**3. Natural products and drug delivery systems against leishmaniasis: stateof-the-art**

The use of tools and materials at the nanoscale enabled the creation of nanoparticulate formulations such as liposomes, microemulsions, and microcapsules of great interest to the pharmaceutical industry. Drug delivery systems using liposomes are the ones most studied because of their high biocompatibility, ease of preparation, and chemical versatility [22]. Basically, liposomes are microscopic vesicles composed of one or more concentric lipid bilayers separated by aqueous media. Liposomes can encapsulate hydrophilic and lipophilic substan‐ ces; the former stay in the aqueous compartment, whereas the latter are inserted into the membrane. Because liposomes are biodegradable, biocompatible, and non-immunogenic,they are highly versatile forresearch,therapeutic, and analytical applications [23].These vesicles are primarilyconsistedofphospholipids (either syntheticornatural), sterols, andantioxidants [24]. Lipidswithacylindricalshapesuchasphosphatidylcholine,phosphatidylserine,phosphatidyl‐ glycerol, and sphingomyelin, which tend to form a stable bilayer in aqueous solution, are commonly used in liposomal formulations. Phosphatidylcholine is the most employed lipid in liposomal formulation studies due to its great stability against pH or salt concentration variations in the medium [25]. The pharmacokinetic properties of liposomes can be simply modifiedbychangingthechemical compositionofthebilayer components.Moreover,peptides, polysaccharides, or affinity ligands such as antibodies can be incorporated into liposomes [12].

Phospholipid-based liposomes are usually used to change the pharmacokinetics profile of severaldrugs,eithernaturalorsyntheticones.Naturalproductssuchascrudeextracts,fractions, or isolated phytocompounds have been incorporated into different colloidal carriers, includ‐ ingliposomes,withpromisingresults.As expectedinthe incorporationof syntheticdrugs,lipid formulations enhance the solubility and bioavailability of extracts and bioactive compounds derived from plants. Additional benefits of phytoformulations include: (i) protection from toxicity; (ii) enhanced pharmacological activity; (iii) enhanced stability; (iv) increased reten‐ tion time; and (v) protection from physical and chemical degradation [26,22]. The ability of colloidal carriers to improve tissue macrophages distribution may have an impact on *Leishma‐ nia* infection. The tendency of nanoformulations, especially liposomes, to be captured by the mononuclearphagocyte systemmaybe anadditional advantage inthe treatmentofleishmania‐ sis. In fact, intraperitoneal and intravenous administration of liposomes proved to be a good biodistribution system for drugs in the treatment of VL, because it increased drug accumula‐ tioninmacrophage-richtissues suchas liver andspleen,thus reducing the toxicity levelto other tissues and organs [27].

Since ancient times, products from plant, mineral, and animal sources have been used in traditional medicine to fight many human diseases. In fact, for centuries traditional medicine has been the only health care system available for the prevention and treatment of several diseases in different cultures. Currently, the practice of traditional medicine still has a great impact on the health of people who have no access to modern health care practices. In fact, an estimated 80% of people living in developing countries rely almost completely on traditional medicinal practices to meet their primary medication needs [28-30]. Thus, the use of natural products as medicines has attracted the interest of research laboratories around the world seeking new bioactive molecules. Among the most studied natural products, plants are a valuable source of compounds with antileishmanial activity. Active compounds derived from plant extracts have been described by several laboratories worldwide [31-34]. The antileishma‐ nial activity of several crude extracts and fractions derived from plants has been attributed to compounds belonging to diverse chemical groups, including phenolic compounds (e.g., chalcones, flavonols, aurones, lignans, coumarins, quinines, tannins), terpenoids (monoter‐ penes, sesquiterpenes, diterpenoids, triterpenes), and alkaloids (indole alkaloids, isoquino‐ line alkaloids, quinoline alkaloids)[35-37].In fact, phytoscience may be an importanttool in the search for novel antileishmanial agents with fewer side effects and lower potential costs. Secondary metabolites isolated from plant extracts or essential oils can be used in several different ways for the development of drugs. Nanoformulation-based delivery systems are a promising approach to developing novel antileishmanial agents.

**3. Natural products and drug delivery systems against leishmaniasis: state-**

The use of tools and materials at the nanoscale enabled the creation of nanoparticulate formulations such as liposomes, microemulsions, and microcapsules of great interest to the pharmaceutical industry. Drug delivery systems using liposomes are the ones most studied because of their high biocompatibility, ease of preparation, and chemical versatility [22]. Basically, liposomes are microscopic vesicles composed of one or more concentric lipid bilayers separated by aqueous media. Liposomes can encapsulate hydrophilic and lipophilic substan‐ ces; the former stay in the aqueous compartment, whereas the latter are inserted into the membrane. Because liposomes are biodegradable, biocompatible, and non-immunogenic,they are highly versatile forresearch,therapeutic, and analytical applications [23].These vesicles are primarilyconsistedofphospholipids (either syntheticornatural), sterols, andantioxidants [24]. Lipidswithacylindricalshapesuchasphosphatidylcholine,phosphatidylserine,phosphatidyl‐ glycerol, and sphingomyelin, which tend to form a stable bilayer in aqueous solution, are commonly used in liposomal formulations. Phosphatidylcholine is the most employed lipid in liposomal formulation studies due to its great stability against pH or salt concentration variations in the medium [25]. The pharmacokinetic properties of liposomes can be simply modifiedbychangingthechemical compositionofthebilayer components.Moreover,peptides, polysaccharides, or affinity ligands such as antibodies can be incorporated into liposomes [12]. Phospholipid-based liposomes are usually used to change the pharmacokinetics profile of severaldrugs,eithernaturalorsyntheticones.Naturalproductssuchascrudeextracts,fractions, or isolated phytocompounds have been incorporated into different colloidal carriers, includ‐ ingliposomes,withpromisingresults.As expectedinthe incorporationof syntheticdrugs,lipid formulations enhance the solubility and bioavailability of extracts and bioactive compounds derived from plants. Additional benefits of phytoformulations include: (i) protection from toxicity; (ii) enhanced pharmacological activity; (iii) enhanced stability; (iv) increased reten‐ tion time; and (v) protection from physical and chemical degradation [26,22]. The ability of colloidal carriers to improve tissue macrophages distribution may have an impact on *Leishma‐ nia* infection. The tendency of nanoformulations, especially liposomes, to be captured by the mononuclearphagocyte systemmaybe anadditional advantage inthe treatmentofleishmania‐ sis. In fact, intraperitoneal and intravenous administration of liposomes proved to be a good biodistribution system for drugs in the treatment of VL, because it increased drug accumula‐ tioninmacrophage-richtissues suchas liver andspleen,thus reducing the toxicity levelto other

Since ancient times, products from plant, mineral, and animal sources have been used in traditional medicine to fight many human diseases. In fact, for centuries traditional medicine has been the only health care system available for the prevention and treatment of several diseases in different cultures. Currently, the practice of traditional medicine still has a great impact on the health of people who have no access to modern health care practices. In fact, an estimated 80% of people living in developing countries rely almost completely on traditional medicinal practices to meet their primary medication needs [28-30]. Thus, the use of natural products as medicines has attracted the interest of research laboratories around the world

**of-the-art**

354 Leishmaniasis - Trends in Epidemiology, Diagnosis and Treatment

tissues and organs [27].


**Table 1.** Natural sources of active substances used in nanoformulations against *Leishmania*.

Table 1 lists the natural sources used in nanoformulations to improve the bioavailability of antileishmanial drugs, thus increasing their expected therapeutic efficacy. However, the botanical species used for isolation of the active constituent have not been described in some formulations such as those containing asiaticoside and acaciaside [38], whereas others have a plant origin but were purchased commercially [39]. It should be noted that the most studied species listed in Table 1 are native to developing countries, where the popular use of medici‐ nal plants is widespread.
