Bibliographic data.
Abstract
Malaria causes hundreds of thousands of human deaths every year, and the World Health Assembly has made it a priority. To help eliminate this disease, there is a pressing need for the development and implementation of new strategies to improve the prevention and treatment, due in part to antimalarial drug resistances. This chapter focuses on two strategies to inactivate the malaria parasite in blood, which are photodynamic therapy (PDT) and inhibition of hemozoin formation. The PDT strategy permits either a control of the proliferation of mosquito larvae to develop some photolarvicides for the prevention or a photoinactivation of the malaria parasite in red blood cells (RBCs) to minimize infection transmission by transfusion. The inhibition of hemozoin formation strategy is used for the development of new antimalarial drug by understanding its formation mechanism.
Keywords
- hemozoin
- photodynamic therapy
- blood decontamination
- heme-drug interaction
- preventive treatment
- curative treatment
1. Introduction
Malaria in humans is an infectious disease caused by parasites of the genus
In 2000, malaria was seen as one of the most critical constraints on global development and considered as a priority challenge of the “Millennium Development Goals” (MDGs). The main objective was to halt and begin to reverse the incidence of malaria by 2015 (Target 6C). The
With regard to preventing malaria in countries at risk, the WHO recommends sleeping under an insecticide-treated mosquito net (ITN) and protecting by indoor residual spraying (IRS). Furthermore, the recommended treatment is an artemisinin-based combination therapy (ACT).
Despite a slight decrease, this disease remains a leading cause of death of children in Africa due in part to antimalarial drug resistances. Declines in cases and deaths caused by malaria are due to the development of new strategies such as the use of photodynamic therapy (PDT) for the control of the infection vector or to induce inactivation of
2. Inhibition of hemozoin formation
2.1. Generalities on the hemozoin production by P. falciparum
Hemoglobin, the main component of red blood cells (RBCs), represents almost 95% of the protein part of the cytosol (liquid fraction of the cell cytoplasm) up to reach 5 mM concentration in the cytoplasm (>300 mg/mL) [2]. Hemoglobin essential for cellular respiration is composed of a protein portion (globin) and a complex molecular structure centered on an iron atom (heme, ferriprotoporphyrin IX, Fe(II)PPIX which carries oxygen, and carbon dioxide from breathing).
During its life cycle in the red blood cell (RBC), the human malaria parasite (Figure 1),
The heme detoxification is a crucial step for the survival and growth of the parasite [15]. Heme is assumed to generate the formation of reactive oxygen species (ROS),
The detoxification of heme begins with the self-oxidation of the Fe(II) in heme group into Fe(III) to form potentially toxic hydroxyferriprotoporphyrin IX (hematin, HO-Fe(III)PPIX; Figure 2) [8, 24, 25]. This detoxification ends with the formation of highly insoluble brown crystals known as hemozoin (malaria pigment; Figure 2) [26, 27] according to biomineralization or biocrystallization processes [28, 29] and not
The mechanism concerning formation of β-hematin (hemozoin) in vivo and in vitro is still ambiguous and will be discussed in the following section.
2.2. Mechanistic assumptions about the hemozoin formation
The heme detoxification by
Before beginning the discussion about mechanistic assumptions of the hemozoin formation, it is worth noting that when comparing the natural hemozoin and its synthetic version (β-hematin), we see a considerable difference in their size and shape. The natural hemozoin consists of small crystals ranging in size from 50 to 500 nm, whereas for the synthetic β-hematin, these crystals are bigger (50 nm to 20 μm) and depend on solvent used for the recrystallization. This difference in size can lead to diverse immunomodulatory responses [32].
The various studies of this mechanism gave rise to a number of assumptions [11, 33, 34] such as spontaneous [35, 36], autocatalyzed [37, 38], enzyme-catalyzed [39], lipid-catalyzed [40–43], and initiated or catalyzed by histidine-rich proteins (HRPs) [44–48], which can be divided into two main types: non-biological and biological conditions (Figure 3).
The first category (non-biological conditions) is based on the assumption that β-hematin formation can happen spontaneously without any external help [35]. This observation comes from studies conducted in acetate solution, which shows that the β-hematin can be formed at a moderate low pH compared to the acidic digestive food vacuole [36].
The second category includes of all other mechanisms and provides a presumption that the β-hematin formation can catalyze itself or requires the presence of biological material (biocrystallization). The first idea about an autocatalytic process is, among other things, due to a recent observation of the continued growth of a preexisting hemozoin crystal [37].
As regards the second idea, it began in 1992 with the work of Slater and Cerami [39] which have shown that heme can react with trophozoite lysate extracts at pH 5–6 to generate hemozoin and that chloroquine, an antimalarial drug, can inhibit this formation. The authors concluded that the creation of the two propionate-Fe(III) linkages during the heme detoxification is catalyzed by an enzyme named heme polymerase. The use of extracts from
Despite being challenged, this heme polymerase theory attempted to explain hemozoin propagation without clarifying its initiation. This breach paved the way for other hypotheses about the formation of hemozoin involving a protein or enzyme [38]. Firstly, Hempelman in 2007 introduced the concept of “biocrystallization” instead of “polymerization” to describe the hemozoin formation process [29]. One of the hypotheses suggested that biocrystallization is caused by enzymes, which postulate the presence of proteins such as histidine-rich proteins (HRPs). Sullivan and coworkers [48] showed that HRPs I, II, and III, present in the parasite’s digestive vacuole, may be able to promote the formation of hemozoin in vitro. In 2008, Jani et al. [46] identified a novel heme detoxification protein (HDP) from
Finally, the last proposed mechanism is the biocrystallization catalyzed by lipids [40–43, 50]. These lipids, produced by the parasite after digesting the transport vesicles and trapped in its food vacuole, have been characterized with spectroscopic studies [7, 41] and known as a neutral lipid blend (NLB) and monopalmitoylglycerol (MPG). In 2007, Pisciotta et al. proved that Fe(III)PPIX can be processed into β-hematin through the action of these lipids with the yield of 80% or more [51] as assumed by Sullivan two years before [27].
The design and development of new antimalarial drugs first begin with the understanding of the mechanism of action of
By way of example, new strategies envisaged include the use of PDT (Section 3) in order to kill mosquito larvae (prevention Section 3.2) or to inactivate malaria parasites in the RBCs (treatment Section 3.3) but also the design of new antimalarial drugs that are able to inhibit the β-hematin formation by heme-drug interaction (treatment Section 4).
3. Photodynamic therapy for preventive and curative treatments
3.1. Generalities
The therapeutic effects of light are known since ancient times and were widely used in combination with natural substances for centuries in Chinese, Egyptian, or Indian civilizations for the treatment of numerous diseases such psoriasis, vitiligo, and rickets [52]. The integration of the concepts of “phototherapy” and then “photosensitivity” in modern medicine is much more recent, since it originated in the work of Niels Finsen, a Danish doctor who demonstrated in the 1890s the positive influence of light on the healing process (Nobel Prize for Medicine in 1903) [53]. However, the concept of exogenous photosensitizer (PS), that is to say, therapeutic molecule introduced for the specific purpose of interacting with light to generate the desired therapeutic effect, was introduced only a few years later, at the turn of the twentieth century by Raab and von Tappeiner as related by Spikes in a very good historical review [54]. In 1900, Oscar Raab, a student at the Department of Pharmacology of the University of Munich in the group of Hermann von Tappeiner, tried to characterize the influence of acridine on the development of
In summary, PDT is an innovative medical treatment involving the concomitant action of three components that are photoactivatable molecule called PS, light of a suitable wavelength, and oxygen present in the biological medium. After light excitation of the PS and energy transfer from the excited PS to oxygen, reactive oxygen species are produced especially singlet oxygen (1O2) that can destroy cancer cells in proximity. It is interesting to notice that the PS itself is nontoxic and turns out to be toxic only with light. Light is also nontoxic by itself. The selectivity of action of PDT allows through a localized light radiation to eradicate tumor cells while preserving healthy cells. PS fluorescence properties are also an asset that is utilized to visualize the diseased tissue. The mechanisms are summarized in Figure 4.
This technique was used clinically for many years, and in 1993, bladder cancer Photofrin PDT receives government approval in Canada. Since then, PDT has been developed in many countries of the world. PDT is an obvious treatment for dermatology applications, and it is used daily for skin diseases such as actinic keratoses, acne, and wine stain [57]. PDT has been also widely employed as a treatment for age-related macular degeneration (ARMD). However, since 2006, intravitreal injections of Avastin, humanized monoclonal antibody having anti-angiogenic activity, significantly reduced the use of PDT to treat ARMD. In urology, the French company Steba Biotech has invested heavily to develop a new PS, the TOOKAD® (currently in phase 3) for the treatment of prostate cancer. The first clinical applications demonstrate the technical feasibility [58]. In gastroenterology, PDT demonstrated its effectiveness for the treatment of superficial cancers of the esophagus in patients ineligible for further treatment, with a postradiation recurrence, severe dysplasia in Barrett, and unresectable cholangiocarcinoma [59]. In gynecology, the interest of PDT has been shown in the treatment of cervical dysplasia of low- and high-grade cervical lesions [60]. Our team developed folic acid-targeted photosensitizers that could be very efficient to treat peritoneal carcinosis, and a preclinical evaluation is under progress [61, 62]. In pulmonology, the number of studies on the treatment of lung cancer is still limited, and the role of PDT in the therapeutic arsenal of the practitioner remains to be demonstrated. PDT appears to be a promising treatment for malignant pleural mesothelioma (MPM). Thus, PDT has been tested in phase I and phase II clinical trials to MPM patients in combination with extrapleural pneumonectomy or pleurectomy/decortication and an intravenous chemotherapy. The first work of the team of Professor Friedberg (University of Pennsylvania, Philadelphia, USA) has shown promising results with a median overall survival of 31 months [63]. PDT is not only a powerful technique to destroy human cells but also for viruses [64], yeasts [65], molds [66], bacteria [67], protozoa [68], parasites [69], and insects (Section 3.2). PDT is used in the development of new strategies to treat malaria and more generally to treat tropical diseases, either by controlling the propagation vector of the disease (Section 3.2), by inactivation of microorganisms responsible for these diseases, or by inactivating parasites (Section 3.3).
3.2. Prevention: destruction of mosquito larvae
3.2.1. Generalities
More than 700 million people are affected annually by mosquitoes in Asia, Mexico, Central America, South America, and Africa. A promising strategy to control diseases transmitted by mosquitoes (malaria, filarial, and dengue fever) is the control of these vectors. Mosquitoes are vectors of pathogens:
3.2.2. Anopheles mosquitoes: the primary vector for malaria
Malaria is spread to humans by the bite of the female anopheles mosquito. In 2012, Fabris et al. described the photolarvicidal activity of a new PS called C12-porphyrin (5-(4-
In collaboration with the Institut de Recherche en Sciences de la Santé (IRSS) located in Burkina Faso, Fabris et al. studied the potential of C12-porphyrin as a photolarvicide for the control of
3.3. Prevention: photoinactivation of parasites in blood
3.3.1. Generalities
With the emergence of many antibiotics, PDT declined for the treatment of parasite-related diseases, and it is only in recent decades that it knew a regain of interest with the increasing problem of antibiotic resistance [80]. Antibiotic resistance is a global problem that reduces the power of conventional treatments of many diseases (both nosocomial and community-acquired infections). It concerns all pathogens including bacteria, fungi, and viruses.
To circumvent this bio-resistance, an attractive approach is PDT as non-antibiotic strategy to inactivate microorganisms (bacteria, viruses, parasites, etc.). This process is called antimicrobial photodynamic therapy (aPDT) [81, 82] or antibacterial PDT [83, 84] but is also known as photodynamic inactivation (PDI) [85–87] or photodynamic antimicrobial chemotherapy (PACT) [88–91]. This treatment can be effective in the case of chronic ulcers, infected burns, acne vulgaris, and a variety of local bacterial infections but also in the case of periodontitis [92], dengue [93], tuberculosis [94], viral infection [95], and malaria [96–99]. A very large variety of microorganisms have been studied and are listed by Alves et al. in a recent review [70] in which the insect pest elimination, water disinfection, and elimination of food-borne pathogens are described. A state of the art of PDT (potential) applications in animal models and clinical infectious diseases has been submitted by Dai et al. in 2009 [95], and numerous PSs are described [99, 100].
3.3.2. Inactivation of P. falciparum in human RBCs
Malaria is no more considered as poverty-related disease in Western countries, and attention has been paid to developing blood decontamination methods, vaccines, or new therapies. The spread of malaria disease, particularly with
The life cycle of
Historically, Ehrlich’s group was the first to use methylene blue (Figure 6) as a PS [106] and Rounds et al. conducted a pioneering work on the photokilling potency of a ruby laser and methylene blue on cells infected by
Riboflavin or vitamin B2 (Figure 6) deficiency is closely related to malaria [109, 110], and its administration can prevent hemozoin formation in the asexual cycle in the food vacuole of erythrocytes. Akompong et al. observed that addition of riboflavin can induce a 65% decrease of the food vacuole volume and subsequently damage to light-exposed contaminated blood [111]. In 2013, Goodrich’s group tested the “Mirasol® pathogen reduction technology” (PRT) system against
In a recent research, Sigala et al. [114] demonstrated that sequencing of
PS | Conditions | Effects | Reference |
---|---|---|---|
Hemozoin | 800 nm; 485 mW/cm2; 60 min | ~0.5 log reduction in parasitemia | [105] |
Methylene blue | 694 nm; 70 J/cm2 | Preferential uptake by infected erythrocytes by imaging |
[107] |
Merocyanine 540 | 485 nm; 26 W/m2; 30 min | 1000-fold reduction in parasitemia | [108] |
Riboflavin | No irradiation /48h | 65% decrease in food vacuole volume | [111] |
Riboflavin | UV ; 6.24 J/mL ; 72 h | <0.002% survival | [112] |
ALA | White light; 0.57 W/cm2; 30 min |
<0.0005% survival | [116] |
ALA | Chemoluminescence by luminol |
75–80% death | [114] |
SnPPIX | No irradiation | IC50 = 6.5 μM (85 μM for chloroquine) on trophozoite lysate |
[118] |
Zn-PPIX | No irradiation | IC50 = 330 nM on RBC | [119] |
Diarylporphyrin | No irradiation | IC50 = 20 nM on erythrocytes | [120] |
Pheophorbide Ph4-OH |
660 nm; 7 W/cm2; 20 min | Total eradication with 2 μM/L | [121] |
PC4 phthalocyanine | >600 nm; 60 J/cm2; 10 min | <0.025% survival with 2 μM/L | [122] |
In 1996, Martiney et al. [117] described a slight inhibition of hemozoin formation by using Zn-PPIX without light. Using trophozoite lysate of
The photosensitized inactivation of
Besides the decontamination of blood or dialysis, numerous studies have been conducted to understand the physiology of the human malaria parasite
4. Curative treatment: drugs inhibiting β-hematin formation
Among various strategies, we will focus in the following part only on antimalarial drugs that inhibit the β-hematin formation by heme-drug interaction (purely π-π interactions). This strategy of drug development uses the heme scaffold itself as a hematin crystallization inhibitor (Figure 2). We can quote quinine, chloroquine, rufigallol and exifone and artemisinin, which are currently used as antimalarial drugs
Several studies and reviews [97] reported that porphyrins can inhibit the process of heme crystallization in the acidic food vacuole of the malaria parasite. As current antimalarial drugs, porphyrins are able to inhibit the β-hematin formation by strong π-π stacking interactions. Several porphyrins have been studied for their use in heme aggregation inhibition.
In 1997, Basilico et al. [127] evaluated the effect of two non-iron metalloporphyrins (PPIX and hematoporphyrin) on the crystallization of α-hematin (Figure 8) to β-hematin also called synthetic hemozoin (Figure 2). Crystallization of hematin may be achieved in 4.5 M sodium acetate buffer at 60°C [35]. Heme and β-hematin may be differentiated by their IR spectroscopic characteristics [128]. IR spectra of β-hematin show two bands at 1662 and 1209 cm−1, which disappear in IR spectra of heme. From this property, Basilico et al. demonstrated that free-base porphyrins inhibit heme crystallization with hematoporphyrin more actively than PPIX. The presence of hydroxyl groups can explain the better inhibitory ability of hematoporphyrin.
In 1999, Tamarelli’s team also showed that Fe(III)PPIX is reduced to Fe(II)PPIX as a novel endogenous antimalarial because Fe(II)PPIX molecules inhibit the crystallization process causing the death of the parasite [129].
Some researchers are interested in the synthesis of free-base porphyrins. In 2008, Bhat et al. [130] synthesized and evaluated the antimalarial activity of a series of porphyrin thiosemicarbazides. Only one compound (Figure 9 left) possesses an ability to inhibit β-hematin formation similar to chloroquine and quinine, the control drugs that are usually used in the malaria treatment. More recently, Abada et al. [120] synthesized a new 5,15-diarylporphyrin (Figure 9 right) with a good activity against
In 2000, Wright’s team highlighted the presence of other metal ions than Fe(III) can influence the conversion of heme to β-hematin. A number of metallo-PPIX, including Fe(III), Cr(III), Co(III), Cu(II), Mn(III), Mg(II), Zn(II), and Sn(IV) showed in vitro an ability to inhibit the β-hematin formation (Figure 10) [131]. In 2003 [132], phthalocyanines, phthalocyanine tetrasulfonate (PcS) and Ni(II)PcS, and anionic porphyrins,
The same behavior was observed by Begum et al. [118] who evaluated the antimalarial activity of free-base PPIX, deuteroporphyrin IX (DPIX), and hematoporphyrin IX (HPIX) and their corresponding complexes with Ga(III), Ag(III), Pd(II), Co(III), Mn(III), Sn(IV), Cr(III), and Fe(III) ions (Figure 10). Once again, SnPPIX at 15.5 μM had a better activity than the chloroquine control. Both GaPPIX and GaDPIX showed an antimalarial activity also.
In the same way, Chemaly et al. [133] observed that cobalamins (cbls) also called vitamin B12 (corrin ring with a chemical structure close to the heme but the central iron atom is replaced by an atom of cobalt) possess antimalarial activity. Methylcobalamin (CH3-cbl), adenosylcobalamin (Ado-cbl), and aquacobalamin (H2O-cbl) (Figure 11) showed increased efficacy over the chloroquine; cyanocobalamin (CN-cbl) was a little more efficient than chloroquine. The in vivo evaluation of vitamin B12 derivatives on the growth of
Rodriguez et al. [134] showed that Mn(II) complexes of alkylated tetraphenylporphyrin with a fluorinated artemisinin derivative (Figure 12) were effective inhibitors of β-hematin formation with an IC50 of 2.6 nM.
Benoit-Vical et al. [135, 136] showed a similar behavior with anionic metalloporphyrins. Alone the
5. Conclusion and perspectives
Malaria eradication is one of the great issues for humankind in the decades ahead. Based on figures from the
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