NANOTHERAPY - Leismania

International Journal of Pharmaceutics 547 (2018) 421–431
Contents lists available at ScienceDirect
International Journal of Pharmaceutics

journal homepage: www.elsevier.com/locate/ijpharm
Promising nanotherapy in treating leishmaniasis T

a a b a
Aline de Souza , Débora Soares Souza Marins , Samir Leite Mathias , Lis Marie Monteiro ,
Megumi Nishitani Yukuyamaa, Cauê Benito Scarimc, Raimar Löbenbergd,
⁎
Nádia Araci Bou-Chacraa,
a
University of São Paulo, Faculty of Pharmaceutical Sciences, Prof. Lineu Prestes Avenue, 580, Bl-13/15, 05508-900 São Paulo, SP, Brazil
b
Federal University of São Carlos, Department of Physics, Chemistry and Mathematics, João Leme dos Santos Highway, Km 110, 18052-780 Sorocaba, SP, Brazil
c
São Paulo State University “Júlio de Mesquita Filho” – UNESP, Faculty of Pharmaceutical Sciences, Department of Drugs and Medicines, Rodovia Araraquara Jaú, Km 01
– s/n, 14800-903 Araraquara, SP, Brazil
d
University of Alberta, Faculty of Pharmacy and Pharmaceutical Sciences, Edmonton, AB T6G 2N8, Canada
A R T I C LE I N FO A B S T R A C T
Keywords: Leishmaniases are infectious diseases caused by an intracellular protozoan in humans by 20 different species of
Nanotechnology Leishmania among more than 53 species. There are at least twelve million cases of infections worldwide and
Human leishmaniasis three hundred and fifty million people are at risk in at least 98 developing countries in Africa, South-East Asia,
Treatment and the Americas. Only Brazil presented high burden for both visceral leishmaniasis (VL) and cutaneous (CL).
Nanotherapeutics
Chemotherapy is the main means of dealing with this infection. Nevertheless, only a few effective drugs are
Drug targeting
available, and each has a particular disadvantage; toxicity and long-term regimens compromise most che-
Drug delivery systems
motherapeutic options, which decreases patient compliance and adherence to the treatment and consequently
the emergence of drug-resistant strains. Nano drug delivery systems (NanoDDS) can direct antileishmanial drug
substances for intracellular localization in macrophage-rich organs such as bone marrow, liver, and spleen. This
strategy can improve the therapeutic efficacy and reduce the toxic effects of several antileishmanial drug sub-
stances. This review is an effort to comprehensively compile recent findings, with the aim of advancing un-
derstanding of the importance of nanotechnology for treating leishmaniases.
1. Introduction as kala-azar, cutaneous (CL) and mucocutaneous leishmaniasis (MCL).

The average ratio of incidents between the cutaneous and visceral
Neglected tropical diseases (NTDs) are a diverse group of infectious forms, respectively the common and the fatal form, is approximately 8
diseases that are predominant in the poorest parts of the world. These times (Herwaldt, 1999; World Health Organization, 2017). There are
diseases are prevalent in tropical and subtropical areas due to in- approximately twelve million cases of infections worldwide and three
sufficient health infrastructures. There are currently 20 NTDs prevalent hundred and fifty million people are at risk in 98 developing countries
in 149 countries, affecting approximately one billion people worldwide from Africa, South-East Asia and the Americas (Akhoundi et al., 2016;
(World Health Organization, 2016a). Among the NTDs, there are at World Health Organization, 2016b).
least seven hundred thousand new leishmaniasis cases and twenty In 2015, six regions were reported to have higher cases of CL and VL
thousand deaths annually worldwide. by the WHO (Europe, Western Pacific, the Americas, Southeast Asia,
Leishmaniasis presents three main forms, visceral (VL), also known eastern Mediterranean and Africa), 87 countries were considered
Abbreviations: DPPA, 1,2-dipalmitoyl-sn-glycero-3-phosphate; DPPC, 1,2-dipalmitoyl-sn-glycero-3-phosphocholine; DSPE, 1,2-distearoyl-sn-glycero-3-phosphoetha-nolamine-N-

[methoxy(polyethylene glycol)-2000]; PAHO, American Health Organization; AMB, amphotericin B; CHOL, cholesterol; CL, cutaneous leishmaniasis; DMSA, dimercaptosuccinic acid;
Nano-D-AMB, dimercaptosuccinic acid nanoparticles; DMPC, dimyristoylphosphatidylcholine; DMPG, dimyristoylphosphatidylglycerol; DOPC, dioleoylphosphatidylcholine; DOPG,
dioleoylphosphatidylglycerol; DOPS, dioleoylphosphatidylserine; DPPC, dipalmitoyl phosphatidylcholine; DPPG, dipalmitoyl phosphatidylglycerol; EE%, encapsulation efficiency;
QauNP, gold nanoparticles conjugated with quercetin; HSH, high shear homogenization; HIV, human immunodeficiency virus; NFOH, hydroxymethylnitrofurazone; L-AMB, liposomal
amphotericin B; LPS, liposome; NLC, nanostructured lipid carriers; MgONPs, magnesium oxide nanoparticles; Nano-D-AMB-MG, magnetic citrate-coated nanoparticles; MONPCG,
MgONPs coated with glucose; MILT, miltefosine; MCL, mucocutaneous leishmaniasis; NanoDDS, Nano drug delivery systems; NE, nanoemulsions; NTDs, Neglected tropical diseases; PRM,
paromomycin; PRM, paromomycin; PCL, poly (amino acids) poly (caprolactone); PGA, poly (glycolic acid); PLA, poly (lactic acid); PLGA, poly (lactide-co-glycolide); PBCA, poly (n-butyl
cyanoacrylate); PACA, polyalkylcyanoacrylates; PDI, polydispersity index; RIF, Rifampicin; SeNPs, selenium nanoparticles; AgNPs, silver nanoparticles; SLN, solid lipid nanoparticles;
SESE, spontaneous emulsification and solvent evaporation; TiAgNps, titanium dioxide and silver nanoparticles; TFL-L, trifluralin liposome; VL, visceral leishmaniasis
⁎
Corresponding author at: 580, Prof. Lineu Prestes Avenue, Bl-13/15, 05508-900 São Paulo, SP, Brazil.
E-mail addresses: [email protected] (A. de Souza), [email protected] (D.S.S. Marins), [email protected] (R. Löbenberg), [email protected] (N.A. Bou-Chacra).
https://doi.org/10.1016/j.ijpharm.2018.06.018
Received 14 March 2018; Received in revised form 5 June 2018; Accepted 6 June 2018
Available online 08 June 2018
0378-5173/ © 2018 Elsevier B.V. All rights reserved.
A. de Souza et al. International Journal of Pharmaceutics 547 (2018) 421–431
Fig. 1. Cycle of life of Leishmaniasis parasite.
endemic for CL and 75 for VL. Southeast Asia is the most affected by VL Nevertheless, only a few effective drugs are available and each one has
(9250) followed by Africa (5796) and eastern Mediterranean (4501). a particular disadvantage and toxicity (Pham et al., 2013); long-term
For CL, the eastern Mediterranean is the most affected (139,033) fol- regimens compromise most chemotherapeutic options. Thus, the search
lowed by the Americas (46,304) and Africa (7984) (World Health for safer, more efficient, innovative, cost-effective therapies is urgently
Organization/Department of Control of Neglected Tropical Diseases, needed for treating leishmaniasis.
2017). During the last decade, nanotechnology drug delivery systems
According to the WHO, in 2015, 25 countries were considered a (NanoDDS) have been used to enhance the performance of drugs in
high-burden for leishmaniasis, which means they present over 100 treating several diseases. Different nanotherapeutics have been ap-
cases of VL and over 2500 cases of CL. Of these, 13 countries show high- proved by the FDA and are currently available for clinical use (Eifler
burden of VL and 11, high burden of CL. Brazil is the only country to and Thaxton, 2011). Therefore, this review is an effort to comprehen-
present high burden for both forms of Leishmaniasis (World Health sively compile the findings of recent studies while underscoring the
Organization, 2016b). importance of nanotechnology for treating leishmaniasis.
Considering the total number of cases of CL in the Americas, 70%
were reported by Peru (5459), Colombia (7541), and Brazil (19,395). In
2. Leishmaniasis infection
the Americas, 69% of the cases of CL affect males and 12.7% occur in
those younger than 10 years old. Secondary infection is reported in
VL, CL and MCL are infections caused by intracellular protozoans in
54.2% of cases and is usually caused by Staphylococcus aureus (Ekiz
humans by 20 different species of Leishmania (World Health
et al., 2017). Another important reported coinfection was CL/human
Organization, 2017) among more than 53 species (Akhoundi et al.,
immunodeficiency virus (HIV), which is present in 198 of the cases
2016).
(0.43%), of which 135 were reported in Brazil and 63 cases in Colombia
The transmission occurs through the bite of female phlebotomine
(Pan American Health Organization, 2017).
sandflies (98 of 800 species infect humans) (Akhoundi et al., 2016;
According to the Pan American Health Organization (PAHO), in
World Health Organization, 2016b). The Old World is affected by the
2015, among the 12 countries affected in the Americas by VL, 96% of
sandfly of the genus Phlebotomus (Kevric et al., 2015) and the New
the cases were reported in Brazil (3289), with 268 deaths and a fatality
World by Lutzomyia (Borghi et al., 2017). Moreover, leishmaniasis can
rate of 7.7%. Of the total number of described cases, 64.64% (2234)
be classified as anthroponotic or zoonotic, the natural reservoir is
were men and 31.9% were children under five years old. For Venezuela,
human or animal, respectively (World Health Organization, 2016b).
Honduras and Colombia, the infected children represent 59.5%, 83.3%
The parasites have two life-cycles (Fig. 1): an extracellular mobile
and 95.2%, respectively. In this same year, 257 (7.4%) of VL/HIV co-
stage (promastigote) exclusive to an invertebrate host and an in-
infection cases were registered, including a single case in Venezuela, 12
tracellular (amastigote) non-mobile stage in a mammalian vertebrate
in Paraguay and 244 of which were reported in Brazil (Pan American
host (Borghi et al., 2017). In vertebrates, Leishmania parasites infect
Health Organization, 2017).
phagocyte cells, especially macrophages, which are considered to be the
In Brazil the Northeast region is the most affect by VL, but the
major cellular compartments for Leishmania in the mammalian verte-
numbers have decreased from 2022 in 2014 to 1523 in 2016, a re-
brate host (Kobets et al., 2012). Promastigotes form, after infecting cells
duction of approximately 25%. Due to this decrease, the total number
of the mononuclear phagocytic system, passing into the amastigote
reported by Brazil also decreased in 2016 (3200). However, all the
form and begin to multiply. Multiplication leads to rupture of the host
other regions reported an increase of VL cases (Ministério da Saúde,
cell releasing parasites, which infect other macrophages (Borghi et al.,
2017a) although the fatality rate decreased in 2015 (6.6%) compared to
2017).
2014 (7.8%) (Ministério da Saúde, 2017b). Despite these figures, the
VL is generally caused by the Leishmania donovani complex, which
southern region of Brazil, comprising three of the ten wealthiest states,
includes the species Leishmania infantum, Leishmania chagasi, and
showed an increase of 40% in the fatality rate (Ministério da Saúde,
Leishmania donovani (De Carvalho et al., 2013; Soares-bezerra et al.,
2017c). For CL, Brazil showed a decrease in all regions in 2016
2004) CL and MCL forms are caused by several Leishmania species,
(Ministério da Saúde, 2017d).
including Leishmania tropica, Leishmania major, Leishmania amazonensis
Chemotherapy is the main means of treating this infection.
(CL) and Leishmania braziliensis (Minodier and Parola, 2007). The lag
422
period between developing cutaneous and mucosal lesions ranges from using metallic, lipid, polymeric nanoparticles, liposome and nano-
months to years (Ekiz et al., 2017). crystal.
The cause of the appearance of mucocutaneous form can be asso- In this review, the cutaneous leishmaniasis was targeted in 45.2%
ciated with the species of parasite, and with the immunity of the host (14 of 31) of the studies, against 41.9% for visceral leishmaniasis. The
and the site of the primary lesion (Crovetto-Martínez et al., 2015). The others 12.9% (4 of 31) of the studies did not determine the target of the
MCL is the result of those species that can be disseminated by haema- formulation. Among the nanostructures, the metallic nanoparticles
togenous or lymphatic system through the mucosal tissues of the mouth were mostly tested for cutaneous leishmaniasis (73.3%), while the lipid
and/or upper respiratory tract (Strazzulla et al., 2013). Im- and polymeric nanoparticles were most tested for visceral leishmaniasis
munosuppressed patients can present similar conditions with different (62.5%).
Leishmania species. Lesions above the waist, various or extensive pri-
mary lesions or delayed healing of primary CL can be also a risk factor 4.1. The role of metallic and metal oxide nanoparticle
(WHO technical report series 949, 2010).
In recent years, metallic nanoparticles have been a focus of interest
3. Overview of current chemotherapy because of their potential in theranostic nanomedicine (Mody et al.,
2010; Xie et al., 2010). Several chemical, physical and biological syn-
Historically, pentavalent antimonials (30 days, 20 mg/kg/day) are thetic methods have been proposed in designing these nanoparticles
the gold standard for treating leishmaniasis (Palumbo, 2010), which (Iravani, 2011). Among these, the green synthesis method stands out,
have been dispensed parenteral as first-line chemotherapy against all which is an ecofriendly and solvent-free approach (Arokiyaraj et al.,
forms of leishmaniasis and still the drug of first choice for treatment 2016; Iravani, 2011).
(Pham et al., 2013). The two pentavalent antimonials available, sodium Considering the literature, several authors have reported the po-
stibogluconate (Pentostan®) and meglumine antimoniate (Glu- tential of inorganic nanoparticles against leishmanicidal activity when
cantime®), are not ideal due to their toxicity and the requirement of tested in vivo. Beheshti and collaborators (2013) reported that selenium
hospitalization for the administration (Palumbo, 2010). The adverse nanoparticles (SeNPs) can inhibit the proliferation of the amastigote
effects of the drug include pancreatitis, cardiotoxicity, nephrotoxicity, and promastigote forms of Leishmania major and limited the growth of
hepatotoxicity (WHO technical report series 949, 2010), which de- CL in animal model. These nanoparticles were biosynthesized via Ba-
creases patient compliance and adherence to the treatment and con- cillus sp as described by Shakibaie et al. (2010). Also it was possible to
sequently the emergence of drug-resistant strains (Jebali and Kazemi, eliminate cutaneous lesions in infected BALB/c mice when SeNPs were
2013). administered after developing cutaneous lesions (Beheshti et al., 2013).
Second-line recommended treatment consists of amphotericin B Silver nanoparticles (AgNPs) showed antimicrobial, antifungal, and
(AMB) deoxycholate (Fungizone®, 30 days with 1 mg/kg), liposomal antiviral properties (Chaloupka et al., 2010). Since 2009, AgNPs have
amphotericin B (AmBisome®, single-dose 10 mg/Kg), pentamidine been studied for treating and enhancing drug substance delivery against
(Pentam®, 3–5 days with 4 mg/kg), miltefosine (MILT) (Impavido®, leishmaniasis (Mohebali et al., 2009), showing to be a highly effective
28 days with 1.5–2.5 mg/day) and paromomycin (PRM) (Humatin®, trypanothione reductase inhibitor in Leishmania donovani (Baiocco
21 days with 15 mg/kg/day). These drug substances can be used as et al., 2011) infection. Complimentary investigations have demon-
combined therapy, which would increase efficacy and tolerance, re- strated that it is possible to reduce the inhibitory concentration of
ducing cost of the treatment and limit drug resistance (Mcgwire and miltefosine by half using AgNPs in synergy against Leishmania parasites.
Satoskar, 2014; Pham et al., 2013; WHO technical report series 949, Kalangi et al. (2016) reported a green synthesis of AgNPs using dill leaf
2010). extract. The synergism of AgNPs associated with miltefosine was de-
monstrated by a decrease in IC50 and increase (2-fold) in leishmanicidal
4. Recent advances in treating leishmaniasis: impact of activity (Kalangi et al., 2016).
nanotechnology Additionally, Allahverdiyev and collaborators (2011) reported the
antileishmanial activity of AgNPs in the presence of ultraviolet (UV)
Among the new molecules, including those for the treatment of light on amastigotes and promastigotes of Leishmania tropica. The
leishmaniasis approved for the development of new drugs, 40% pre- findings indicated a significant decrease in antileishmanial activity by
sents low aqueous solubility. Additionally, considering those in the AgNPs. The proliferation and metabolic activity of the parasite in
discovery pipeline, this figure raises to 90% (Kalepu and Nekkanti, promastigotes was reduced by 1.5 to 3-fold, respectively, in the dark,
2015). NanoDDS is an alternative and promising approach that allows and 2 to 6.5-fold, respectively, under UV light. Also, inhibition of
improving the solubility characteristics of class II and IV drugs of the amastigotes in host cells was most significant in the presence of UV
Biopharmaceutical Classification System. The solubility of the drug in light (Allahverdiyev et al., 2011). Given this, Mayelifar and coworkers
aqueous medium is determinant for its therapeutic efficacy (Saffie- (2015) showed the influence of a low dose ultraviolet B (UVB) radiation
Siebert et al., 2005; Sharma et al., 2016). along with AgNPs in treating CL. These findings demonstrated the ex-
Furthermore, the use of NanoDDS can increase therapeutic efficacy cellent pronounced inhibitory effect in the group that received AgNPs
by releasing leishmanicidal drug substances in macrophage-rich organs and phototherapy UVB. The results indicated synergism of UVB radia-
such as bone marrow, liver, and spleen. This strategy takes advantage of tion with a cumulative dose of 150 mJ/cm2 with AgNPs at a con-
a particulate matter uptake mechanism by macrophages, which is the centration of 2 mg/kg. AgNPs, UVB radiation or combined treatment
main phagocytic cell involved in leishmaniasis infection. These cells were able to inhibit the growth of the cutaneous lesions and control
express receptors that efficiently internalize nanoparticles (NPs) in the infection (Mayelifar et al., 2015).
range of 50–500 nm (Siefert et al., 2016). Phagocytosis, which allows The use of nanoparticles under UV and infrared (IR) light have high
nanoparticles to be engulfed, can increase intracellular drug con- toxicity by generating reactive oxygen species (ROS) causing the death
centration and a modified drug release can be achieved (Coelho et al., of the organism. Jebali and Kazemi (2013) evaluated antileishmanial
2014). effects of some nanoparticles with AgNPs, AuNPs, TiO2NPs, ZnONPs
Thus, NanoDDS can direct antileishmanial drug substances for in- and MgONPs on Leishmania major parasites under UV, IR, and dark
tracellular localization in its site of action, improving the efficacy and conditions. In this study, increased antileishmanial activity was ob-
decreasing the toxic effects of these drugs (Gupta et al., 2010; Salouti served for AgNPs, followed by AuNPs, TiO2NPs, ZnONPs, and MgONPs.
and Ahangari, 2014). In the last decade, several studies have proposed Thus, both UV and IR light improved antileishmanial properties of these
applying NanoDDS for treating leishmaniasis (Kalangi et al., 2016) nanoparticles, which must be considered in future studies (Jebali and
423
Table 1
Metallic and metal oxide nanoparticle delivery systems for treating leishmaniasis.
Drug/active substance Ref. Size (nm) IC50 Method of preparation
Selenium Beheshti et al. (2013) 80–220 1.62 ± 0.6 µg/mL promastigote biosynthesized via Bacillus sp.
4.4 ± 0.6 µg/mL amastigote
Silver Kalangi et al. (2016) 35 12.5 μM MILT + 50 µM AgNP promastigote green synthesis
Miltefosine
Quercetin Das et al. (2013) 15.07 15 ± 3 µM wild type green synthesis
40 ± 8 µM sodium stibogluconate resistant strain
Gold 30 ± 6 µM paromomycin-resistant strains
Zinc Delavari et al. (2014) 20 37.8 µg/ml promastigote from Selekchem Company, USA
Silver Zahir et al. (2015) 12.82 ± 2.50 14.94 µg/mL promastigote green synthesis
83.22 ± 1.50 3.89 µg/mL amastigote
Ref.: reference; IC50: 50% inhibitory concentrations; MILT: miltefosine; AgNP: silver nanoparticles.
Kazemi, 2013). found that AgNPs were the most active against Leishmania parasites
Allahverdiyev et al. (2013) observed the leishmanicidal effect of after 24 h exposure when it was evaluated in vitro antileishmanial ac-
titanium dioxide and silver nanoparticles (TiAgNps) on the biological tivity. The authors also showed the unique trypanothione/trypa-
properties of Leishmania infantum and Leishmania tropica parasites. The nothione reductase system of Leishmania cells, which was expressively
study aimed to compare their metabolic activity, survival, and viability inhibited by synthesized AgNPs. Thus, these AgNPs presented pro-
within host cells both in the presence of dark and UV light. The findings mising leads for developing cost-effective and safer alternative treat-
show that TiAgNps reduced viability rates of Leishmania infantum and ment against VL (Zahir et al., 2015).
Leishmania tropica promastigotes by 10 and 3-fold, respectively, in the Metal oxide and metallic nanoparticles are widely used in various
dark, although these values decreased closely 20-fold for each species applications and usually classified as non-toxic due to the absence of
using UV light, in contrast to control (Allahverdiyev et al., 2013). toxicity of the bulk material. Nevertheless, these nanoparticles (NPs)
As alternative, metallic nanoparticles have been combined with naturally have toxicity to bacteria and fungi (Djurišić et al., 2015).
bioactive compounds improving antileishmanial activity. Das et al. Toxicities associated with NPs in infectious agents are usually related to
(2013) developed and evaluated gold nanoparticles conjugated with their causing damage such as generating ROS and oxidative DNA da-
quercetin (QAuNP) against leishmanial macrophage infection. Macro- mage (Niazi and Gu, 2009). Additionally, NPs can be potentially dan-
phage uptake of gold nanoparticles and antileishmanial activity were gerous to the central nervous system in some properties, such as lyso-
studied against both the wild- and resistant-type parasites. The authors some dysfunction, autophagy, oxidative stress, and the activation of
revealed antileishmanial activity of QAuNP against drug resistant certain signaling pathways (Wei et al., 2015).
strains with a high selectivity index (Das et al., 2013). Consensus on toxicity mechanisms remains inconclusive, with dif-
In a recent study, Abamor and Allahverdiyev (2016) proposed to ferent studies demonstrating contradictory findings. The relation be-
investigate antileishmanial activity of TiAgNps, in vitro, in combination tween the NP mechanisms and toxicity is complex and difficult to un-
with essential oils of Nigella sativa obtained by different extraction derstand, demonstrating that there is need for further research in this
methods. Its major constituent, thymoquinone, showed inhibitory ef- area. Table 1 shows the metallic nanoparticles for treating leishma-
fects on Leishmania infantum and Leishmania tropica parasites. An en- niasis.
hanced inhibitory effect of the combined agents on Leishmania tropica Metallic and metal oxide nanoparticles have potential to be devel-
promastigotes (1.5–25 folds) and amastigotes (5–20 folds) was ob- oped for treating leishmaniasis, as shown in Table 1.
served in contrast when the substances were used alone, while de-
creasing their toxicity to minimal levels. The presence of synergism was 4.2. Liposome: challenges and opportunities
attributed to different action mechanisms of investigated agents
(Abamor and Allahverdiyev, 2016). Despite being invented over 50 years ago, there are only 15 lipo-
In addition to metallic, metal oxide nanoparticles have shown to be some formulations on the market, mainly for anticancer therapy
a promising approach as an alternative to antibiotics in treating in- (Bulbake et al., 2017). Since the 1970s, the efficacy of intravenous
fectious diseases, interacting with vital mechanisms of infectious administration of liposomal formulations has improved together with a
agents, such as DNA and enzymes, and disrupting their components better understanding of the liposomal structure (Lopes et al., 2012).
(Panáček et al., 2006). Liposomes are small artificial vesicles (80 nm to 100 μm) consisting of
Bafghi and coworkers (2015) showed the activity of magnesium concentric spheres of lipid bilayers created from cholesterol and phos-
oxide nanoparticles (MgONPs) and MgONPs coated with glucose pholipids. The most common method used for liposome preparation is
(MONPCG) on Leshmania major. The authors evaluated cell viability the thin-film hydration procedure (Sharma and Sharma, 1997). The
and expression of two genes (GP63 and Cpb) after incubation with lipids are dissolved in organic solvent, such as trichloromethane (Cui
MgONPs and MONPCG. Thus, the expression of these genes was re- et al., 2015), chloroform (Soema et al., 2015) and a dry lipid film is
duced with an increase of nanoparticle concentration. Consequently, then formed when the solvent evaporates (Bangham et al., 1965). The
the increase of incubation time led to reduction of their expression in next step is to hydrate the film with an aqueous solution, such as a
MgONPs treated promastigotes; however, a reduction was not observed buffer solution pH 7–7.4, using a temperature higher than the lipid
in MONPCG treated promastigotes (Bafghi et al., 2015). transition temperature (Sharma and Sharma, 1997).
Delavari et al. (2014) evaluated in vitro antileishmanial activity of Alterations in the pharmacokinetic and biodistribution profiles and/
zinc oxide nanoparticles (ZnONPs). ZnONPs showed dose dependent or in establishing a modified release of the drug due to association with
antileishmanial activity by induced apoptosis in Leishmania major these carrier systems lead to improvements in the pharmacological and
(Delavari et al., 2014). therapeutic properties of the drugs. After in vivo administration and
Zahir and collaborators (2015) proposed synthesizing AgNPs and depending on their physicochemical properties, liposomes are per-
titanium dioxide (TiO2) nanoparticles using aqueous leaf extract of ceived as external materials being cleared by cells of the mononuclear
Euphorbia prostrata, which present antileishmanial activity. Comparing phagocytic system (Kelly et al., 2011), which are infected by parasites
the metallic (AgNP) and metal oxide nanoparticles (AgONP), it was in leishmaniasis. Thus, the accumulation of antimicrobial drug
424
substances through their combination with liposomes can deliver re- formulations TFL-A3 and TFL-A6 were assessed in vitro against Leish-
levant benefits to the therapy (Gaspar et al., 2008a,b). mania infantum resulting in IC50 1.2 ± 0.4 µM and IC50 1.8 ± 1.3 µM,
The liposomal AMB (L-AMB) (AmBisome®), used for the treatment respectively, and in vivo in a murine model of zoonotic visceral leish-
of systemic fungal infections, has become a standard treatment for VL maniasis. Furthermore, the findings reported trifluralin analogues were
(Van de Ven et al., 2012) and a second line treatment for CL. New et al. capable to target the intracellular amastigote form of Leishmania in-
(1981) first reported L-AMB efficacy against leishmaniasis in 1981. fantum in infected macrophages revealing the therapeutic activity of
Only almost two decades after this first study, in 1997, the FDA ap- liposomal formulations (Carvalheiro et al., 2015).
proved this product for treating this disease (Vyas and Gupta, 2006).
L-AMB is composed of high transition temperature phospholipids 4.3. The scope of lipid nanoparticle
and cholesterol, designed to incorporate AMB securely into the lipo-
somal bilayer. The AMB, after being released from the liposomes, is Lipid colloidal drug carriers such as nanoemulsions (NE), solid lipid
thought to transfer through the cell wall and bind to ergosterol in the nanoparticle (SLN) and nanostructured lipid carrier (NLC) have been of
parasite of Leishmania cell membrane. Hence, AMB forms aqueous pores great interest to drug delivery scientists mainly due to their versatile
within the plasma membrane and increase the permeability to mono- nature and interesting advantages as administration of poor water-so-
valent cations and small metabolites (Saha et al., 1986; Ramos et al., luble drug (Date et al., 2007). These include a higher degree of safety,
1996). AMB also showed to have affinity to cholesterol of host mac- mainly biocompatibility and biodegradability, and the efficacy com-
rophages cells (Mouri et al., 2008; Readio and Bittman, 1982), that is prising their feasibility to be tailored for a wide range of formulations
required to bind and internalize the parasite into macrophages according to the route of administration or disease (Attama et al., 2012;
(Pucadyil et al., 2004). AMB sequester cholesterol from host macro- Yukuyama et al., 2017a).
phages cells and inhibit the infection of Leishmania (Paila et al., 2010). These carriers have the potential to enable oral administration of
More recently, Chattopadhyay and Jafurulla (2011) proposed a novel antileishmanial drugs targeting the lymphatic system. Leishmaniasis
AMB leishmanicidal mechanism, which included a combination of the disseminates through the lymphatic and vascular systems and infects
interaction with ergosterol of Leishmania and the cholesterol of host monocytes and macrophages in liver, spleen, bone marrow and lymph
macrophages. nodes. Charman and Stella (1986) found that the solubility of the drug
The pharmacokinetics studies of L-AMB were performed in im- in triglycerides (> 50 mg/mL), and the octanol:water partition coeffi-
munosuppressed patients with fungal infections. It has never been cient (log P > 5) contributes to improve its absorption to lymphatic
conducted in leishmaniasis patients (Kip et al., 2018) Pharmacokinetics system. Later, Paliwal et al. (2009) and Caliph et al. (2000) showed that
studies revealed a statistically significant relationship between mean triglycerides with long chain are better transported to lymphatic system
area under curve (AUC) and probability of nephrotoxicity and a non- than the medium chain ones. Furthermore, Ibrahim et al. (2013) de-
linear pharmacokinetics (Lestner et al. 2016). Seibel et al. (2017) monstrated the influence of the type and ratio of lipids in the phar-
showed that all immunosuppressed children (40), but three, had side macokinetic of AMB after oral administration. This study showed that
effects after administration of L-AMB. The patients that received 10 mg/ lipid-based formulation could point to higher steady state concentra-
kg of L-AMB presented more side effects than those who received tions in the tissues after multiple doses, which can improve the de-
2.5 mg/kg. The study also showed a non-linear pharmacokinetics. Pa- struction of leishmanial parasites. Recent advances in lipid-based nano
tients treated with 0.6 mg/kg of AMB (0.060 ± 0.01 µg/mL) presented formulations corroborated these findings. The lymphatic uptake and
significantly higher Cmax (mean ± SD) than patients treated with oral bioavailability of curcumin-SLN coated with N-carboxymethyl
2 mg/kg of L-AMB (0.016 ± 0.004 µg/mL) allowing reducing the side chitosan were 6.3-fold and 9.5-fold higher than that of free curcumin,
effects of AMB (Bekersky et al., 2002). For leishmaniases, Wijnant et al. respectively. These results suggest that SLN could be an efficient oral
(2017) compared the skin pharmacokinetics of L-AMB with AMB, in delivery system for curcumin (Baek and Cho, 2017). Additionally, after
murine models of Leishmania major. The study showed that after mul- oral administration in rats, topotecan (TPT), a water-soluble che-
tiple administration, on day 10, the drug level in the lesion location was motherapeutic agent lipid nanoparticle allowed to enhance the in-
3-fold higher for L-AMB than for AMB. The study also showed the linear testinal lymphatic transport of TPT (Wang et al., 2017).
correlation between dose level, intralesional AMB concentration and NEs are a colloidal particulate system, being submicron in size, with
relative reduction in parasite load and lesion size. varying roles as carriers of drug substances. Their size ranges from 10 to
However, the use of L-AMB continues to be restricted due to a major 1000 nm (Jaiswal et al., 2015) and the main components are lipid li-
drawback; its repeated administration results in accumulation due to quid, surfactant and aqueous phase (Gasco et al., 1991). These com-
slow elimination from the body, finally directing to nephrotoxicity, in ponents form a dispersion of two immiscible phases, which are kineti-
addition to its high cost (Costa Lima et al., 2014). For a patient cally stable and thermodynamically unstable. Under the selected
weighing 35 kg, L-AMB costs US$ 126 for a daily treatment (10 mg/kg), surfactant type, they can be presented as oil-in-water (O/W) or water-
which means a 6.3-fold higher cost for AMB (30-day treatment, 1 mg/ in-oil (W/O) NE, or even generate a cationic or anionic NE (Fryd and
kg, alternating days) (WHO, 2010). However, Sundar et al. (2010) Mason, 2012; Rodriguez-Aller et al., 2015).
showed that a single-dose regimen of L-AMB (10 mg/Kg) is effective, The SLN exchanges the liquid lipid of the emulsions by a solid lipid,
noninferior and less expensive to treatment with AMB deoxycholate (15 which results in lipids being solid at room and body temperature. The
alternate-day infusions of 1 mg/Kg during a 30-day hospital stay). mean diameter of the NLS ranges from 40 to 1000 nm (Müller et al.,
Several liposomal formulations have been described as an alter- 2002; Weber et al., 2014). The NLC, the second generation of lipid
native to AmBisome®. Paromomycin (PRM) delivered by liposomes nanoparticles, are composed of colloidal particles that present a matrix
exposed preferential targeting of the antibiotic to the spleen, lungs and composed of a binary mixture of solid lipid with liquid lipid providing a
liver, relative to free PRM, which resulted in improved therapeutic ef- less ordered structure but still solid in body temperature (Poonia et al.,
ficacy and lower toxic effects in murine models infected with 2016).
Mycobacterium avium and Leishmania infantum (Gaspar et al., 2015). Two main processes are required for obtaining NE, SLN and NLC:
Additionally, liposomal trifluralin (L-TFL) showed decrease in parasite high- and low-energy methods. The first one, driven by mechanical
loads in a murine visceral model of infection by Leishmania donovani force, comprises high-pressure homogenization, ultrasound and mi-
(Carvalheiro et al., 2009). crofluidization. They involve mainly shearing, collision, and cavita-
Later, the same authors, Carvalheiro and coworkers (2015), devel- tional force for breaking down the droplets into a nanoscale range
oped trifluralin analogues liposomes, TFL-A3 and TFL-A6, to further (Attama et al., 2012; Date et al., 2007; Yukuyama et al., 2017b). The
enhance TFL antileishmanial activity. The efficacy of the liposomal second one is driven by the physicochemical energy, which consists of
425
the spontaneous curvature change of the phases to break down the Table 2.
particles to deliver the final nanodroplets, during the phase transition
process. The low-energy process includes the phase inversion tem- 4.4 Polymeric nanoparticle: synthetic and natural matrices
perature and composition methods (PIT and PIC), spontaneous emul-
sification (Anton et al., 2008; Koroleva and Yurtov, 2012; Yukuyama Polymeric nanoparticles are solid colloidal particles, with size of
et al., 2016) and the D-Phase emulsification method (Sagitani et al., less than 1 µm, made of various biocompatible polymeric matrices
1991). Naseri et al. (2015) describe two other techniques for preparing (Date et al., 2007). The drug may be dissolved, retained or adsorbed in
SLN and NLC, solvent emulsification /evaporation and supercritical the polymer matrix, or in the case of nanocapsules, solubilized in the
fluid extraction of emulsions (SFEE), both techniques use organic sol- oily nucleus (Dimer et al., 2013). Polymeric particles have capacity to
vent to prepare the nanoparticles and each one uses different ap- impact specific drug release kinetic patterns and increase biocompat-
proaches to remove the solvents. ibility. Biodegradable polymers include synthetic polymers such as
Koester and collaborators (2015) successfully incorporated chalcone polyalkylcyanoacrylates (PACA), poly (lactic acid) (PLA), poly (n-butyl
in nanoemulsions for topical administration in treating CL. This na- cyanoacrylate) (PBCA), poly (lactide-co-glycolide) (PLGA), poly (ca-
noemulsion improved activity against intracellular amastigotes of L. prolactone) (PCL), poly (glycolic acid) (PGA), poly (amino acids) and
amazonensis in THP-1 cells. Additionally, considering the parasitic in- natural polymers such as gelatin, albumin, chitosan, and alginate
hibition profile, this formulation demonstrated both stability and (Banik et al., 2016).
maintenance of leishmanicidal activity (Koester et al., 2015). Different methods have been employed to load antileishmanial drug
Lopes et al. (2012) proposed the encapsulated oryzalin containing substances into polymeric nanoparticles such as emulsion or micro-
dinitroanilines in SLN for parenteral administration. The formulation emulsion polymerization (Monteiro et al., 2017b), interfacial poly-
showed encapsulation efficiency > 75% without cytotoxicity effect for merization (Chaubey and Mishra, 2014) and precipitation polymeriza-
all concentrations tested indicating a very protective role to mamma- tion (Kumar et al., 2015). Their major drawbacks refer to inadequate
lian cells. Thus, suggesting that this strategy may improve the toler- biodegradability and/or the possible presence of organic solvent toxic
ability and therapeutic range of dinitroanilines. residues (Ahlin Grabnar and Kristl, 2011). The removal of solvent re-
Pham and coworkers (2014) proposed an SLN based on nano- presents a time-consuming procedure and any residue can pose a risk to
cochleates. These are stable cationic phospholipid precipitates with the patient.
multilayered cylindrical structures, composed of positively charged Despite a diverse number of polymer molecular structures, most of
calcium ions and negatively charged phospholipids (Nagarsekar et al., them (probably > 95%) are not suitable for clinical use. Different
2016) combining two drug substances: AMB and MILT, which could be weight, architecture and the specific linking chemistry used during the
administered by the oral route. After nanocochleate preparation, the polymer conjugation can impact in safety and efficacy. The discussion
encapsulation efficiency was 54% and 59% for AMB and MILT, re- of an appropriate regulatory framework has become fundamental
spectively. Drug release is present preferentially in intestinal medium (Duncan, 2011). Gaspar and Duncan (2009) described the challenges of
containing bile salts. The release rate of MILT was slightly higher than the regulatory agencies and the importance to treat each polymer used
that of AMB, probably because of the amphiphilic mechanisms of the in therapeutic as unique, based on route of administration, doses,
former. Therefore, AMB-MILT-loaded nanocochleates revealed to be a dosing frequency and proposal clinical use.
promising oral delivery system for VL therapy (Pham et al., 2014). De Carvalho et al. (2013) developed AMB nanoencapsulated in
Jung and collaborators (2009) prepared the SLN which can entrap PLGA and dimercaptosuccinic acid (DMSA) nanoparticles (Nano-D-
poor water-soluble drugs, AMB, with high drug entrapment efficiency AMB). Its efficacy was evaluated in treating CL. Because hyperthermia
by using solvent evaporation (SESE) and spontaneous emulsification based on magnetic nanoparticles results in controlled release of the
low energy method. Entrapment efficiency of AMB in the SLN reached drug (De Carvalho et al., 2013; Kumar and Mohammad, 2011), mag-
up to 76.5 ± 5%. The cytotoxicity of AMB-entrapping SLN against netic citrate-coated nanoparticles (Nano-D-AMB-MG) were combined in
normal kidney cells (293 cells) presented to be lower compared with this nanosystem, in an attempt to improve the release of AMB by
those of the commercial AMB-products, Fungizone® and AmBisome®. magneto hyperthermia. Although Nano-D-AMB-MG showed the same
Kharaji and coworkers (2015) have reported PRM-SLN formulation potential as free D-AMB in reducing cutaneous leishmaniasis lesions,
containing 15% lipid composition, which showed efficacy in parasite the Nano-D-AMB-MG treatment promoted significantly greater reduc-
inhibition. In another study, the authors (Heidari-Kharaji et al., 2016) tions in the number of parasites and in cell viability than free D-AMB.
reported the PRM-SLN formulation as a novel drug delivery for treating This suggests that these NPs were more efficacious than free D-AMB
leishmaniasis. The preparation was safe and inhibited the propagation therapy, allowing the dose frequency required to reach the same ther-
of L. major parasites in infected mice. Thus, the authors have success- apeutic level to be reduced, and thus favoring an extended dosing in-
fully demonstrated acceptable efficacy and safety of the PRM-SLN for- terval (De Carvalho et al., 2013).
mulation as a novel drug against CL. PRM-loaded SLN may increase Rifampicin (RIF) is well-known and described as an antituberculosis
drug penetration into macrophages and efficient uptake by macro- drug; its antileishmanial activity has been reported (Neuber, 2008).
phages may explain the higher efficacy of this treatment (Heidari- Chaubey and Mishra (2014) developed a novel RIF-loaded mannose-
Kharaji et al., 2016). conjugated chitosan nanoparticulate system targeting macrophages for
Buparvaquone application in leishmaniasis therapy has been limited treating visceral leishmaniasis. This targeted delivery system was effi-
by its poor-water solubility. Aiming to overcome this disadvantage, cient, viable, safe and affordable. Ex vivo pharmacokinetic and biodis-
Monteiro et al. (2017a) first described a successful preparation of NLC tribution studies resulted in an expressive increased concentration of
containing buparvaquone. This drug delivery system has the potential RIF in liver and spleen. The cellular drug uptake was 16.2 times higher
to improve the availability of affordable therapy due to the low cost of than that of the free drug (Chaubey and Mishra, 2014).
raw materials and the use of high-pressure homogenization, a scale-up Kumar et al. (2015) developed PLGA-PEG encapsulated AMB na-
feasible technology (Monteiro et al., 2017a). noparticles to target the macrophage of visceral leishmaniasis infected
NLCs have been proposed for treating various neglected diseases tissues. This system showed cytotoxicity of extracellular promastigote
such as malaria (Omwoyo et al., 2016; Parashar et al., 2016), Chagas 1.4-fold lower than free AMB. In addition, amastigote inhibition in the
disease (Morilla and Romero, 2015; Vargas de Oliveira et al., 2017), splenic tissue was expressively higher than with conventional AMB
schistosomiasis (Kolenyak-Santos et al., 2015), dengue fever (Tsai et al., (93.02 ± 6.63% versus 74.42 ± 14.78%). Thus, AMB encapsulated
2012) and tuberculosis (Beg et al., 2017). However, this platform has PLGA-PEG NPs showed to have greater potential than free AMB in
been still poorly explored for treating leishmaniasis, as shown in terms of therapeutic efficacy in in vitro and in vivo studies (Kumar et al.,
426
Table 2
Lipid matrix nanoparticle delivery systems for treating leishmaniasis.
Drug/active Ref. Size (nm) PDI Zeta Potential (mV) EE% Lipid Class Method of
substance component preparation
Paromomycin Gaspar et al. 110 < 0.1 −30 ± 2 96 ± 4 DPPC LPS Dehydration-
(2015) DPPG rehydration method
Trifluralin Carvalheiro 192 ± 7 and 187 ± 17 – 40 ± 5 and 38 ± 4 80 ± 6 and 81 ± 12 DOPC LPS lipid film hydration
et al. (2009) DOPG with some
modifications
Trifluralin Carvalheiro 170–200 < 0.2 −(30 a 47) 45 a 91 DMPC LPS lipid film-hydration
analogues et al. (2015) DMPG method followed by
extrusion
Chalcone Koester et al. 171.9 ± 18.7 0.14 ± 0.01 −39.43 ± 3.56 – Soybean NE spontaneous
(2015) Lecithin emulsification
Amphotericin B Jung et al. 84.4 ± 6.0 – −50.4 ± 5.0 76.5 ± 5 DPPC SLN SESE method
(2009) CHOL
DSPE
DPPA
Oryzalin Lopes et al. < 140 < 0.2 −35 > 75 Tripalmitin SLN emulsification-
(2012) solvent
Amphotericin B Pham et al. 250 ± 2 < 0.1 −2.3 ± 0.6 54 AMB CHOL SLN hydrogel method
and (2014) 59 MILT DOPS
Miltefosine
Paromomycin Heidari- 120 0.67 ± 0.05 532.43 ± 164.40 42–46 CHOL SLN modified HSH
Kharaji et al. microemulsion
(2016) technique
Buparvaquone Monteiro et al. < 350 < 0.3 < −21.0 100 Miglyol 182 NLC high-pressure
(2017a) Softisan 154 homogenizer
WitepsolE85 method
Ref.: references; DPPG: dipalmitoyl phosphatidylglycerol, DPPC: dipalmitoyl phosphatidylcholine, DMPC: dimyristoylphosphatidylcholine, DMPG: dimyr-
istoylphosphatidylglycerol, DOPC: dioleoylphosphatidylcholine, DOPG: dioleoylphosphatidylglycerol, DPPC: 1,2-dipalmitoyl-sn-glycero-3-phosphocholine, CHOL:
cholesterol, DPPA: 1,2-dipalmitoyl-sn-glycero-3-phosphate (monoso- dium salt), DOPS: dioleoylphosphatidylserine, DSPE: 1,2-distearoyl-sn-glycero-3-phosphoetha-
nolamine-N-[methoxy(polyethylene glycol)-2000] (ammonium salt), Chalcone: (E)-3-(3-nitrophenyl)-1-(3,4,5-trimethoxyphenyl) prop-2-en-1-one, LPS: liposome,
NLC: nanostructured lipid carriers, SLN: solid lipid nanoparticles, NE: nanoemulsions, SESE: spontaneous emulsification and solvent evaporation, HSH: high shear
homogenization, EE%: encapsulation efficiency and PDI: polydispersity index.
2015). ions or molecules, usually obtained by direct crystallization (bottom-up

Monteiro and coworkers (2017b) prepared hydro- approach) or grinding (fragmentation) of the material (top-down ap-
xymethylnitrofurazone (NFOH), a drug candidate, PBCA nanoparticle proach) (Müller et al., 2011; Shegokar and Müller, 2010), composed
presenting encapsulation efficiency of 64.47 ± 0.43%. Where PBCA- exclusively of the drug (Möschwitzer, 2013; Müller et al., 2011) pre-
NFOH-NPs demonstrated IC50 values of 0.33 µM and 4.90 µM for pared in dispersion media using stabilizers (surfactants and/or poly-
amastigotes and promastigotes of L. amazonensis, respectively. The se- mers), resulting in a colloidal system. Thus, in the liquid medium, this
lectivity index was 370.6 for PBCA-NFOH-NPs, which was a 49-fold system is called a nanosuspension (Müller et al., 2011; Rabinow, 2004).
increase than free NFOH. The activity of PBCA-NFOH-NPs presented Poor water-soluble drug substances represent 40% of the top 200
great efficacy for delivery aimed at macrophages (Monteiro et al., oral medicines marketed in the US, 33% of drug substances listed in the
2017b). The authors have filed a patent application for this invention US Pharmacopeia, 75% of drug candidates under development and 90%
(BR 10 2014 007923-8). of molecules in the discovery pipeline (Rodriguez-Aller et al., 2015).
In a similar way, Britti et al. (2015) claimed ownership of in- Nanocrystals can improve the dissolution velocity and the saturation
tellectual property WO 2015 177820 where polymer nanoparticles are solubility of these drugs. The essence of the nanonization of poor water-
employed as an effective vehicle for compounds based on antimony and soluble drug substances rests mainly on Noyes-Whitney equations
antimonials, such as Glucantime®. The system was prepared from an (Noyes and Whitney, 1897) and Prandtl (1904). These equations de-
aqueous nucleus in which the active ingredient is entrapped, sur- scribe how a decrease in particle size facilitates increasing the surface
rounded by a polymeric biocompatible and biodegradable shell based area and reducing the thickness of the diffusion layer, and thus, pro-
on PLA. This invention claims that the system allows reduction of cel- vides an increase in dissolution rate.
lular toxicity in treating this disease since the active ingredient is car- An additional advantage of nanocrystals refers to their greater ad-
ried and concentrated only within the macrophages, avoiding systemic hesiveness compared to particles in the micrometer range in the bio-
effects related to the therapy with antimonial medications (Britti logical membrane and surface of the gastrointestinal tract. As a result,
et al.,2015). drug absorption can be increased independent of the fed or fasting state
Table 3 presents the properties of polymer nanoparticles for treating (Müller et al., 2011). However, it is important to ensure the physical
leishmaniasis. As can be observed, there are few studies proposing these chemical properties of the drug nanocrystal during the manufacturing
nanoparticles possibly because of their limitations. In all procedures, process and in storage throughout its shelf life (Chen et al., 2017) since
the use of organic solvents was necessary with the exception of the these characteristics are critical for drug dissolution velocity in the
method described by Monteiro and coworkers (2017b). nanosuspension.
Kayser et al (2003) develop a nanosuspension of AMB by high-
pressure homogenization, using polysorbate 80 and poloxamer P188.
4.5. Nanocrystal, an encapsulating-carrier free nanoparticle
This formulation showed to be more active than micronized AMB for
visceral leishmania model, after oral administration in rats. The re-
Nanocrystals are drug particles with crystalline or amorphous
duction of parasite in liver was 28.6%. In our group, Marins et al.
character in the submicron or nanometric range, generally between 100
(2017) reported a successful formulation using NFOH and polysorbate
and 500 nm. The nanocrystals are solids formed by a network of atoms,
427
Table 3
Polymeric nanoparticle delivery systems for treating leishmaniasis.
Drug/active Ref. Size (nm) PDI Zeta Potential (mV) EE% Polymers Method of preparation
substance
AMB De Carvalho et al. 456.60 ± 133.60 0.431 ± 0.001 −32.60 ± 4.64 – PLGA method described by Amaral et al., with slight
(2013) DMSA modification
AMB-MG 675.20 ± 40.28 0.584 ± 0.001 −28.00 ± 4.86 prepared by chemical condensation reaction of
aqueous ions in alkaline medium
RIF Chaubey and 215.2 ± 2.4 0.109 ± 0.18 26.2 ± 1.7 39.1 ± 6.3 Chitosan inducing the gelation method with suitable
Mishra (2014) Mannose modifications
AMB Kumar et al. (2015) 30–35 – – – PLGA precipitation method
NFOH Monteiro et al. 151.50 ± 61.97 0.104 ± 0.01 −10.10 ± 6.47 64.47 ± 0.43 PBCA anionic emulsion polymerization method
(2017b)
Ref.: references; AMB: desoxycholate amphotericin B, AMB-MG: desoxycholate amphotericin B with magnetic citrate-coated maghemite, DMSA: dimercaptosuccinic
acid, PLGA: poly (glycolic acid) (PGA), PBCA: poly (n-butyl cyanoacrylate), RIF: rifampicin, NFOH: hydroxymethylnitrofurazone, EE%: encapsulation efficiency and
PDI: polydispersity index.
80. NFOH, a nitrofurazone reciprocal prodrug, is a promising drug Funding sources

candidate, which presented potential use in treating Chagas disease and
leishmaniasis (Chung et al., 2003). This work was supported by “Fundaçao de Amparo a Pesquisa do
Estado de Sao Paulo (FAPESP)” [grant number 2017/08332-3]
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NANOTHERAPY - Leismania

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International Journal of Pharmaceutics 547 (2018) 421–431

Contents lists available at ScienceDirect

International Journal of Pharmaceutics

Promising nanotherapy in treating leishmaniasis T

1. Introduction as kala-azar, cutaneous (CL) and mucocutaneous leishmaniasis (MCL).

Abbreviations: DPPA, 1,2-dipalmitoyl-sn-glycero-3-phosphate; DPPC, 1,2-dipalmitoyl-sn-glycero-3-phosphocholine; DSPE, 1,2-distearoyl-sn-glycero-3-phosphoetha-nolamine-N-

Fig. 1. Cycle of life of Leishmaniasis parasite.

2015). ions or molecules, usually obtained by direct crystallization (bottom-up

80. NFOH, a nitrofurazone reciprocal prodrug, is a promising drug Funding sources

5. Final considerations and future trends References

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