Nanoparticle properties (mean particle diameter [z‐average] and polydispersity index from dynamic light scattering, zetapotential [ZP] from particle electrophoresis).
\\n\\n
More than half of the publishers listed alongside IntechOpen (18 out of 30) are Social Science and Humanities publishers. IntechOpen is an exception to this as a leader in not only Open Access content but Open Access content across all scientific disciplines, including Physical Sciences, Engineering and Technology, Health Sciences, Life Science, and Social Sciences and Humanities.
\\n\\nOur breakdown of titles published demonstrates this with 47% PET, 31% HS, 18% LS, and 4% SSH books published.
\\n\\n“Even though ItechOpen has shown the potential of sci-tech books using an OA approach,” other publishers “have shown little interest in OA books.”
\\n\\nAdditionally, each book published by IntechOpen contains original content and research findings.
\\n\\nWe are honored to be among such prestigious publishers and we hope to continue to spearhead that growth in our quest to promote Open Access as a true pioneer in OA book publishing.
\\n\\n\\n\\n
\\n"}]',published:!0,mainMedia:null},components:[{type:"htmlEditorComponent",content:'
Simba Information has released its Open Access Book Publishing 2020 - 2024 report and has again identified IntechOpen as the world’s largest Open Access book publisher by title count.
\n\nSimba Information is a leading provider for market intelligence and forecasts in the media and publishing industry. The report, published every year, provides an overview and financial outlook for the global professional e-book publishing market.
\n\nIntechOpen, De Gruyter, and Frontiers are the largest OA book publishers by title count, with IntechOpen coming in at first place with 5,101 OA books published, a good 1,782 titles ahead of the nearest competitor.
\n\nSince the first Open Access Book Publishing report published in 2016, IntechOpen has held the top stop each year.
\n\n\n\nMore than half of the publishers listed alongside IntechOpen (18 out of 30) are Social Science and Humanities publishers. IntechOpen is an exception to this as a leader in not only Open Access content but Open Access content across all scientific disciplines, including Physical Sciences, Engineering and Technology, Health Sciences, Life Science, and Social Sciences and Humanities.
\n\nOur breakdown of titles published demonstrates this with 47% PET, 31% HS, 18% LS, and 4% SSH books published.
\n\n“Even though ItechOpen has shown the potential of sci-tech books using an OA approach,” other publishers “have shown little interest in OA books.”
\n\nAdditionally, each book published by IntechOpen contains original content and research findings.
\n\nWe are honored to be among such prestigious publishers and we hope to continue to spearhead that growth in our quest to promote Open Access as a true pioneer in OA book publishing.
\n\n\n\n
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Nanoparticles (NPs) are a tool for specifically targeting drugs or diagnostics to selected tissues or cell types [1–3]. Their use in cancer research and therapy is of special interest [4–9] as well as to overcome the blood‐brain barrier [10, 11]. At least in theory, they are a tool to optimise pharmacological data such as drug release, tissue specificity and even cell specificity [2].
In some cases, drug crystals have been used successfully as nanocarriers [12, 13]. NPs composed of polymers may be loaded with drugs which they release in a controlled manner, or they are coated with molecules which give them specific surface characteristics to bind and be taken up by certain cells. Despite these attractive goals and 30 years of research, there are no polymeric nanoparticles in practical, pharmaceutical use. There is hope to apply nanoparticles to deliver drugs across the blood‐brain barrier [10, 14, 15].
The reasons for this obvious failure include following: first, the unresolved problem of cytotoxicity of several nanocarrier types [16], low drug loading and insufficient delivery of the bound drug and lack of production facilities to supply demand.
The problem of toxicity could be overcome at least partially by high selectivity with regard to the cells by which the NPs are taken up. Such a strategy is especially interesting in the case of cells, infected with microbes which only multiply intracellularly, such as viruses and some parasites, as these often alter the surface of the host cell, thereby offering the specific targets needed. In this case, even toxic NPs could be useful, as they would exert their toxicity mainly or even better only in or against infected cells which would inhibit the multiplication of the pathogens and destroy them.
At the moment, there are some data showing that tissue specificity may be achieved. One of the interesting targets is the endothelial barrier of the brain. Despite the big potential [17], there are no data concerning infected cells. As it is important to develop drugs against intracellular parasites such as Toxoplasma or Leishmania, therefore the goal is to establish a system which would allow to trace the fate of nanoparticles in infected cell cultures. It should be possible to evaluate the cell and parasite proliferation and the differential uptake of NPs.
A fluorescence‐activated cell sorter (FACS) represents a useful tool to measure particles which differ in size and more importantly, in fluorescence [18]. Thus, it is possible to count extracellular parasites and their host cells separately, if they differ in size. To find the intracellular parasites and to differentiate between infected and non‐infected cells, green fluorescent protein‐transfected parasites were used. In the past, it was shown that it is possible to follow the fate of Leishmania in a cell culture which is conventionally treated (by adding drugs at the necessary concentration) [19].
Because the FACS is able to discriminate between fluorescences of different wave lengths, the purpose of this study was to establish a system with stained NPs as an additional reacting partner [20]. In the case of Leishmania, only phagocytic cells, mainly macrophages, act as host cells and the parasite becomes internalised through phagocytosis. There are some data that NPs without drugs may even interfere with normal white blood cell functions, including phagocytosis.
As NPs are recognised as foreign structures, they are eliminated by phagocytising cells [21, 22]. Thus, it should be easier to treat microorganisms which multiply within macrophages, because the nanoparticles would be concentrated automatically in the desired target cells. An example for this strategy is Leishmania [23]. Another interesting goal of nanoparticle research is targeting NPs to the brain [11, 14, 24]. Toxoplasma gondii offers a possibility to combine these aims. T. gondii is a parasite which multiplies in different cell types including macrophages and phagocytising cells in the brain [25]. The main problems in treatment of toxoplasmosis are infections during pregnancy and Toxoplasma encephalitis in the case of immunocompromised patients [25–28]. In normal Toxoplasma infections, the multiplication of the parasites is stopped by the immune system, but cysts remain in all formerly infected tissues including the brain, serving as a source for exacerbations. Therefore, efficient treatment of all infected cells to prevent cyst formation would be an interesting goal. Thus, we started our experiments with NPs in T. gondii‐infected cultures, knowing that T. gondii has a completely different mode of penetration which is mostly independent of the support of the host cell [29].
To come closer to in vivo conditions and to make it easy to observe an effect, the culture should work for at least 3 days to allow several cycles of multiplication.
Initially, all experiments with FACS should be controlled by microscopy, to prove that the interpretation of the FACS data is consistent with the images seen under the microscope.
The established and considered system consisted of three components: nanoparticles, parasites and cells which differed in size and shape. However, there were also infected cells, cells loaded with nanoparticles and infected cells with nanoparticles which should be differentiated as well. To trace the fate of parasites and nanoparticles with FACS, they had to be stained with dyes which are distinguishable from each other. Because the green fluorescent protein, Toxoplasma was transfected with, shows fluorescence in green and yellow [33, 34] a red dye to stain the nanoparticles gave sufficient results. Of the dyes tested, rhodamine B gave the best results. The intensity of fluorescence corresponds with the amount of dye, fixed inside the core of the NPs and should increase exponentially (to the third) with the increasing radius of the NPs. In larger particles, however, there seems to be a quenching, as light is unable to penetrate from the core of the particle to the surface.
Next, a broader spectrum of NPs of different sizes was tested to see, which gave the best results. To be able to compare the FACS data with microscopical counting, the NPs had to be larger than 100 nm; otherwise, microscopical identification, especially of intracellular particles, would be impossible. In Table 1, one of the two best candidates is shown. As the results obtained with the two different NPs in these experiments were identical, only data with MC81cs are shown here.
MC81 | Core | Core‐shell (cs) | Cs + pentamidine | |||||
---|---|---|---|---|---|---|---|---|
Z‐ave (nm) | 133.1 | 213.4 | 221 | |||||
PI | 0.065 | 0.046 | 0.071 | |||||
ZP (mV) | pH | Distilled water | −93.20 | 5.52 | −84.79 | 5.5 | −79.70 | 5.55 |
10E‐3M NaCl | −70.33 | 5.53 | −63.40 | 5.51 | −61.66 | 5.51 | ||
10E‐2M NaCl | −50.85 | 5.54 | −30.60 | 5.51 | −29.00 | 5.45 | ||
Surface charge density (μC/cm2) | −2.54 | −0.93 | −0.96 | |||||
MC81c | MC81cs | |||||||
No drug | Pentamidine | Spiramycin | ||||||
Size (nm) | 133.1 | 213.4 | 222.1 | 198.1 | ||||
PI | 0.065 | 0.046 | 0.071 | 0.04 |
Nanoparticle properties (mean particle diameter [z‐average] and polydispersity index from dynamic light scattering, zetapotential [ZP] from particle electrophoresis).
The nanoparticle suspensions were homogeneous in size, checked by electron microscopy—data not shown—and were shown to be non‐toxic, by measuring growth of cell cultures in their presence.
Figure 1A shows an infected cell in the presence of NPs. NPs with diameters between 200 and 300 nm were focused on as they were perfect for these purposes, being visible under a microscope, and therefore allowing the opportunity to compare microscopically the results, obtained with FACS with the situation in the cell culture.
Situation in cell culture: macrophages, parasites and nanoparticles (NPs).
The same area photographed using different filters: the arrow points to a macrophage cell infected with one Toxoplasma cell.
Three channel photography (FITC/PI/neutral): NPs are attached to the macrophage, and some are scattered around.
Two channel photography (FITC/PI): the parasite inside the cell is clearly visible.
One channel photography (FITC): only the parasite (green) is visible.
One channel photography (PI): the parasite is invisible, the cell appears red as a result of uptaken NPs, and some extracellular NPs are visible.
Figure 1B–D demonstrates how different filters are able to distinguish the dyes used. In a first series of experiments, different amounts of NPs added to cell culture were tested with the result that approximately 60,000 particles per cell gave measurable and reproducible results in this system. Most of the NPs were phagocytised by the cells within the first few hours.
As parasites not only infect cells and multiply—increasing in number in an unpredictable way— they will also destroy host cells, thereby diminishing their number.
To calibrate the exact increase or decrease in the different components, ‘Perfect Counting Beads’ (Caltag Laboratories) were added before FACS scan and all data were adjusted to the beads count.
The particle size (FSC‐x‐axis) and granularity (SSC‐y‐axis) were determined. In A, toxoplasmas‘and in B, macrophages were counted in relation to beads in order to calculate absolute numbers. The beads are always seen in the same position. In parallel, the particles were characterised by fluorescence (see Figure 3).
Figure 2 shows an example of data obtained with a culture of J744‐A1 cells infected with T. gondii. Each sample had to be measured twice: once to count the free parasites (Figure 2A) and a second time to count the cells (Figure 2B) separated by their size (FSC) and their granularity (SSC).
Particle size (FSC‐x‐axis) and granularity (SSC‐y‐axis) of (A) Toxoplasma cells and (B) macrophages population.
Granularity (SSC) and green fluorescence (FL1) of non‐infected, untreated cells (A), infected, untreated cells (B), infected and treated with pure nanoparticles (C), uninfected cells, treated with nanoparticles (D) and infected cells, treated with pentamidine‐loaded nanoparticles (E), given after 1 day of incubation.
For analysis, the counted cells were sorted by fluorescence then. The series of dot blots in Figure 3 compares uninfected, untreated control cells (A), infected cells (B), infected cells treated with unloaded nanoparticles (C), uninfected cells treated with unloaded NPs (D) and infected cells treated with pentamidine‐loaded NPs (E).
The dot blots show changes in green fluorescence and granularity. In addition, the mean values of the particles in the gates are given in Table 2, as the numbers are hard to calculate from the images. The shift in the mean values is often more impressive than the density or position of the dots.
Experiment | R1 % | R1 X mean | R1 X G–M | R2% | R2 X mean | R2 X G–M |
---|---|---|---|---|---|---|
A C | 98.84 | 8.35 | 7.35 | 1.16 | 102.68 | 77.60 |
B C + T | 50.83 | 23.42 | 20.62 | 49.17 | 108.24 | 91.94 |
C C + T + NPs | 73.05 | 18.68 | 16.16 | 26.95 | 165.08 | 116.78 |
D C + NPs | 85.46 | 13.72 | 11.16 | 14.54 | 88.33 | 80.10 |
E C + T + NPs + P | 69.55 | 19.58 | 16.84 | 30.45 | 103.65 | 86.43 |
Granularity (SSC) and green fluorescence (FL1) with the corresponding values of Figure 3.
Exp.: part of the experiment corresponding to A to E; R%: percent of counts in this gate; R1 X mean: mean value of counts in gate 1; R1 X G‐M: geometrical mean value of counts in gate 1; R2 X mean: mean value of counts in gate 2; R2 X G‐M: geometrical mean value of counts in gate 2.
Figure 3A illustrates the fluorescence of the macrophages of the cell control with its characteristic unspecific autofluorescence. The presence of Toxoplasma and/or NPs induces a movement into the area of higher fluorescence (Figure 3B–E). Whereas the Toxoplasma induces a stronger shift into the green fluorescence (Figure 3B), the NPs induced a smaller one (Figure 3D) which is an effect of an unspecific stimulation of the cells resulting in an increased autofluorescence [30].
The corresponding Table 2 shows the percentage of particles in the gate for non‐infected cells (R1) and the percentage in the gate of infected cells (R2) as well as the corresponding mean values (mean) and geometrical mean values (G‐M).
Green fluorescence is represented on the x‐axis and granularity on the y‐axis.
Macrophages, activated by nanoparticles, have a basic fluorescence which is at least partially an indicator of their activity [36]. Thus, controls of cells, treated only with nanoparticles, are essential. For data processing, other combinations may be selected, such as granularity or red fluorescence. There is always an overlap of data however, and the interpretation of the blots must be proofread against the mean values of the particles within the gates—here given in the corresponding tables.
In the following series of experiments, a cell system was established in a manner that after infection on day zero, there is a continuous multiplication of Toxoplasma at least until day three. Defined concentrations of cells were put into wells, and parasites in different ratios were added for this purpose. The ratio parasite to cell is given as MOI (multiplicity of infection). All tests were carried out in three wells in parallel, and all experiments were carried out at least twice. The most promising results were obtained with MOI\'s of 1–10.
Figure 4 shows the results of one of these experiments. MOI\'s of 10, 5, 2 and 1 were used, and free parasites (A), total cells (B) and infected cells (C) were determined at the first, second and third day after infection. There was a large increase in free parasites over the 3 days with MOI\'s of 10 and 5, a moderate increase with an MOI of 2 and almost no increase with an MOI of 1 (Figure 4A). In parallel, there was no such strong increase in total cell number as with the uninfected controls (Figure 4B). With the high MOI\'s of 10 and 5, there was a decrease at day two and an increase at day three. Only with MOI\'s of 1 and 2, there was a slight increase in cells over the 3 days. The number of infected cells indicates that with a MOI of 10 and 5, almost all cells were infected, whereas with MOI\'of 2 and 1, many cells remained uninfected until day three (compare Figure 4B and C).
Influence of multiplicity of infection (MOI) 1.36 × 105 cells per ml was infected with different multiplicities of infection (10, 5, 2 and 1). A number of free parasites (A), total cell number (B) and number of infected cells (C) were determined over 3 days.
It was shown that MOI 2 is most appropriate for these tests, because there was an increase in the parasites and of the cells over the 3 days.
In a culture of infected cells, running for at least 3 days, there will be individual death of cells and parasites. Some of the free Toxoplasma in the culture will die and—as the infected cells disintegrate after liberating multiplied parasites—will shift into the debris. Thus, there will be an unpredictable increase or decrease in cell counts. To differentiate between an increase of non‐infected cells and a loss of infected cells, both of which result in an increase in the percentage of non‐infected cells, it was necessary to determine the total number of cells and the proportion of infected and non‐infected cells in relation to the cell input on day zero. Before measuring, cells were fixed with paraformaldehyde, and after ‘Perfect Counting Beads’ (Caltag Laboratories) were added, the samples were counted.
There was an indication that even unloaded NPs have an inhibitory effect. To prove this, the influence of pentamidine‐loaded and unloaded nanoparticles on Toxoplasma‐infected cell cultures was determined. Figure 5 shows the histograms in each case for day 2 of non‐infected cells (A), infected untreated cell controls (B), cells only treated with NPs (C), infected cells treated with unloaded NPs (D) and pentamidine‐loaded NPs (E). The histograms show the changes in green fluorescence (FL1) and number of counts. One table with all data obtained (Figure 5A) is shown as an example of how CellQuest® analyses data. Data of corresponding tables, with the mean values of the gates for all 3 days, are given in Table 3. It is shown that the presence of Toxoplasma induced a shift to higher fluorescence. Comparing the data of infected cells, treated with pentamidine‐loaded nanoparticles with those treated with unloaded nanoparticles, demonstrates that nanoparticles alone had an effect on T. gondii multiplication.
1. day | 2. day | 3. day | |||||||
---|---|---|---|---|---|---|---|---|---|
All | M1 | M2 | All | M1 | M2 | All | M1 | M2 | |
Cell control [%] | 98.6 | 1.4 | 93.0 | 7.0 | 92.0 | 8.0 | |||
Mean | 9.29 | 16.77 | 16.14 | ||||||
Geomean | 7.30 | 7.08 | 70.91 | 12.57 | 11.11 | 66.29 | 10.23 | 8.68 | 65.62 |
Median | 6.79 | 6.73 | 57.25 | 10.75 | 10.37 | 61.53 | 9.22 | 8.58 | 59.89 |
Infected cells [%] | 35.0 | 65.0 | 33.0 | 67.0 | 49.53 | 50.5 | |||
Mean | 160.49 | 127.46 | 63.414 | ||||||
Geomean | 75.89 | 18.78 | 156.81 | 70.30 | 23.32 | 121.25 | 42.25 | 20.27 | 86.415 |
Median | 73.63 | 19.81 | 145.90 | 66.12 | 25.71 | 103.66 | 43.325 | 22.07 | 77.042 |
Cells + NPs [%] | 93.0 | 7.0 | 90.5 | 9.5 | 85.5 | 15.5 | |||
Mean | 14.63 | 18.76 | 22.96 | ||||||
Geomean | 10.06 | 8.77 | 67.19 | 13.70 | 11.60 | 65.49 | 13.21 | 9.81 | 74.96 |
Median | 8.28 | 7.99 | 62.08 | 11.44 | 10.84 | 61.53 | 11.44 | 9.91 | 69.16 |
Cells + Toxopl. + NPs [%] | 34.0 | 66.0 | 33.5 | 66.5 | 71.03 | 29.0 | |||
Mean | 159.64 | 118.23 | 57.484 | ||||||
Geomean | 76.71 | 19.57 | 156.14 | 142.73 | 23.22 | 117.34 | 27.56 | 15.92 | 106.691 |
Median | 72.34 | 21.29 | 143.30 | 64.94 | 25.71 | 101.82 | 22.275 | 15.96 | 84.292 |
Cells + Toxopl.+ NPs (pentamidine‐loaded) [%] | 37.0 | 63.0 | 35.0 | 65.0 | 69.0 | 31.0 | |||
Mean | 157.60 | 115.67 | 43.75 | ||||||
Geomean | 73.90 | 20.18 | 158.34 | 65.71 | 23.49 | 113.57 | 27.49 | 27.49 | 79.96 |
Median | 67.93 | 21.48 | 144.60 | 61.80 | 25.71 | 95.60 | 25.95 | 17.31 | 68.54 |
Mean values of total cells and gates of Figure 5. In addition to the mean values, the percentage of M1 and M2 of total cells for each part is given.
1,2,3,4 and 5 refer to numbers in discussion.
FACS counts of non‐infected, infected and NPs‐treated cell. Histograms are shown in each case for day 2 of non‐infected cells (A), infected untreated cell controls (B), cells only treated with NPs (C), infected cells treated with unloaded NPs (D) and pentamidine‐loaded NPs (E). The histograms show the changes in green fluorescence (FL1) and number (counts). M1 indicates the non‐infected cells and M2 the infected ones. (T = Toxoplasma gondii).
Simply comparing the mean values of M2 (the gate with the infected cells) would lead to a misinterpretation: the geometrical mean value would indicate that NPs even enhance Toxoplasma multiplication (106.69 vs. 86.41‐labelled with ‘1’ in Table 3), and the median would also suggest this (84.26 vs. 77.04 labelled with ‘2’ in Table 3).
By looking at the percentage, one sees that with NPs, there was an increase in cells in the gate of non‐infected cells (M1: 71.0 vs. 49.5% labelled with ‘3’ in Table 3) and as the mean value of all cells indicates, there was an inhibition by unloaded NPs visible as reduction in green fluorescence (57.48 vs. 63.41 labelled with ‘4’ in Table 3). The median indicates that the inhibition was substantially (22.27 vs. 43.32 labelled with ‘5’ in Table 3).
The mean value of the green fluorescence marker reflects the parasitic load, as fluorescence is proportional to parasite number. Thus, few cells with high numbers of parasites may increase the mean value despite the fact that there were lots of non‐infected cells. The median indicates the shift of the population towards infected or non‐infected cells. The closer the median of infected, treated cells come to non‐infected control cells, the better the treatment success. The geometrical mean gives some information, concerning the heterogeneity, but avoids the overestimation of exceptionally heavy infected single cells.
By measuring 10,000 cells, FACS offered the opportunity to statistically treat these data in different ways, resulting in a more complex interpretation. In addition to this evaluation of data, one had to take into account that nanoparticles are known to stimulate the macrophages [30–32]. As an increase in unspecific fluorescence was seen, an inhibition of Toxoplasma growth by unloaded nanoparticles was not surprising.
The explanation was that the nanoparticles counteracted the suppression of activities caused by the parasites [33], and this unspecific stimulation of macrophages by nanoparticles was more effective than the inhibition of parasites within downregulated host cells.
As cells, treated with nanoparticles, were always used as controls to estimate the unspecific increase in fluorescence, it was realised that there was a substantial inhibition by unloaded nanoparticles in all experiments.
In an additional series of experiments, the effect of nanoparticles without any drug was specifically proven. Data of an experiment to determine the effect of particle number on the multiplication of T. gondii during a period of 3 days are given in Figure 6.
Effect of different concentrations of NPs (MC81cs) on cell proliferation and of Toxoplasmagondii (T. g) growth. (A) A number of all remaining cells (infected and non‐infected) after 1, 2 and 3 days of infection and treatment. (B) A number of free (extracellular) Toxoplasmagondii. There are no Toxoplasma in NPs‐treated, non‐infected cells. (C) A number of infected cells after treatment with different concentrations of NPs.
Part A shows the increase in the infected and non‐infected cells with different NPs concentrations. As can be seen, NPs in a high concentration (conc.4) inhibited proliferation over the 3 days. The lower concentrations led to a small increase on day two and a larger increase on day three. With infected cells, there was no difference between conc. 4 and 3, and only a slight decrease in cells with conc. 2. But with the lowest concentration, conc. 1, there was a decrease over the 3 days.
Part B shows the increase in Toxoplasma in the presence of NPs. Concentrations 4 and 3 suppressed the propagation of Toxoplasma. There was a reduced number of free Toxoplasma compared with the infection control. At concentrations 1 and 2 on the third day, there was a large increase in free Toxoplasma with concentrations even higher than in the untreated control.
Part C shows the number of infected cells which decreased at all NPs concentrations on day two and increased on the third day. The third concentration led to the smallest number of infected cells over the 3 days.
Cells were infected with an MOI of 2. The concentrations of NPs were as follows:
Conc 1: 118,000 NPs/cell | Conc 3: 24,000 NPs/cell |
Conc 2: 60,000 NPs/cell | Conc 4: 12,000 NPs/cell |
As discussed above, the effect of NPs was interpreted as activating the functions suppressed by Toxoplasma. On the other hand, there may be negative effects on macrophage functions, too [34]. Thus, in other cases (with other cells or with other parasites), the effect could be different. If there is stimulation, a treatment with nanoparticles alone could have some influence on a Toxoplasma infection, as drug‐loaded particles have.
One way to prove this is to repeat these experiments in other, non‐phagocytising host cells. The problem is that they will not take up the nanoparticles as easily as the macrophages do. As there are other microorganisms which also multiply within macrophages, there could be other indications for this type of treatment.
In all experiments described so far, Toxoplasma and NPs were added simultaneously to the cells. When nanoparticles influence the activities of phagocytising cells, and T. gondii alters the host cell activities, it is interesting to ask, whether the presence of NPs or T. gondii interferes with the taking up of the other, is there some type of mutual exclusion? Thus, experiments were carried out with NPs, added four hours after infection with T. gondii, or cells were infected 4 h after treatment with NPs. There were no differences in the taking up of NPs or parasites or in the effect of treatment after 3 days. The slope of the parameters was simply shifted (data not shown).
In the future, one will see, whether Leishmania major which in contrast to T. gondii are able to grow only in macrophages and are also inhibited by unloaded NPs. A few reports indicate that this should be true [21]. With Leishmania, first data in animal models were published [35, 36]. The fact that Leishmania major multiplies only in phagocytising cells makes them even more interesting for a further use of nanoparticles.
A question to be answered is, whether there is disintegration of nanoparticles by the host cells. There was fluorescence on the third day, what could be the result of dye released after disintegration? Microscopical observation revealed that nanoparticles were still present, at least the non‐degradable, fluorescence‐labelled polystyrene cores of these core‐shell nanoparticles.
With the methods used, a disintegration of the nanoparticles could not be demonstrated in detail as it should start with the cleavage of the ester groups of the polymer shell by esterases which would not alter the structure in a way that could be seen with a microscope. As it only happens inside the cells, this alteration cannot be found with FACS, as there is no change in granularity.
As the core particles remain undigested, granularity will indicate the presence of particles. In the case that there would be no disintegration, this may be an advantage of an in vitro system using phagocytising cells, as the activation will persist. The consequences for in vivo conditions remain to be determined. Allen showed in 1988 that repeated application of liposomes could led to an impairment of Kupffer cells in the liver and fixed macrophages in the spleen which remove most of these NPs [37].
Our aim was to establish a system which allows the observation of the interaction of nanoparticles and microorganisms, infecting a cell culture, because there should be difference between infected and non‐infected cells which could be used for targeting. The results are very promising. As various cell lines are able to produce interleukins or other modulators, there is the possibility to characterise the influence of nanoparticles in even more detail.
The data that NPs without any drugs have the same effect as drug‐loaded NPs offer the opportunity to use NPs directly for treatment. Perhaps part of the effect of Atovaquone crystal nanoparticles in a Toxoplasma‐mouse model should be attributed to the effect of nanoparticles [13], rather than to the direct effect of the drug against the parasite.
Core‐shell latex nanoparticles (MC81cs see Table 1) were synthesised by seeded, aqueous polymerisation of butyl cyanoacrylate onto polystyrene cores. Polystyrene cores were prepared by emulsion polymerisation of styrene in a water/ethanol mixture (16:1; v/v) in the presence of rhodamine B and purified by dialysis against deionised water. One gram of these core particles in water with a pH of 2 was used as seed for the polymerisation of 2 g butyl cyanoacrylate [38]. In the case of pentamidine loading, 5 mg pentamidine/g polymer was added to the polymerisation medium. Resulting core‐shell nanoparticles were purified by dialysis against de‐ionised water after neutralisation with sodium hydroxide (1 M aqueous solution).
The particle size, determined as Zave (average particle diameter) and the polydispersity index (PI), was measured by photon correlation spectroscopy (PCS), using a Zetamaster S (Malvern Instruments). Electrophoretic mobilities were measured to reflect the effective surface charge (Zetamaster S, Malvern Instruments). For transformation into zeta potential, the Smoluchowski model for ideal smooth spheres was used. Measurements were carried out in ultra‐pure water (Millipore), 0.01 M NaCl solution and in 0.001 M NaCl solution.
Surface charge density was titrated by means of 0.1 mM PDADMAC solution (MW approx. 100,000) at a combination of particle charge detector PCD‐03 pH (MÜTEK) and automatic titrator Titrino 716 (Metrohm). Purified, aqueous nanoparticle suspensions were stored in the refrigerator until use.
‘Perfect Counting Beads’ (Caltag Laboratories) were used to adjust the cell and T. gondii number. Immediately before counting with FACS, a defined number of beads were added and for calculation of inhibition and growth, all cells and T. gondii were adjusted to the known bead concentration.
Tachyzoites of the RH (CAT‐GFP) strain of T. gondii (obtained from D. Soldati; Centre of Molecular Biology, Heidelberg University, Germany) were maintained in vitro in human epitheloid carcinoma cells (HELA) by serial passage into RPMI medium supplemented with 10% FCS (Gibco‐BRL) twice a week (Gibco‐BRL).
Macrophages and parasites were counted in a Fuchs‐Rosenthal chamber and adjusted to the concentrations indicated. In most cases, macrophages of a concentration of 1.36 × 105 per ml were used and the multiplicity of infection (MOI) in most experiments was 2.
Macrophages: The intracellular Toxoplasma infection studies were performed on J 774‐A1 cells (mouse monocyte macrophages, ACC 170; German Collection of Microorganisms and Cell Cultures). The macrophages were grown in Dulbecco\'s MEM containing 10% heat‐inactivated foetal calf serum (Boehringer, Germany) at 37°C in 5% CO2 atmosphere.
Parasites, infected cells and non‐infected cells were counted with FACS‐scan analytical flow cytometry and equipped with a 15 mV, 488 nm air‐cooled argon ion laser (Becton Dickinson). Multiparametric data were analysed using CellQuest® Software. Ten thousand ‘particles’, defined by size and granularity, were measured for each analysis.
The optimised instrument parameters for the assay were as follows: forward scatter (E 00, log mode), side scatter (319 voltage, log mode) fluorescence 1 (FL1; 613 voltage, log mode) and fluorescence 2 (FL2; 528, log mode).
Each experiment was carried out in a triple manner and performed in a special laboratory. The equipment was decontaminated with FACS‐safe solution (1% active chlorine, Becton Dickinson).
Adding formaldehyde to a final concentration of 0.2% resulted in a preservation of the samples. Samples could be stored for days in a refrigerator and be measured at a more convenient time.
An epifluorescence microscope (Axioskop; Zeiss) was used to view the infection fate of J774 A1 cells with T. gondii GFP. The microscope was equipped with a 50 W high‐pressure mercury lamp (HB050; Osram) and 10×, 40× and 100× objectives (Zeiss). Narrow band filter sets HQ‐F41‐007 and HQ‐F41‐001 (AHF Analysentechnik) were used to analyse the GFP and red signals, respectively, at a magnification of 1000×. Image processing was performed with a standard software package delivered with the instrument (Zeiss Axiovision 3.1).
Solitary plasmacytoma (SP) is an infrequent form of plasma cell neoplasm according to literature data, accounting for between 5–10% of all plasma cell neoplasms.
It is characterized by the presence of neoplastic monoclonal plasma cells that do not have systemic distribution, but gather in limited locations even if there is no systemic proliferative plasma cell disease.
We can divide it into 2 groups: solitary bone plasmacytoma (SBP) and extramedullary plasmacytoma (EMP).
When the localization is prevalent in the bones of the axial skeleton, type skull, vertebrae, etc. we speak of solitary plasmacytoma of the bone (SBP), while EMP, as a localization, is frequent in the nasal cavities and in the nasopharynx.
The mean age of patients with SBP or EMP, with a male–female ratio of SP 2: 1, is 55 years.
With advancing age, the incidence rate increases exponentially while maintaining a lower incidence compared to multiple myeloma (MM).
In the black race the impact of the SP is about 30% higher than in the white race. [1]
A great help in the better definition of the tumor mass was obtained with the FDG-PET, Positron emission tomography-computed tomography, [2] that allows direct visualization of the tumor burden, combining the morphological images of the CT scan with a particular molecular process (depending on the radiopharmaceutical injected) the most widely used radiopharmaceutical agent is a glucose analogue which allows to evaluate the response to treatment and the prognosis of different cancers.
The limit of the skeletal X-ray investigation of the whole body (WBXR), is represented by showing only osteolysis related to the presence of MM cells, while the FDG-PET allows to view the tumor load.
Obviously, this investigation is not without limitations, one of these are the false negative or false positive results, possible, if inflammatory or infectious processes in progress, as well as subcentimetric lesions cannot be detected by the FDG-PET.
Aid is provided by the combined CT component, which provides higher resolution bone images than that obtained with normal radiography.
Through a direct anatomical correlation of FDG uptake foci.
The systematic review reported by Van Lammeren-Venema et al. [3] also compared FDG PET and FDG PET/CT with WBXR and CT.
The detection rate of FDG PET/CT, compared with WBXR, ranged from 1.27 to 1.45; specificity was low (29–50%) and sensitivity ranged from 67 to 100% when using WBXR as a reference test. Regelink et al. mentioned that FDG-PET underestimates rib lesions, as it could be detected by low-dose CT integrated into PET.
A limitation, to date not resolved, is the detection of cranial lesions that FDG-PET / CT does not detect due to the high absorption of FDG in the brain, while the identification of extramedullary disease was satisfactory with FDG-PET, given this reported consistently in studies comparing FDG-PET/CT with WBXR.
Other PET radiopharmaceuticals have been developed to visualize various biological processes, in addition to FDG which is specific to glucose metabolism, among these we can mention 18F fluoride being re-evaluated for skeletal imaging, and the 11C-methionine amino acid analogue. and 11C-choline, an analogue precursor of phosphatidylcholine, one of the main constituents of membrane lipids, which to date have only been evaluated in small series of patients with MM.
Multiple myeloma [4], is a clonal malignant plasma cell neoplasm that despite the development of new therapies that have improved the depth and duration of responses as well as survival, to date this disease remains incurable in most cases for many patients.
Understanding the biology of disease, technological advances, such as next-generation sequencing techniques, have shown that the disease is genetically extremely heterogeneous and this has allowed us to stratify patients, based on risk, into different disease groups. Given this that can significantly translate into the choice of therapy and clinical results.
Simultaneously with these new acquisitions the therapeutic scenario has been completely revolutionized by the discovery of new therapeutic agents, including immunomodulatory drugs (IMiDs) such as Lenalidomide and Pomalidomide; proteasome inhibitors (PIs) including Bortezomib, Carfilzomib and Ixazomib; monoclonal antibodies (MAbs) including Daratumumab and Elotuzumab; and histone deacetylase inhibitors such as Panobinostat which have helped improve and improve the overall survival of patients with this disease.
The use of many new therapeutic agents, in addition to increasing therapeutic choices, has also changed our therapeutic reference models, in fact, over the years the treatment of patients with this pathology has mainly been based on high-dose radiation, but to date, in consideration of the new drugs available to us, studies are needed to evaluate their use and benefit also in this category of high-risk patients.
A 58 year old woman was diagnosed asyntomatic Multiple Myeloma Ig G K International stage system (ISS) II.
She first presented in march 2018 in March 2018 because about 15 days before she was admitted to the nephrology department for acute renal failure, macrohematuria, hydronephrosis, renal colic.
For the confirmation during the hospitalization from the laboratory tests of the monoclonal component it was sent to our clinic.
Physical examination was negative.
The blood chemistry tests showed protein electrofhoresis showed a monclonal spike (M spike) 1 gr /dl: IgG tests 1000 mg / dl, IgM 34 mg / dl, IgA 44 mg / dl, serum Kappa light chains 294 mg / dl, serum lambda light chains 24 mg / dl Kappa light chains urine 187 mg / L, Lambda urine light chains <4.7 mg / dl, FLC ratio is 58, beta 2 microglobulin: 4.3 mg /L, Hb 13 gr/dl, normal creatinine and calcium, proteinuria 0.8 g/24 h, microalbubinuria 68 mg/L.
At the evaluation of the bone biopsy the plasma cell clonality was equal to 10–40%. At the phenotypic analysis and morphological examination plasma cells infiltrate was equal to 24%. (Table 1).
IMMUNOPHENOTYPIC STUDY IN FLOW CYTOMETRY METHOD USED DIRECT IMMUNO FLORESCENCE Antigens studied: CD19, CD38, CD 138, CD 56, CD 45 RESULT CLONAL MYELOMA PLASMA CELLS: CD 138+ CD 38++ CD19-CD56+ bright CD 45 NEG = 24% |
Phenotypic analysis of bone biopsy.
The karyotype analysis was 46 XX normal karyotype, the FISH study showed the TP53 in 35% of the nuclei analyzed.
Whole body MRI: no bone lesions, negative the Total Body CT.
Therefore, we have started the patients for periodic checks.
After one year from diagnosis, in May 2019 she reported back pain for which performed blood tests and instrumental tests TB CT and MRI.
The Total Body CT showed: “In a context of widespread reduction in calcium content, suspicious osteostructural alterations due to secondary disease localization of the skeletal segments included in the study volume are not appreciated. Apex cuneiform deformation of the anterior trunk of D12, widespread spondyloarthrosis manifestations. No focal tomodensitometric alterations of current pathological significance affecting the lung parenchyma bilaterally. Non-ilo-mediastinal and laterocervical lymphadenomegaly. Non-pleural -pericardial effusion. No gross changes affecting the abdominal parenchymatous organs, distended bladder with regular walls, no adenomegaly at the level of the main abdominal-pelvic lymph node stations, no free abdominal fluid “.
Unlike the CT, the MRI of the abdomen showed: “collapse of D12 and pathological tissue with a paravertebral site with abdominal tissue formation that concentrically englobes the aorta and pleural effusion.
The MRI of dorsal and lumbar spine showed: at the level of the interbody space D11-D12 presence of posterior median disc protrusion, at the level of the interbody space D12 -L1 presence of protrusion of the annulus fibrosus with posterior median expression.
The spinal cord presents regular morphology and no pathological signal.
At the level of the interbody space L 3-L4 and L5-S1 presence of disc protrusion.
The body of D12 appears crushed and deformed into a wedge, the vertebral body itself exhibits a hypointense signal in the images in T1 as from the presence of spongiosa edema in vertebral distress, probably of a recently established post traumatic type, also at the dorsal level it is possible to document the presence of a sleeve that seems to envelop the vertebral structures, in the front and in the antero-lateral position bilaterally and which extends from D12 to D5.
Bilaterally concomitant with the presence of a payment.
From the blood tests emerged: lipase increase 995 U / L, monoclonal component: 2.6 gr / dl, creatinine 1 mg / dl, calcium 9.8 mg / dl, LDH 172 U/l, HB 12.49 gr / dl, protein in the urine: 1, 4gr/24/ h, Kappa light chains urine 604 mg / L, beta 2 microglobulin 5.2 mg / dl, creatinine clerance 68 mm/h, serum K light chains 570 mg / dl, creatinine clerance 63 ml/min, microalbuminuria 98 mg /L, immunoglobulins IgG 1950 mg / dl, IgA immunoglobulins 20 mg / dL, IgM immunoglobulins 22 mg/dL.
The radiotherapy evaluation did not indicate treatment and she was treated with VTD (Bortezomib 1.3 mg/m2 days 1,4,8,11, −thalidomide 100 mg/day, and dexamethasone 40 mg days 1,4,8,11) for six cycles, obtaining only temporary biochemical partial response but extramedullary progression with increased pleural effusion.
Indeed the total body PET/CT was performed (3.12.19) which highlighted: “presence of a very large area of net and inhomogeneous pathological hyperaccumulation of radio glucose coinciding with dense tissue on the co-registration CT, which is extended, in front of the rachis, from the first dorsal metamers (D3/D4) to the upper limiting of the soma of L5, displacing and, at times, partially incorporating the posterior mediastinal structures (esophagus) along its course, and, more completely, the large thoraco-abdominal vessels up to the aorto-iliac “carrefour”, with SUV max up to 9.7.
A circumscribed and apparently more isolated area of pathological hyperaccumulation is observed at the height of the right lung apex, in the paravertebral, at the level of D2.
Isolated pathological hyperaccumulations of radioglucose are found in the anterior mediastinum, coinciding with pleuro-pericardial pseudonodulation, at the height of the posterior aspect of the xiphoid, in the right parasternal in the context of the chest wall, in the form of two circumscribed areas of which the most voluminous with Standardized uptake value max 7.0 and the other smaller max 5.7.
On an ancillary basis, the co-registration CT images include extensive pleural effusion on the right and relatively more modest on the left. (Table 2).
Image of PET.
We also decided to performed the phenotypic analysis on peripheral blood showed Plasma cell equal to 1.6%* (Table 3).
IMMUNOPHENOTYPIC STUDY IN FLOW CYTOMETRY METHOD USED DIRECT IMMUNO FLORESCENCE Antigens studied: CD19, CD 20, CD 138, CD38, CD 56, CD 45, intracytoplasmatic chains kappa and lambda RESULT Mature lymphocytes = 8,6% CLONAL MYELOMA PLASMA CELLS: CD 138+ CD 38++CD19-CD56+ bright, CD 45 low with kappa clonal restriction = 1,6% |
Phenotypic analysis on peripheral blood.
She repeated bone marrow biopsy which that showed plasma cell infiltration on morphological examination equal to 70%, while the phenotypic analysis on bone marrow blood showed Plasma cell CD138+ CD38++ CD19- CD56 + bright CD45 low with clonal kappa restriction of intracytoplasmic = 13%* (Table 4).
IMMUNOPHENOTYPIC STUDY IN FLOW CYTOMETRY METHOD USED DIRECT IMMUNO FLORESCENCE Antigens studied: CD19, CD 138, CD38, CD 56, chains kappa and lambda RESULT Mature lymphocytes = 20% CLONAL MYELOMA PLASMA CELLS: CD 138+ CD 38++CD19-CD56+ bright, CD 45 low with kappa clonal restriction = 13% |
Phenotypic analysis on bone marrow blood.
Therefore we decided to subject the patient to therapy with cyclophosphamide (1.5 gr/die, day 1 e day 3) for debulking plus evacuative thoracentesis, unfortunately we did not perform phenotypic study of the pleural fluid, and subsequently we started therapy with Daratumubab lenalidomide and dexamethasone (Daratumubab was initiated at the standard dose of 16 mg/kg for week IV for 4 infusions plus lenalidomide 25 mg daily for 21 of 28 days, and dexamethasone 40 mg on week (Dara Rd) .
The treatment was well tolerated and no pulmonary or hematological adverse events occurred.
After one cycle of Dara Rd. therapy, for new reappearance of pleural effusion, the patient underwent thoracentesis; this time by performing the phenotypic analysis (Table 5).
IMMUNOPHENOTYPIC STUDY IN FLOW CYTOMETRY METHOD USED DIRECT IMMUNO FLORESCENCE Antigens studied: CD3, CD3/4, CD 3/CD8, CD19, CD16–56, CD117, CD 138, CD38, CD45, intracytoplasmatic chains kappa and lambda RESULT Mature lymphocytes = 60% CLONAL MYELOMA PLASMA CELLS: CD 138+ CD 38-, CD56+, CD 45 + heterogeneous, cy kappa + = 10% |
Phenotypic analysis of pleural effusion.
While the plasma cells are absent to the re-evaluation of the phenotypic study on peripheral blood and so we continued the treatment until the fourth cycle.
After 4 cycles of therapy we repeated PET/CT that was unfortunately compatible with persistence of disease.
The PET/CT showed persistence of a large area of hyperaccumulation of the tracer in coincidence of pathological tissue from D3 to L5 that incorporates the posterior mediastinal structures in its course.
Persistence of pathological accumulation in the anterior mediastinum, in the pleuro-pericardial region in increase compared to the previous examination, extending from the xiphoid to the anterior costophrenic recess, area of hyperaccumulation in the right parasternal and at the level of the mediastinal pleura close to the ascending aorta.
Despite the progression of disease the CD38 negativity remained to the phenotypic re-evaluation of the pleural fluid (Table 6).
IMMUNOPHENOTYPIC STUDY IN FLOW CYTOMETRY METHOD USED DIRECT IMMUNO FLORESCENCE Antigens studied: CD 19, CD 56, CD 138, CD38, CD45, cyVS38c. RESULT Mature lymphocytes = 40% CLONAL MYELOMA PLASMA CELLS: CD 138+ CD 38-*, CD56 + bright, cyVS38c+, CD 19- = 7,5% *Therapy with Daratumubab |
Phenotypic analysis of pleural effusion.
CD38 [5] is a transmembrane glycoprotein that is highly expressed on multiple myeloma cells and on normal lymphoid and myeloid cells albeit at low levels.
the mechanism of action is that of an ectoenzyme involved in the regulation of the intracytoplasmic concentration of calcium and of the catabolism of extracellular nucleotides.
The anti-CD38 fully human IgG1-k monoclonal antibody, Daratumumab, carries out its cytotoxic effect through a series of mechanisms following binding to CD38, including antibody-dependent cell-mediated cytotoxicity (ADCC), complement-dependent cytotoxicity (CDC), antibody dependent cell-mediated phagocytosis (ADCP) and direct induction of apoptosis are its main mechanisms of action.
another effect of Daratumumab recently described is its immunomodulatory action.
A phase I/II dose escalation study in 104 patients with relapsed or refractory multiple myeloma evaluated the safety of Daratumumab.
The most common adverse events were grade 3 or 4 pneumonia and thrombocytopenia.
Two phase [5] III studies are evaluating patients with relapsed or refractory disease; one of these studies is comparing Daratumumab plus bortezomib and dexamethasone versus bortezomib and dexamethasone and the other is comparing daratumumab plus lenalidomide and dexamethasone versus lenalidomide and dexamethasone.
Pending the final results of these studies, however, we want to underline how the CASTOR study (Velcade / dex versus Dara /Velcade/ dex) was interrupted early because at an interim analysis the study reached its final point with a ratio of very impressive risk of 0.39 in favor of the Daratumumab arm. The POLLUX study (Rev / dex vs. Dara/Rev./dex) also showed similarly impressive results with a hazard ratio of 0.37 in favor of the Dara arm. Two further Phase III studies are ongoing in patients with previously untreated multiple myeloma; one is comparing Daratumumab plus bortezomib, melphalan, and prednisone with bortezomib, melphalan and prednisone) and the other is evaluating Daratumumab plus lenalidomide and dexamethasone with lenalidomide and dexamethasone.
We wanted to report this clinical case only to hypothesize a possible role of Daratumumab in the treatment of extramedullary recurrences and above all its possible overcoming of the pleural barrier.
The selection of resistant clones is known in the course of myeloma recurrence, but the negativity/masking of CD 38 in the pleural fluid could demonstrate the overcoming of the pleural barrier by Daratumubab.
Obviously we have no previous data, but the phenotypic analysis of the marrow and peripheral blood is the same for the other antigens evaluated.
Most likely we should have performed a PET/CT at the onset of staging for a better evaluation of any extramedullary localization and perhaps choose different or more aggressive therapeutic treatments.
Molecular biology studies certainly in the near future will help us better understand which forms are most at risk and perhaps will guide us better in therapeutic choices.
But to date, the treatment of extramedullary plasmacytoma remains a therapeutic challenge even in the era of new drugs.
Despite significant progress in the treatment of multiple myeloma, the disease remains incurable in a vast majority of patients.
The approval of promising new agents will undoubtedly improve outcomes for myeloma patients.
Daratumumab is a monoclonal antibody that is now approved for treatment of multiple myeloma patients and has shown significant response in the real world setting.
Our case illustrates the potential to overcome the pleural membrane and therefore a possible role also in the treatment of extramedullary localizations of multiple myeloma.
We thank the nursing staff of the Department of Hematology Hospital San Giuseppe Moscati Taranto Italy who collaborated in the production of this work and especially:
Luciana Angela Talo’ for the patient management and Elisabetta Leggieri and Tamburrano Addolorata for the therapy management.
The authors declare no conflict of interest.
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