected
the area under the curve (AUC) of drug mice as well as prevent recrudescence.
plasma concentration (Wong et al., Artemether loaded solid lipid
2008). Availability of higher nanoparticles were produced using
concentration of drug improves the glyceryl trimyristate and soybean oil for
interaction with infected RBCs and treating malaria. Mean particle size, zeta
parasite membranes (Mosqueira et al., potential and drug encapsulation
2004). Long-circulating NDDs are able efficiency were around 120 nm, −38 mV
to improve the AUC of the drugs, and 97% (w/w) respectively.
enhance selectivity and thereby able to Experimental results showed that these
reduce the doses (Owens and Peppas, nanoparticles were effective than free
2006). A good number of novel NDDs drug and corresponding marketed
were investigated for treating malaria formulation in treating malaria (Nayak et

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Gogoi 156

al., 2010a). Akhtar et al. (2012) curcuminoids loaded lipid nanoparticles

developed curcumin loaded chitosan as compared to free curcuminoids
nanoparticles for treating malaria. The (Nayak et al., 2010b).
mean particle size and zeta potential of In addition to delivery of traditional
the nanoparticles were 178 nm and antimalarial drugs, NDDs are used for
+78±7.6 mV, respectively. Experimental delivering genetic materials which
results showed delay in degradation of interfere with gene expression by
curcumin encapsulated in nanoparticles preventing the translation of proteins
in comparison to free curcumin in mouse from mRNA. In one study, antisense
plasma. In vivo results showed better oligonucleotides (ODNs) against
antimalarial activity of these malarial topoisomerase II gene were
nanoparticles than free curcumin. loaded in chitosan nanoparticles.
Chloroquine loaded chitosan Antisense interferes with the gene
nanoparticles were prepared using expression by preventing translation of
ionotropic gelation between chitosan and proteins from mRNA and thereby
sodium tripolyphosphate. These inhibits the growth of P. falciparum.
nanoparticles were evaluated for Chitosan and oligonucleotides in 1:1 or
attenuation of P. berghei infection in 2:1 proportions were prepared with
Swiss mice. Results showed that these negative and positive surface charge
nanoparticles have the capability of fight respectively. Positively charged antisense
parasite infection, oxidative stress, ODN chitosan nanoparticles showed
inflammation and DNA damage similar P. falciparum growth inhibition
(Tripathy et al., 2013). Curcuminoids- as the free ODN, and the negatively
loaded lipid nanoparticles for parenteral charged nanoparticles showed the highest
administration were successfully growth inhibition (87%). This may due to
prepared using trimyristin, tristerin, the fact that less stable chitosan-ODN
glyceryl monostearate and medium chain complexes, as the anionic ones obtained
triglyceride. Particle size and zeta in presence of excess of nucleic acid,
potential were 120−250 nm and −28 to may have led to an earlier complex
−45 mV, respectively, depending nature dissociation and faster onset of action
of lipid used. In vivo results showed 2- (Foger et al., 2006). Recently, a NDD
fold increase in antimalarial activity of based DNA vaccine formulation has been

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157 Nanomedicine for antimalarial drug delivery

prepared for magnetic transfection. the target site (Torchilin, 2006). In

Plasmid DNA encoding for a fragment of malaria, the disease infected erythrocytes
the merozoite surface protein MP1 was in blood and hepatocytes can be targeted
attached to the surface of polyethylene- by tagging the ligands on the surface of
imine-coated superparamagnetic iron the NDDs specific to them. In another
oxide nanoparticles. Due to magnetic study, immunoliposomes using 1,2-
transfection, the magnetic NDDs have Dioleoyl-sn-glycero-3-phospho -choline
been proven to improve efficiency and (DOPC) and cholesterol were developed
rate of gene delivery to different tissues for delivering chloroquine and
and they elicited IgG2a and IgG1 fosmidomycin. These liposomes were
responsible for the protective immunity tagged with monoclonal antibody
against malaria (Al-Deen et al., 2013). In BM1234 specific to parasite infected
another study dihydroartemisinin loaded RBCs. In vitro experiments showed 10
solid lipid nanoparticles (DHA-SLNs) fold increase in antimalarial activity of
were prepared to overcome the poor drug following encapsulation in
water-solubility, poor pharmacokinetic immunoliposomes as compared to free
profile and inadequate clinical outcome drug (Urban et al., 2011). Dendritic
of monotherapy. In vitro and in vivo derivatives based on 2,2-bis(hydroxy-
results showed the enhancement of methyl) propionic acid and pluronic
therapeutic efficacy of DHA-SLNs in polymers have been studied for
comparison to the free DHA. Results delivering antimalarial drugs CQ and PQ
showed the potential of using this to target Plasmodium-infected red blood
formulation of clinical application cells (pRBCs). Experimental results
(Omwoyo et al., 2016). demonstrated the possibility of using
dendrimers for effective targeted delivery
Active targeting of therapeutic agents to pRBCs
In active targeting, the surface of the (Movellan et al., 2014). Owais et al.
NDDs are conjugated with specific (1995) developed chloroquine loaded
ligands such as carbohydrates, proteins, liposomes tagged with antibody against
peptides or antibodies specific to the infected erythrocytes and tested their
disease infected cells or tissue, which efficacy in chloroquine-resistant P.
guide the NDDs or drug to accumulate in berghei infected mice. Results showed

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Gogoi 158

+
that selected homing of chloroquine to reduce CD8 T cell and supress pRBC
malaria-infected erythrocytes helped in sequestration in the brain. It is an ideal
curing of the chloroquine-resistant adjuvant drug to prevent and treat
malarial infections with reduced dose cerebral malaria. Dende et al. (2015)
(Owais et al., 1995). Quinine dihydro- showed that curcumin alone was
chloride is one of the drugs of effective effective in reducing leukocyte as well as
in treating cerebral malaria, but, pRBC sequestration in the brain,
delivering it to the brain capillaries is maintaining BBB integrity whereas
difficult. Transferrin has high affinity for arteether prevented pRBC sequestration
receptors present in brain capillaries and in the brain, parasitemia builds up in
hence transferrin-targeted SLNs were blood. Combination of Curcumin-
prepared for targeted delivery of quinine artether administered after the onset of
hydrochloride to brain. SLNs prepared neurological symptoms, was very
using hydrogenated soy phosphatidyl- effective in counteracting all the
choline, triolein, cholesterol and distearyl investigated parameters governing
phosphatidylethanolamine, followed by leukocyte as well as pRBC sequestration.
covalent coupling of transferrin were All the animals were protected against
reported to be effective in delivering mortality at least for 90 days.
quinine hydrochloride to brain (Gupta et
al., 2007). Challenges and Future Prospects
Zhao et al. (2014) demonstrated Malaria is affecting large number of
during experimental cerebral malaria people worldwide with huge mortality
(ECM) that brain becomes severely rate. Nanoscale materials are offering
dysfunctional due to multiple unique and novel opportunities to
pathological events such as blood–brain address the issues related to the anti-
barrier (BBB) disruption, vascular malarial therapy. Today advancement of
leakage, and immune cell accumulation nanotechnology is providing powerful
(especially CD8 T cell infiltration). They platforms ranging from diagnostic,
demonstrated using mice model that detection of diseases in the early stage
olfactory bulb region is a vulnerable and delivery of therapeutics for the
location for vascular leakage during neglected diseases like malaria. But,
ECM. Curcumin has the potential to safety is a major concern for production

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159 Nanomedicine for antimalarial drug delivery

of these NDDs/ nanoparticles. Owing to nanomedicine (Sanhai et al., 2008).

smaller size, these nanoparticles are
highly reactive due to huge surface area,
which must be addressed before using
them in clinical setup. Moreover, prior
knowledge of biodistribution of NDDs in
the body following systemic
administration; pictorial evidence of
NDDs distribution in vivo following
administration, understanding the mass
transport across the body's
compartmental boundaries; developing
new mathematical and computer models
that will contribute to a 'periodic table' of
nanoparticles for predicting risk and
benefit parameters as well
establishment of standards or reference
materials and consensus testing protocols
that can provide benchmarks for the
development of novel classes
materials, are few concerns related to the
But, seeing the potential of NDDs in
biomedical engineering and healthcare
sector, large amount of works are being
done globally to overcome these
challenges; more and more NDDs are
reaching the clinical applications. As a
result, number of nano-formulation
getting FDA approval is increasing in
recent years.
CONCLUSIONS
Malaria is a complex disease that has
been affecting the people from tropical
and subtropical countries. But, the recent
as development in nanomedicine is opening
up new possibilities and is providing
better solution in treating complex
diseases like malaria. Effective malaria
of treatment strategies are anticipated in
near future.

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