Review Special Focus: Trypanosomatid Diseases For reprint orders, please contact [email protected]

Drug resistance in leishmaniasis: current drug-delivery systems and future perspectives Leishmaniasis is a complex of diseases with numerous clinical manifestations for instance harshness from skin lesions to severe disfigurement and chronic systemic infection in the liver and spleen. So far, the most classical leishmaniasis therapy, despite its documented toxicities, remains pentavalent antimonial compounds. The available therapeutic modalities for leishmaniasis are overwhelmed with resistance to leishmaniasis therapy. Mechanisms of classical drug resistance are often related with the lower drug uptake, increased efflux, the faster drug metabolism, drug target modifications and over-expression of drug transporters. The high prevalence of leishmaniasis and the appearance of resistance to classical drugs reveal the demand to develop and explore novel, less toxic, low cost and more promising therapeutic modalities. The review describes the mechanisms of classical drug resistance and potential drug targets in Leishmania infection. Moreover, current drug-delivery systems and future perspectives towards Leishmaniasis treatment are also covered. Current challenges in the classical leishmaniasis therapy include accessibility of very few drugs, appearance of resistance to the available drugs (Figure 1), toxicity and lack of cost–effectiveness [1–4]. Furthermore, due to lack of noteworthy commercial return from ‘neglected diseases’ has resulted in unsatisfactory funding for drug development in leishmaniasis [5–9]. In these circumstances, strategies to increase therapeutic efficacy of available drugs have been more successful compared with the development of new drugs. Hence, therapeutic efficacy of available antileishmanial drugs can be improved via development of controlled and targeted drug-delivery formulations to overcome resistance [10–15]. There are numerous drug-delivery systems available for leishmaniasis, however, to date, the most extensively investigated drug-delivery systems are nanotechnology-based colloidal carriers [2,16–20]. Moreover, the understanding of how drug resistance appears during classical therapy can lead to avoid the predicament, for instance by developing drug-delivery formulation to target the resistance mechanism. This article focuses on: Resistance mechanisms towards current classical therapeutic modalities;

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Biochemical and enzymatic machineries that could be employed as putative drug targets to overcome resistance against classical drugs;

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An overview on nanotechnology-based formulations and current nanocarriers

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approaches to address classical drug resistance in Leishmania infection. Resistance mechanism towards classical therapeutic modalities Drug resistance is a foremost barrier for successful treatment of leishmaniasis [21]. Since there are very few drugs in the pipeline, resistance towards classical therapeutic modalities has an enormous impact on the treatment of leishmaniasis [22]. Therefore, a perceptive of the molecular and biochemical mechanisms of clinical resistance is important, not only for the development of rational drug design [23], but also to improve the efficacy of available classical therapeutic modalities used in the treatment of leishmaniasis. Prevention and inhibition of resistance towards classical therapeutic modalities has become the utmost concern for WHO [201]. The main mechanism of resistance is reducing the active drug concentration within the parasite cell. The parasite may decrease the drug concentration by a diversity of mechanisms, including decreased uptake, increased efflux, prevention of drug activation, inactivation of the active drug by metabolism or sequestration, and finally by developing an amplified amounts of the target enzyme [21]. The mechanism of resistance against classical first-line antimonial therapeutic modalities has been found to be multifactorial. Laboratory-derived Leishmania, resistant to Sb(III), have been obtained. The resistance mechanisms involved were mainly based on reducing the concentration of the active drug Future Med. Chem. (2013) 5(15), 1877–1888

Masoom Yasinzai*1, Momin Khan1,2 , Akhtar Nadhman1 & Gul Shahnaz3 Department of Biotechnology, Faculty of Biological Sciences, Quaid-i-Azam University, Islamabad, Pakistan 2 Department of Microbiology, Institute of Basic Medical Sciences, Khyber Medical University, Peshawar, Pakistan 3 Department of Pharmacy, Faculty of Biological Sciences, Quaid-i-Azam University, Islamabad, Pakistan *Author for correspondence: Tel.: +92 051 9064 4137 Fax: +92 051 2617901 E-mail: [email protected] 1

ISSN 1756-8919

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Review | Yasinzai, Khan, Nadhman & Shahnaz Key Terms ATP-binding cassette transporters/efflux pump:

Biological membrane transporter protein having Walker A and B motif with ‘C’ motif just upstream of the Walker B is ATP-binding protein called ABC protein which utilize ATP hydrolysis energy to translocate various substrate across biological membrane.

Redox-active: Drugs that are

involved in the production of reactive oxygen species, causing disruption of cellular moieties.

Sb(III) inside the cell. This activity could be exhibited either by reducing Sb(III) uptake or by increasing efflux/sequestration of the Sb(III) in combination with trypanothione (TSH) by increasing the levels of TSH. In fact, both mechanisms of resistance have been observed in several Leishmania mutant strains developed in the laboratory. A new model for drug resistance was reported in which Sb(V)/As(V)containing compounds, having the Pentostam® (antileishmanial drug), are reduced within the cell to Sb(III)/As(III), conjugated to TSH and effluxed out by the As-thiol pump. The development of the metalloid-thiol pump substrates was proposed to be the rate-limiting step in this resistance mechanism as increased levels of TSH generate resistance [24]. Resistance against classical second-line therapeutic modalities has also been reported in vitro in numerous Leishmania species. [5,25]. Resistance to pentamidine in Leishmania has been associated with changes in the concentrations of polyamines and arginine within the cell, and previously conducted studies have proposed that pentamidine could be transferred

into cells through a polyamine or arginine transporter [26]. Furthermore, resistance to amphotericin B (AmB) been produced in vitro and was investigated to be related with a change in cell membrane fluidity [27]. It was found that the main sterol of the resistant parasite strain was the modification of an ergosterol. These alterations are due to the depletion of function of S-adenosyl-l-methionine-C-24 of sterol-methyltransferase. Thus, these alterations reduced the AmB attachment to sterol-modified membranes [28]. Resistance to classical first- and second-line therapeutic modalities has also been associated with several ATP-binding cassette transporters including MRP1 (now termed as MRPA; gene symbol ABCC1) and P-glycoprotein (P-gp; gene symbol ABCB1) [29]. P-gp is encoded by a small gene family with two isoforms class I (MDR1) and II (MDR2) expressed in mammalian cells. Leishmania genome has at least one P-gp homolog. The gene product of Leishmania is greatly homologous to the mammalian MDR1 and it was characterized from numerous Leishmania species [30]. The high level of homology between

Amplified amount of target enzyme

Ergosterol receptor

Leishmania cell

Phagolysosomal degradation products

Modification in drug binding site

Vesicles

Decreased apoptosis DNA and linked protein Nucleus Mitochondria

Efflux pumps Increased drug efflux Lipophosphoglycan

Alteration in membrane fluidity

Parasitophorous vaculoe Drug transporter Decreased drug influx Macrophages Future Med. Chem. © Future Science Group (2013)

Figure 1. Mechanism of drug resistance in a Leishmania cell.

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Drug resistance in leishmaniasis: current drug-delivery systems & future perspectives Leishmania and human MDR1 demonstrates that the Leishmania parasite could exhibit resistance by active extrusion of the drug. The efflux of rhodamine 123 in Leishmania amazonensis resistant cells and the lack of retention of puromycin in vinblastine -resistant Leishmania donovani are related with this assumption [31,32]. Furthermore, earlier studies have reported that infection with antimony (Sb)-resistant (Sbr) L. donovani induces the upregulation of MRPA and permeability of P-gp in host cells [33]. Subsequently, extrusion of intracellular Sb was observed after administration of sodium Sb gluconate. Using inverted vesicles for cell membranes, it was observed that a metal efflux pump is functioning in the Leishmania cell membrane. The metal itself is not distinguished by the efflux pump, but, indeed, it identifies the metal conjugated with thiols, such as TSH and glutathione [34]. Thiol-associated efflux of the drugs is mediated by the ABC transporters of the MRPA family. Resistance studies in L. donovani cells, chosen for in vitro resistance to miltefosine have shown an interconnection between resistance and decreased accumulation of the drug [33]. This reduced accumulation was induced by the failure of the inward transport of the drug into the cell. Therefore, the promising strategy that could be implemented to tackle the abovementioned limitations, related with leishmaniasis therapy, is to target the resistance mechanisms. The development of therapeutic modalities against the TSH system, polyamine biosynthesis, surface lipids and efflux pumps are likely to be the most promising strategies to prevent resistance towards antileishmanial classical therapeutic modalities. Drug targets & innovative approaches to overcome resistance Over the past years, there has been tremendous endeavor towards the development of efficient therapy against leishmaniasis. However, resistance towards classical therapeutic modalities has appeared as the foremost pitfall in leishmaniasis treatment. Target-based drug delivery hold tremendous potential to overcome drug resistance. The TSH system, polyamine biosynthesis, surface lipids and efflux pumps could be turned into targets, provided that the following criterion can be convened: n The target must be important for the life and survival of parasites; The target must be such that a complement in the mammalian host either does not exist or

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is sufficiently diverse to permit selective inhibition; The target must overcome plausible resistance mechanism to enhance therapeutic efficacy of classical therapeutic modalities.

n

„„TSH

system as a target Resistance of Leishmania species towards firstline antimonial therapeutic modalities, in many instances, is due to increased synthesis of TSH [35]. Moreover, TSH reductase (TryR) is an essential enzyme involved in the management of oxidative stress of the Leishmania parasites. As Sb induces oxidative stress, a reducing environment inside the cell and the availability of thiols become essential for Sb resistance [35]. TSH (the major cellular thiol) has a double function in Sb resistance, that is, protection of the parasite from oxidative stress by retaining an intracellular reducing environment, and encouraging resistance by establishing conjugates with Sb(III) for efflux and/or sequestration [34]. Inhibition of TryR would result in a decrease in TSH synthesis and as a consequence to overcome resistance towards redox-active anti­ monials [35]. Moreover, it was proposed that if TSH level is lowered in the cell, it would be feasible to decrease resistance [34]. This hypothesis was supported further when resistance was reversed in the cells by using difluoromethyl­ ornithine and buthionine sulfoximine (inhibitors of spermidine and glutathione biosynthesis) along with metal combination [36–39]. Inhibition studies reported that several compounds inhibited TryR enzyme but did not inhibit the host glutathione reductase enzyme [40]. These studies establish that TryR is a crucial enzyme for parasite survival. Consequently, TryR is an attractive target enzyme to overcome antimonial resistance because of the absence of TSH redox system in mammals. „„Polyamine

biosynthesis as a target The polyamines are crucial for the survival and growth of the Leishmania. They also play a vital role in the regulation of lipid peroxidation caused by the immune system and drugs [41,42]. The polyamine transporters are responsible for transporting both putrescine and spermidine (polyamine) and regulating the intracellular polyamine level. During infection in the host, uptake of polyamines is reduced [43], and in response the enzymes involved in the polyamine biosynthesis are produced in www.future-science.com

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Review | Yasinzai, Khan, Nadhman & Shahnaz Key Term Thiolated polymers:

Polymers generated by the covalent immobilization of thiol moieties (-SH) on an already well-established polymeric backbone.

large quantities [44]. Thus, establishment of inhibitors to prevent polyamine biosynthesis may be quite useful to increase the intracellular uptake of pentamidine. A number of enzymes of this pathway are unique and are not found in the mammalian system. One of the enzymes is the S-adenosyl methionine decarboxylase (AdoMetDC) and a number of inhibitors of this enzyme are found to be lethal to Leishmania parasites [45]. Moreover, several inhibitors for other enzymes of this pathway such as spermidine synthase [46] and ornithine decarboxylase [47] are also reported in the literature. Therefore, the transporters of putrescine and spermidine could also be considered good targets and the regulators of the polyamines could be recognized as indispensible targets [48]. Furthermore, nanotechnology-based colloidal cargoes could be used to facilitate the intracellular uptake of pentamidine. „„Sterol

biosynthesis as a target Ergosterols on the surface of the Leishmania play a vital role in the survival and growth. Cholesterol replaces the ergosterol in humans. AmB targets the ergosterols by binding carbon 19 of AmB with the OH group of ergosterols [27]. Resistance in Leishmania has been developed and reported against this drug. An excellent approach is to target the pathway for the synthesis of ergosterol, which is different from that of the cholesterol. The pathway has been studied deeply and a number of unique enzymes are involved in the synthetic pathway [49], such as squalene synthase, which is involved in the sythesis of squalene; squalene epoxide, which converts squalene to tetracyclic sterol skeleton; and 24,25-sterol methyltransferase, which is not present in humans. Inhibitors of these putative enymes, such as zaragozic acids, quinuclidines [50], terbinafine [51], azasterols [52,53] and triazole SCH 56592 [54], have been used against different species of Leishmania and were found quite effective. So far, these inhibitors have not been tried or practised on humans. More efforts will be required to design new and better alternative inhibitors in order to overcome the resistance against the available classical drugs. „„Efflux

pump as a target The ABC transporters are the well-known and widely reported family of efflux pumps. The ABC family is present in all organisms ranging from archeobacteria to lower and higher 1880

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eukaryotic organisms. There are two main transporters in the Leishmania – MRPA and P-gp. Resistance in Leishmania parasites against various therapeutic drugs is increasing in developing countries and in many cases it is owing to overexpression of ABC efflux pumps [30,31,55,56]. The inhibition of the function of these efflux pumps transporter represents a promising strategy to overcome drug resistance in clinical milieus [57]. Mostly inhibition of efflux pumps can lead to useful outcomes, that is, enhance the net uptake of efflux pump substrate into resistant cells and drug delivery. Numerous efflux pumps inhibitors/modulators have been previously reported being capable of reversing multidrug resistance in vitro in mammalian cells, such as calciumchannel blockers, hydrophobic peptides calmodulin antagonists, hormone derivatives, flavonoids, protein kinase inhibitors and antibiotics [58]. The clinical effectiveness of these modulators is limited by their toxicity, for instance, verapamil produces cardiac cytotoxicity at the concentration required to inhibit drug resistance [59]. Natural or synthetic sesquiterpenes, flavonoids, acridonecarboxamide derivatives modulators of human P-gp, or phenothiazines restore in Leishmania the sensitivity to pentamidine, sodium stibogluconate and miltefosine by modulating intracellular drug concentrations [60,61]. In Leishmania species, conventional modulators, such as verapamil and cyclosporine A, are not capable efficiently overcoming in vivo multidrug resistance phenotype of the parasite at noncytotoxic concentrations [62]. The inhibition of efflux pumps is a promising strategy in drug delivery. In view of the fact that it has been revealed that polymeric pharmaceutical excipients for instance Tweens® or Pluronics® can inhibit efflux pumps. Several other polymers have been evaluated concerning their prospective efflux pump inhibitory property including thiolated polymers or thiomers [63]. In recent years thiomers have emerged as a promising tool for drug-delivery systems due to their superior properties, such as stability [64], biocompatibility [65], in situ gelling [66], permeation enhancing [67], sustained release [65], high intracellular uptake [68] and efflux pump inhibition [69–71]. According to previous findings, drug-delivery systems based on thiomers might be a promising tool for cutaneous/mucocutaneous leishmaniasis by combating possible resistance mechanisms including reduced drug uptake, plasma membrane permeability, faster drug clearance and efflux of the drug. future science group

Drug resistance in leishmaniasis: current drug-delivery systems & future perspectives Current antileishmanial drug-delivery systems Drug-delivery systems are crucial as many active pharmaceutical modalities, to be utilized in treatment, cause serious adverse effects when disseminated nonspecifically. Lacking of an appropriate drug-delivery system, the active pharmaceutical modalities may accumulate in healthy and normal tissue, incite adverse reactions, lower bioavailability and cause inefficient targeting. Most of the modern researches in the field of drug delivery for infectious diseases are emphasizing on the physiological- and biopharmaceutical-related issues to be addressed in the development of therapeutic delivery systems. There are numerous

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drug-delivery systems available for leishmaniasis but successful treatments with lipid-based nanocarrier liposomes have shown promising results. So far, the most experimentally investigated drug-delivery systems for leishmaniasis are nanotechnology-based colloidal carriers. Nanotechnology presents an extraordinary opportunity in rational delivery of drugs to the infection site following systemic administration. Examples of nanotechnology progress in pharmaceutical product include liposomes [20], niosomes [72], nanodisks [73], emulsions [74], solid lipid nanoparticles [75], polymeric nanoparticles [76] and polymeric drug conjugates (Figure  2) [77,78]. Therefore, current status of nanotechnology-based

Hydrophobic tail

Targeting ligand

Oil phase

Drug in oil droplets

Hydrophilic head

Polymer backbone

Water phase Drug moiety Drug aqueous solution Phospholipid bilayers

Lipid excipients

Hydrophobic part Hydrophilic part

Polymeric matrix

Targeting agent

Receptor binding site

Drug core

Proteins embeded in lipid layers

Antibody attached drug for targeting

Solid lipid Future Med. Chem. © Future Science Group (2013)

Figure 2. Nanotechnology-based colloidal drug-delivery formulations. (A) Liposome, (B) emulsion, (C) polymer–drug conjugate, (D) polymeric nanoparticles, (E) nanodisks, (F) niosomes and (G) solid lipid nanoparticles.

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Review | Yasinzai, Khan, Nadhman & Shahnaz Key Terms Surfactants: Amphiphilic

organic compounds having both hydrophobic (water insoluble) groups and hydrophilic (water soluble) groups.

Gp63 or leishmanolysin:

Zinc metalloprotease, virulence factor and major surface protein of Leishmania, also known as promastigote surface protease.

PEGylated: Techniques that produce PEGylated drug formulation by the covalent attachment of synthetic macromolecules of PEG to a drug surface.

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colloidal drug-delivery systems and the advances in the evaluation and development of novel drugdelivery systems against leishmaniasis shall be addressed in detail in the following sections. „„Liposomes

Liposomes, the first phospholipid bilayer system, described in 1965, were rapidly described as a drug-delivery system [79]. In 1977, Ward and Hanson were the first to report the influence of liposome encapsulation of Sb(V) for targeted delivery to the spleen and liver macrophages infected with visceral leishmaniasis [19,20]. In fact, after intravenous administration of liposomes, Sb levels in the liver and spleen of mice were 20-fold higher than that obtained by free drug and were sustained for up to 14  days [80]. However, the interest in liposomal Sb(V) decreased near 1981 and marketable expansion was not encouraged on account of its adverse effects in monkeys [81]. The concept to explore the antileishmanial property of AmB entrapped in multilamellar liposome vesicles in order to increase its selective uptake and to reduce its toxicity arose about the same time as for Sb(V) [82]. Multilamellar liposomes vesicles loaded with AmB never reached the commercial value but initiated a model for the development of a three lipid-based drugdelivery system of AmB licensed for clinical use (Ambisome ®, Amphocil® and Albecet ®) [83–85]. However, only Ambisome true liposomal formulation is recommended for treating patients with leishmaniasis who are resistant to antimonials [86]. In the past 10 years, in an endeavor to enhance efficacy, overcome resistance and further reduce toxicity [72], liposomes decorated with surface ligands including proteins, peptides, polysaccharides, antibodies, glycolipids, lectins and glycolipid have been developed. Surface-decorated liposomal systems have been absolutely considered as ‘magic bullets’ [87,88]. Antileishmanial outcome of the liposome encapsulated AmB was increased further by decorating the naturally occurring macrophage-activator tetrapeptide, tuftsin (Thr-Lys-Pro-Arg) on the surface of liposomes. This could be due to the enhanced and improved drug tolerance after liposomization in addition to the increased uptake of tuftsinbearing AmB-loaded liposomes by the macrophages [89]. The design of employment of a specific receptor by LDL and acetylated LDL on Leishmania-infected macrophages was also Future Med. Chem. (2013) 5(15)

utilized in vitro to specifically deliver the antileishmanial drug adriamycin [90]. Previously, a synergistic potential effect of IFN-g and doxorubicin incorporated in manno­sylated liposomes was observed in experimentally induced visceral leishmaniasis therapy [91]. Induced cellular immunological responses against antigens encapsulated in the liposomes developed with mannopentose and dipalmitoyl phosphatidyl ethanolamine (using Leishmania major infection in susceptible BALB/c mice) was reported in literature [92]. Regardless of extensive research, liposomemediated therapy in clinics is not a reality. Moreover in the current scenario, the efficacy of liposomes needs to be explored against other traditional drug carriers (e.g., neoglyco­ proteins, niosomes, polymeric microspheres and nanoparticles, polymer–drug conjugate, among others) [78,93,94]. „„Niosomes

Over the past years, drug-delivery systems for the treatment of infectious diseases have gone through a revolutionary turn. Due to progress in biotechnological research and utilization of genetic engineering tools, many disease specific therapeutic modalities have been designed. Furthermore endeavors have been made to effectively deliver these therapeutic modalities. Niosomes are vesicles consist of nonionic surfactants. These are biodegradable, comparatively less toxic, more stable, relatively low in cost and an alternative to liposomes. These particular characteristics make niosomes more promising than liposomes for commercial manufacturing [95]. Niosomal sodium stibogluconate was shown to be more effective than liposomal vesicular formulations and free drug against experimental murine visceral leishmaniasis [73,96]. More recently, in vivo studies demonstrated that the niosomes containing autoclaved L. major have a significant result in the prevention of cutaneous leishmaniasis in BALB/c mice [97]. Furthermore, vaccination of C57BL/10 mice specifies that subcutaneous vaccination against cutaneous leishmaniasis with purified gp63 entrapped into niosomes, encouraged considerable resistance to this disease [98]. Advancement of a commercial antiparasitic vaccine for human appliance is a central goal that faces modern science. Therefore, further research will be required to investigate immunological pathways, followed after vaccination with Leishmania antigens loaded future science group

Drug resistance in leishmaniasis: current drug-delivery systems & future perspectives into niosomes, and possible unwanted adverse effects in order to assess real potential for a vaccination trial in humans. „„Nanodisks

Nanometer-scale, apolipoprotein-stabilized phospholipid bilayer disk complexes termed nanodisks (NDs) are novel transport vehicles different from liposomes because they do not hold an aqueous core and are completely soluble in aqueous phase media [99,100]. NDs harboring poorly soluble antileishmanial agent AmB-nanodisks demonstrate an effective therapy for experimental cutaneous leishmaniasis (L. major) infection in BALB/c mice. Surprisingly, AmB nanodisks were illustrated to have a long-term effect in that parasite burden continued to decrease for more than 100 days subsequent the final treatment. The results shown for intraperitoneal administration are most likely because of the small size of the ND [73]. „„Emulsions

In recent years, there is an increasing concern in the lipid-based formulated tools for the delivery of lipophilic drugs. Among them, emulsion forming drug-delivery systems emerge to be a distinctive and commercially feasible approach to overcome the problem of low bioavailability associated with the lipophilic drugs. While short-course treatment with novel lipid formulations of AmB offers a best approach over prolonged conventional treatment regime in visceral leishmaniasis, the high prices have rendered these agents mainly irrelevant in the developing and poor countries where the disease burden of visceral leishmaniasis is more prevalent. Short-course treatment with AmB-fat emulsion has been reported as an active and cost-effective treatment for the patients of visceral leishmaniasis, including those with Sb-resistant infection [33]. The piperine emulsion with stearylamine or PEGylated lipid nanospheres was injected intravenously to BALB/c mice. Stearylamine bearing emulsion produced higher diminution in parasite burden in liver (90%) and spleen (85%) than plain and PEGylated formulations [101]. „„Solid

lipid nanoparticles These are colloidal lipid-derived delivery systems having physiologically compatible ingredients approved for pharmaceutical employment in humans [102]. The employment of solid lipids in place of liquid oils is the best promising idea future science group

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for controlled release of drugs, as drug mobility in a solid lipid should be significantly lower relative to liquid oil. Mehnert demonstrated a detailed overview about the different ways of solid-lipid nanoparticles production and applications [103]. Recently, solid-lipid nanoparticles loaded by cysteine proteinase genes showed a promising DNA vaccine-delivery system for leishmaniasis [75]. „„Polymeric

nanoparticles Polymeric nanoparticles can be valuable in the therapy of infectious diseases, such as leishmaniasis, as the small size of the nanoparticles formulation supports its proficient passage through biological barriers, enhanced cellular uptake and the delivery of the therapeutic modalities in infected tissues [104–106]. Readers are advised to study the review article by Vauthier for several methods of the preparation of polymeric nanoparticles [107]. The foremost benefit of polymeric nanoparticles in contrast to liposomes is the aptitude that they have to tolerate physiological strain or greater biological stability [92]. When polymeric nanoparticles are utilized for therapy of leishmaniasis, it is essential to consider the category of polymer employed as it hydrophobicity will persuade the internalization by macrophages, which are the core targets in leishmaniasis. For instance, nanoparticles based on polymethyl methacrylate reveal improved targetingto macrophages as compared with nanoparticles based on polyalkylcyanoacrylate [77]. Numerous studies confirm the effectiveness of polymeric nano­ particles in the therapy of visceral leishmaniasis [108–112]. Primaquine-loaded nanoparticles were showed to be more efficient (21-fold) as compared with free primaquine in purging the Leishmania parasite [113]. A twofold enhanced effect was observed in J774A1 macrophages that were infected with L. donovani by encapsulating b-aescin in poly(d,l-lactide-co-glycolide) nanoparticles [15]. More recently, the PEGylated poly(lactic acid) nanoformulations encapsulated with bisnaphthalimidopropyl derivatives were investigated in human and THP-1 murine J774 cells as in vitro model for leishmaniasis. The designed formulation was more proficient in diminishing parasitic growth within human macrophages as compared with murine cells, indicating host cell-mediated metabolism. Basu et al. investigated a series of several naturally derived thera­peutic modalities as a potential antileishmanial by encapsulation in diverse www.future-science.com

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Review | Yasinzai, Khan, Nadhman & Shahnaz colloidal drug-delivery systems, including liposomes, niosomes, microspheres and nanoparticles [114–116]. The potential to decrease the parasite count in the spleen was highest when the naturally derived therapeutic modalities were loaded in colloidal drug-delivery systems in the following order: nanoparticles > niosomes > liposomes > microspheres > free drug. „„Polymer–drug

conjugate Polymer therapeutics is considered to be a promising field in the healthcare system. The rapid advancement in polymer engineering and bioconjugation strategies, and a profound understanding of cytology has opened up exhilarating new challenges and prospects. Polymer therapeutics (conjugation of drug with polymer) is another development to improve drug efficacy and greatly reduce toxicity [107]. For example, conjugation of lipophilic drug to a hydrophilic biodegradable polymer could increase the hydrophilicity of the drug, drug plasma circulation time and retention in the infectious tissue [107], resulting in an enhanced therapeutic effect and decreased toxicity. Many of the polymeric drug conjugates are synthesized and they have worked better or equal in activity to the marketed drug like in the case of N-(2-hydroxypropyl) methacrylamide– AmB. These findings showed the efficacy and nontoxicity of these drug conjugates rather than using the available fungizones, which are more toxic [22,78]. Future perspective Current scenario of drug resistance and their severe side effects to the first- and second-line classical therapeutic antileishaminal modalities has compelled the scientific community for new and improved alternative drugs. However, the deficiency of any substantial marketable return for the neglected diseases, for instance leishmaniasis, has resulted in unsatisfactory financial support, for drug development and design. In this milieu, strategies based on the enhancement of existing classical therapeutic modalities have shown more successful and promising outcomes than those related to the design and synthesis of novel therapeutic modalities. Advances include the development of more effective and safer target-based drug-delivery formulations for available classical thera­peutic modalities, novel drug combinations or coadministration of target inhibitor with classical 1884

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drug. As specific enzymes and structures in/on the Leishmania parasite are involved in classical drug resistance, hence, targeting specifically the Leishmania parasite within the host could be promising approach. TSH system, polyamine biosynthesis, surface lipids and efflux pumps could be potential targets to enhance therapeutic efficacy of classical therapeutic modalities. Biological thiol-dependent enzymes have currently received widespread interest in the literature owing to their association in a diversity of physiopathological conditions. Therefore, in a biological system, the selective inhibition of the activity of these enzymes by configuration of the thiol moiety may potentially initiate the advancement of a chemotherapeutic treatment. As TryR contains a dithiol motif at its active site cysteine residues, that is, Cys52 and Cys57 and can be inhibited by highly thiophilic polymer as an effective enzyme inhibitor. Over the last decade, chemically modified thiophilic polymers (thiolated polymers) have been broadly investigated for their use in drug-delivery systems. In particular, thiolated polymers exhibiting permeation enhancing, increased uptake, enzyme and efflux pump inhibitory characteristics have been tested and developed. Nanocarriers based on thiomers can be potential pharmaceutical excipients to enhance the therapeutic efficacy and circumvent resistance of already available conventional antileishmanial drugs via enzyme/efflux pumps inhibition. With greater understanding of resistance mechanisms and advances in polymeric-/lipidexcipient design, there is an opportunity to develop improved colloidal nanocarriers that boost delivery of combination therapies as well as the potential to use combination drug with target inhibitors. Use of safe and efficient nanocarriers platforms seem to be a promising tool on the way to alleviate many of the challenges in clinical leishmaniasis therapy to benefit patients in the future. Financial & competing interests disclosure The authors extend sincere thanks to the Higher Education Commission of Pakistan and Pakistan Science Foundation for their financial assistance. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. No writing assistance was utilized in the production of this manuscript. future science group

Drug resistance in leishmaniasis: current drug-delivery systems & future perspectives

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Executive summary Resistance towards classical drugs for the treatment of leishmaniasis „„

The development of resistance towards classical therapeutic modalities is one of the major challenges in effective leishmaniasis treatment.

Perceptive of the biochemical and molecular mechanisms of clinical resistance is important for the development of rational drug design. Plausible mechanism of classical drugs resistance „„

Main mechanism of resistance includes: „„ First-line antimonial therapeutic modalities have been resistant owing to: efflux/sequestration of the active drug in association with trypanothione (TSH), and by increasing the levels of TSH and P-glycoprotein efflux pumps. „„ Resistance against classical second-line therapeutic modalities has been induced due to: modification of drug receptor binding site (sterol binding receptor), amplified biosynthesis of competitor substrate (polyamine) for drug transporter and active extrusion of the drug by efflux pumps. Potential drug targets „„

„„

Target-based drug delivery hold remarkable potential to overcome drug resistance.

TSH system, polyamine and sterol biosynthesis, and efflux pumps could be putative drug targets. Nanotechnology-based drug-delivery systems „„

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Pharmaceutical polymeric-/lipid-excipients have shown the capability to overcome resistance and enhance drug uptake.

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Several novel drug-delivery systems have been researched and tested to surmount resistance, including liposomes, niosomes, nanodisks, emulsions, solid lipid nanoparticles, polymeric nanoparticles and polymeric drug conjugates.

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Santos DO, Coutinho CE, Madeira MF et al. Leishmaniasis treatment – a challenge that remains: a review. Parasitol. Res. 103(1), 1–10 (2008). Van Griensven J, Balasegaram M, Meheus F, Alvar J, Lynen L, Boelaert M. Combination therapy for visceral leishmaniasis. Lancet Infect. Dis. 10(3), 184–194 (2010). Di Giorgio C, Faraut-Gambarelli F, Imbert A, Minodier P, Gasquet M, Dumon H. Flow cytometric assessment of amphotericin B susceptibility in Leishmania infantum isolates from patients with visceral leishmaniasis. J. Antimicrob. Chemother. 44(1), 71–76 (1999). Sundar S, Sinha PR, Agrawal NK et al. A cluster of cases of severe cardiotoxicity among kala-azar patients treated with a highosmolarity lot of sodium antimony gluconate. Am. J. Trop. Med. Hyg. 59(1), 139–143 (1998). De Lalla F, Pellizzer G, Gradoni L, Vespignani M, Franzetti M, Stecca C. Acute pancreatitis associated with the administration of meglumine antimonate for the treatment of visceral leishmaniasis. Clin. Infect. Dis. 16(5), 730–731 (1993).

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Drug resistance in leishmaniasis: current drug-delivery systems and future perspectives.

Leishmaniasis is a complex of diseases with numerous clinical manifestations for instance harshness from skin lesions to severe disfigurement and chro...
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