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Synthesis of polyelectrolyte nanocapsules with iron oxide (Fe3O4) nanoparticles for magnetic targeting
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Synthesis of polyelectrolyte nanocapsules with iron oxide (Fe3 O4 ) nanoparticles for magnetic targeting Karolina Podgórna, Krzysztof Szczepanowicz ∗ Jerzy Haber Institute of Catalysis and Surface Chemistry Polish Academy of Sciences, Niezapominajek 8, 30-239 Krakow, Poland
h i g h l i g h t s
g r a p h i c a l
a b s t r a c t
• Performance synthesis of polyelectrolyte coated magnetically responsive nanocapsules for targeted drug delivery. • Zeta potential and size of the magnetic nanocapsules determined with electrophoretic mobility, light scattering measurements and nanoparticle tracking analysis. • Response of magnetic nanocapsules on constant magnetic field evaluated by direct visualization.
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Article history: Received 30 October 2015 Received in revised form 9 February 2016 Accepted 10 February 2016 Available online xxx Keywords: Encapsulation Targeted drug delivery Magnetic properties Layer by layer Nanocapsules Iron oxide magnetic particles
a b s t r a c t Magnetic vehicles have become highly promising for delivery of therapeutic actives as they can be targeted to selected pathologically changed tissues/cells through the application of a magnetic field gradient. The aim of this work was to prepare and characterize nanocapsules with iron oxide nanoparticles for magnetic targeting. Nanocapsules were prepared by encapsulation of oil droplets containing hydrophobic Fe3 O4 nanoparticles (NP) in polyelectrolyte shells, using the layer by layer technique. The average size of synthesized nanocapsules was ∼100 nm and the batch concentration was 1011 nanocapsules/ml. Morphology of magnetic carriers were investigated by Cryo-Scanning Electron Microscopy. © 2016 Elsevier B.V. All rights reserved.
1. Introduction Selective targeting of therapeutic agents is one of the greatest challenges for modern medicine. Increasing concentration and
∗ Corresponding author. E-mail address: [email protected] (K. Szczepanowicz).
bioavailability of drugs, prolonging circulation of actives in the body fluids, is essential for future success of many therapies (e.g. cancer, diabetes) [1–3]. Targeted drug delivery systems are extremely significant in cancer therapies since serious side effects are related with unspecific accumulation of highly toxic chemotherapeutics in healthy tissues that have direct influence on therapy efficiency [4]. A number of novel drug carriers have been design to achieve controlled
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Please cite this article in press as: K. Podgórna, K. Szczepanowicz, Synthesis of polyelectrolyte nanocapsules with iron oxide (Fe3 O4 ) nanoparticles for magnetic targeting, Colloids Surf. A: Physicochem. Eng. Aspects (2016), http://dx.doi.org/10.1016/j.colsurfa.2016.02.017
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Fig. 1. Formation of nanocapsules core (MN core) with Fe3 O4 nanoparticles (NP) and adsorption of subsequent layers of polyelectrolytes.
and targeted drug delivery. Systems based on micelles, vesicles, nanospheres and nanocapsules are commonly used for transport of therapeutic agents [5–7]. Nanocapsules are typically colloidal particles with size from 10 to 1000 nm. They consist of colloidal core and polymeric shell. One of the most promising methods to form nanocapsules is the layer-by-layer (LbL) technique. Since 1998 when Shukorukov et al. [8], proposed the methodology of forming polyelectrolyte multilayers on solid particles by the layer by layer approach, it has been the subject of intensive research and further extended to other types of cores including liquid cores e.g. emulsion droplets [9–17]. Various drug targeting strategies has been developed, of which one of the most fascinating is the magnetic targeting, where an active substance or active carrier is bound to magnetic species, injected into a patient’s blood stream, and then it is accumulated with a powerful magnetic field in the target area [18–20]. Polyelectrolyte nanocapsules formed by the LbL technique can also be functionalized by magnetic nanoparticles and that type of magnetically responsive nanocapsules could be guided with magnetic field gradients and therefore, could transport the biologically active components with an optimum therapeutic concentration of the pharmaceuticals to the desired tissue of the organism [21]. There are two general approaches proposed to incorporate magnetic species into polyelectrolyte carriers: the incorporation into polyelectrolyte shell where magnetic nanoparticles are used as building blocks of a shell (deposited via LbL approach or directly synthesized in formed polyelectrolyte layer) [22,23] or their incorporation in a capsule core [24,25]. In our previous work, we functionalized our liquid core—polyelectrolyte shell nanocapsules by incorporation of hydrophilic Fe3 O4 nanoparticles into multilayer shell to form magnetically responsive nanocarriers [26]. Magnetic nanoparticles were embedded in a polyelectrolyte shell through the LbL approach. In this paper we were focused on encapsulation of hydrophobic magnetic nanoparticles (various sizes) in emulsion cores of polyelectrolyte nanocapsules as the alternative way to provide magnetic functionaliy. Furthermore, the obtained magnetic nanocapsules were characterized by size, size distribution, zeta potential and concentration and visualized by Cryo-SEM.
chloride, were obtained from Sigma-Aldrich Poznan, Poland. PLL(20000)-g[3.5]-PEG(5000) PLL-g-PEG copolymer was obtained from SuSoS AG Dübendorf, Switzerland. Toluene and ethanol were obtained from Avantor Performance Materials Gliwice, Poland. All materials were used without further purification. The distilled water used in all experiments was obtained with the three-stage Millipore Direct-Q 5UV purification system. 2.2. Nanocapsules’ synthesis Magnetic nanocapsules cores (MN core) were prepared by a modified method described before by Szczepanowicz et al. [15]. Briefly, nanocapsules were formed by addition of hydrophobic phase containing AOT anionic surfactant (340 g/dm3 ), Fe3 O4 nanoparticles (0.5 g/dm3 for 5 nm and 10 nm nanoparticles and 0.25 g/dm3 for 20 nm nanoparticles) in the mixture of toluene:ethanol (1:100), to polycation solution (PLL in 0.015M NaCl, natural pH) under gentle mixing with a mechanical stirrer. That was used instead of mixing by magnetic stirrers to avoid aggregation of magnetic species. The optimal ratio of surfactant and polycation were determined by measuring zeta potential of emulsion drops and examining their stability. Stable emulsion was obtained when zeta potential of emulsion drops with adsorbed polyelectrolyte layer reached the constant value [27] just after overcharging. The LbL deposition was performed using the saturation procedure, with PLL as the polycation and PGA as the polyanion [28] to form polyelectrolyte multilayer shell. Fixed volume of
2. Experimental 2.1. Material and reagents The toluene suspension of Fe3 O4 nanoparticles (NP) 5 nm, 10 nm and 20 nm at concentration 5 mg/ml, biocompatible polyelectrolytes Poly-l-lysine hydrobromide PLL (MW ∼ 15000–30000), and Poly-l-glutamic acid sodium salt PGA (MW ∼ 15000–50000), oil soluble surfactant docusate sodium salt AOT ≥99%, sodium
Fig. 2. Example of determining the optimal surfactant/polyelectrolyte ratio: the dependence of zeta potential of AOT/PLL-stabilized nanoemulsion droplets—nanocapsules’ cores (MN cores) on PLL/AOT ratio (star denotes the optimal ratio of PLL/AOT used to form a stable polyelectrolyte layer).
Please cite this article in press as: K. Podgórna, K. Szczepanowicz, Synthesis of polyelectrolyte nanocapsules with iron oxide (Fe3 O4 ) nanoparticles for magnetic targeting, Colloids Surf. A: Physicochem. Eng. Aspects (2016), http://dx.doi.org/10.1016/j.colsurfa.2016.02.017
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Fig. 3. Example of determining optimal nanocore/polyelectrolyte ratio: the dependence of zeta potential of nanocapsules core on PGA/MN core ratio (star: optimal ratio of PGA/MN core used to form stable second layer).
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Fig. 4. Layer-to-layer variations of zeta potential of MN 5 nm n-layers nanocapsules (n number of layers).
2.4. Nanocapsules’ zeta potential determination nanoemulsion suspension was added to the oppositely charged polyelectrolyte solution (PGA in 0.015M NaCl) under mixing with mechanical stirrer and the shell formation was followed by the measurements of zeta potential of the suspension. The procedure of sequential deposition of PLL and PGA layers was repeated until a required number of polyelectrolyte layers of the shell were formed. After preparation of stable nanocapsules toluene and ethanol were evaporated because of their toxicity. To create pegylated nanocapsules, PGA-terminated hybrid nanocapsules with six layers were coated with the layer of PLL-g-PEG using the same procedure as described above, i.e., by adding nanocapsules (PGA terminated) into filtered PLL-g-PEG polymer solution.
The zeta potential of magnetic nanocapsules and polyelectrolytes was measured by the microelectrophoretic method using Malvern Zetasizer Nano ZS apparatus. Each value was obtained as an average from three consecutive measurements with 20 runs. All experiments were performed at 25 ◦ C in 0.015M NaCl. 2.5. Nanocapsules’ stability studies To evaluate the colloidal stability of magnetic nanocapsules, their freshly prepared suspensions, were stored in 0.015M NaCl at room temperature. Size distribution (hydrodynamic diameter) and zeta potential of nanocapsules were measured just after preparation and after appropriate storage time as described above.
2.3. Nanocapsules’ size and concentration measurements
2.6. Nanocapsules’ visualization
Size distribution (hydrodynamic diameter) of magnetic nanocapsules (MN) was determined by DLS (Dynamic Light Scattering) using Zetasizer Nano Series from Malvern Instruments. Measurements were performed in optically homogeneous square polystyrene cells and with the detection angle of 173◦ . Each value was obtained as average from three runs with at least 20 measurements. Moreover, size distribution and concentration was measured by NTA (Nanoparticle Tracking Analysis) using NanoSight NS500. All measurements were performed at 25 ◦ C in 0.015M NaCl.
For the cryo-SEM imaging a droplet of capsules suspension was put on the cold sample holder. Then the holder was attached to the transfer rod and immediately immersed (frozen) in liquid nitrogen using Quorum PPT2000 cryo-preparation stage (Polaron, Quorum Technologies, United Kingdom). The holder with the frozen sample was cryo-transferred at the temperature of liquid nitrogen vapors to the chamber of the cryo-unit where the sample was subjected to sublimation at −70 ◦ C for 15–30 min. (until all visible ice crystals disappeared). The sample was then sputter coated with platinum (5 nm thickness). Following coating, specimen was transferred to
Fig. 5. Zeta potential distribution of formed pegylated nanocapsules MN 5 nm 6L-PLL-g-PEG.
Please cite this article in press as: K. Podgórna, K. Szczepanowicz, Synthesis of polyelectrolyte nanocapsules with iron oxide (Fe3 O4 ) nanoparticles for magnetic targeting, Colloids Surf. A: Physicochem. Eng. Aspects (2016), http://dx.doi.org/10.1016/j.colsurfa.2016.02.017
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Fig. 6. The example of Cryo-SEM micrograph of nanocapsules core containing 5 nm Fe3 O4 nanoparticles.
Fig. 7. Stability of magnetic nanocapsules suspensions: dependence of size and zeta potential of nanocapules (MN core 5 nm and MN 5 nm 6L-PLL-g-PEG) on time.
the cooled stage of the Jeol JSM 7600F field emission scanning electron microscope FESEM (Jeol Ltd., Tokyo, Japan). 3. Results and discussion 3.1. Synthesis of magnetic nanocapsules The results of ours previous studies have indicated that iron oxide nanoparticles can be successfully incorporated in polyelectrolyte shell of nanocapsules [25]. In this paper we decided to propose another approach for the incorporation of iron oxide magnetic particles in our carriers. We encapsulated hydrophobic Fe3 O4 nanoparticles with various sizes (5, 10 and 20 nm) in the liquid cores of nanocapsules (Fig. 1). Nanoemulsion containing hydrophobic iron oxide nanoparticles was prepared according to method proposed previously [26], assisted by ouzo effect [29]. For the preparation of the emulsion of capsule cores, 0.1 ml of hydrophobic phase containing anionic, FDA approved surfactant AOT (34%), hydrophobic Fe3 O4 nanoparticles (5, 10 or 20 nm), toluene and ethanol was added to aqueous solution (0.015M NaCl) of polycation PLL 0.2 g/dm3 . Volume of
polycation PLL solution used to form stable interfacial AOT/PLL complex used as stabilizer for liquid core was determined by zeta potential measurements. The optimal volume of polyelectrolyte was chosen when zeta potential of formed droplets reached constant value close to the value obtained for free polyelectrolyte in solution. In those conditions the amount of free unadsorbed polyelectrolyte in the emulsion was minimized as most of it was consumed to form AOT/PLL interfacial complex [27]. The optimal ratio of polycation PLL to surfactant (AOT) was 1.21 [g/g] (Fig. 2). After 3 h of mixing under mechanical stirrer, nanoemulsion containing magnetic nanoparticles was left to evaporate toxic solvents. The average size of obtained nanocores determined by Dynamic Light Scattering (DLS) and Nanoparticle Tracking Analysis (NTA) was ∼70, 80 and 90 nm for cores with NP 5 nm, 10 nm and 20 nm, respectively, (Table 1) with the polydispersity index (PDI) <0.25. The zeta potential of suspension of nanocores was ∼+60 mV for each type of carrier, which indicated that the surface charge was high enough to prevent aggregation through the electrostatic stabilization. Various encapsulation efficiency of hydrophobic Fe3 O4 nanoparticles was observed for various nanoparticles sizes. For iron oxide magnetic particles with size 5 and 10 nm maximum concentration achieved was 0.0025 mg/ml. Two times lower concentration was achieved for 20 nm magnetic particles 0.00125 mg/ml. Above this values, precipitation of magnetic nanoparticles from nanocapsules suspension was observed. On such prepared nanocores containing magnetic nanoparticles, the sequential adsorption of polyelectrolytes by the saturation method was performed to form a polyelectrolyte multilayer shell. The biocompatible polyelectrolyte pair was used: PGA as the polyanion and PLL as the polycation. Fixed volume of positively charged nanocores suspension was added to the polyanion solutions (2 g/l 0.015M NaCl) under mechanical stirring, to form stable second layer. Volumes of PGA solution used to form a second polyelectrolyte layer were chosen empirically by analyzing the results of the simultaneous zeta potential measurements and were found optimal when the zeta potential of formed capsules reached the constant value just after overcharging (Fig. 3). By applying this approach the amount of unadsorbed PGA in the nanocapsules’ suspension was minimized, as most of it was used to form polyelectrolyte layers on nanocapsules. The zeta potential of formed nanocapsules was reversed to −42 mV. This process was repeated to obtain the desired number of layers. Fig. 4 shows a typical zig-zag dependence of the zeta potential of nanocapsules on the polyelectrolyte deposition cycle, which can be considered as the evidence of the formation of consecutive layers of capsules’ shells. After formation of polyelectrolyte shell with 10 polyelectrolyte layers, size of the nanocapsules increased by ∼30 nm with respect to the initial size of capsules’ cores (cf. Table 1). Polymeric shell was further modified, by PEG-ylation, in order to provide additional steric stabilization in body liquids. Moreover, PEG-ylation prevents nanocapsules from the process of opsonization, thus, the clearance by the immune system and macrophage uptake may be avoided Table 1 Size distribution of nanocores with Fe3 O4 nanoparticles (MN core and MN 10 layers) by DLS and NTA. DLS
NTA
Size Number [nm]
Size Number [nm]
Empty NP 5 nm NP 10 nm NP 20 nm
MN core
MN 10 layers
MN core
67.24 68.66 82.67 94.34
98.2 87.38 119.7 111.5
72.9 79.5 89.2 97.8
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[30,31]. PGA-terminated hybrid nanocapsules with six layers were coated with pegylated PLL (PLL-g-PEG) using the same procedure as for polyelectrolyte layers. Optimal amount of PLL-g-PEG for formation of pegylated layer was achieved when the zeta potential of capsules reached a value similar like for pegylated copolymer in solution, c.a 0 mV. Fig. 5 presents zeta potential distribution of formed pegylated nanocapsules (MN 5 nm 6L-PLL-g-PEG). 3.2. Nanocapsules characterization Concentration of magnetic nanocapsules was determined using NanoSight NS500 and it was ∼1011 nanocapsules/ml. The example of Cryo-SEM micrograph of the core of nanocapsules containing 5 nm Fe3 O4 nanoparticles is shown on Fig. 6. The size of the most of observed particles were ∼80 nm, which is in agreement with the values obtained by DLS and NTA analysis. The observed aggregates can result from the preparation procedure. The stability test for nanocapsules was based on the analysis of the time dependent changes in their size distribution and zeta potential. The freshly prepared suspensions of nanocapsules cores (MN cores with NP 5 nm, 10 nm, 20 nm) and pegylated nanocapsules (MN 5 nm 6L-PLL-g-PEG) had been stored in 0.015M NaCl solution at room temperature for up to one month, during this time we did not observed any significant changes in size and zeta potentials (Fig. 7). A constant magnetic field can be used to concentrate suspension of iron oxide particles, which tend to accumulate at the place with high magnetic field strength [32]. We visualized that effect for freshly prepared nanocapsules cores containing MP with the size 5, 10 and 20 nm as illustrated in Fig. 8. After placing the magnet adjacent to a beakers side we observed changes of nanocapsules distribution in beakers. At the beginning of experiment nanocapsules dispersion was homogeneous in all cases. After 1 h magnetic nanocapsules interacted with the magnetic field and were concentrated next to the magnet at the beaker wall, whereas without strong magnetic field their distribution remained unchanged. Therefore, we demonstrated that encapsulation of magnetic Fe3 O4 nanoparticles in nanocapsules core allowed obtaining nanocapsules sensitive to magnetic field. 4. Conclusions Polyelectrolyte coated magnetically responsive nanocapsules were successfully synthesized by direct encapsulation of nanoemulsion droplets containing hydrophobic Fe3 O4 nanoparticles in the polymer multilayer shell prepared using the layer by layer (LbL) technique. Various sizes of hydrophobic magnetic nanoparticles (5, 10 and 20 nm) were used for the preparation. The average size of synthesized nanocapsules was around 100 nm. For the purpose of biomedical application the nanacapsules shells were pegylated that was evidenced by zeta potential measurements. They maintain colloidal stability for the period not shorter than 30 days. In this paper and our previous study [26], we demonstrated that magnetic nanoparticlesparticles can be easily incorporated into either core or shell of nanocapsules of the size of c.a. 100 nm. Thus, our magnetically responsive nanocapsules may contribute to the further development of new strategies for targeted drug delivery systems. The optimal localization of magnetic nanoparticles depends on their nature (hydrophobic or hydrophilic) and on particular application. In our opinion the magnetic properties of the carriers are less vulnerable to the effect of environment if iron oxide nanoparticles are located in the nanocapsule’s core. On the other hand encapsulation of magnetic nanoparticles in the shell can produce higher loading, thus, higher susceptibility to magnetic field.
Fig. 8. Suspensions of nanocapsules containing Fe3 O4 nanoparticles (with sizes 5 nm (a), 10 nm (b), 20 nm (c), respectively) next to magnet.
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Synthesis of polyelectrolyte nanocapsules with iron oxide (Fe3 O4 ) nanoparticles for magnetic targeting Karolina Podgórna, Krzysztof Szczepanowicz ∗ Jerzy Haber Institute of Catalysis and Surface Chemistry Polish Academy of Sciences, Niezapominajek 8, 30-239 Krakow, Poland
h i g h l i g h t s
g r a p h i c a l
a b s t r a c t
• Performance synthesis of polyelectrolyte coated magnetically responsive nanocapsules for targeted drug delivery. • Zeta potential and size of the magnetic nanocapsules determined with electrophoretic mobility, light scattering measurements and nanoparticle tracking analysis. • Response of magnetic nanocapsules on constant magnetic field evaluated by direct visualization.
a r t i c l e
i n f o
Article history: Received 30 October 2015 Received in revised form 9 February 2016 Accepted 10 February 2016 Available online xxx Keywords: Encapsulation Targeted drug delivery Magnetic properties Layer by layer Nanocapsules Iron oxide magnetic particles
a b s t r a c t Magnetic vehicles have become highly promising for delivery of therapeutic actives as they can be targeted to selected pathologically changed tissues/cells through the application of a magnetic field gradient. The aim of this work was to prepare and characterize nanocapsules with iron oxide nanoparticles for magnetic targeting. Nanocapsules were prepared by encapsulation of oil droplets containing hydrophobic Fe3 O4 nanoparticles (NP) in polyelectrolyte shells, using the layer by layer technique. The average size of synthesized nanocapsules was ∼100 nm and the batch concentration was 1011 nanocapsules/ml. Morphology of magnetic carriers were investigated by Cryo-Scanning Electron Microscopy. © 2016 Elsevier B.V. All rights reserved.
1. Introduction Selective targeting of therapeutic agents is one of the greatest challenges for modern medicine. Increasing concentration and
∗ Corresponding author. E-mail address: [email protected] (K. Szczepanowicz).
bioavailability of drugs, prolonging circulation of actives in the body fluids, is essential for future success of many therapies (e.g. cancer, diabetes) [1–3]. Targeted drug delivery systems are extremely significant in cancer therapies since serious side effects are related with unspecific accumulation of highly toxic chemotherapeutics in healthy tissues that have direct influence on therapy efficiency [4]. A number of novel drug carriers have been design to achieve controlled
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Fig. 1. Formation of nanocapsules core (MN core) with Fe3 O4 nanoparticles (NP) and adsorption of subsequent layers of polyelectrolytes.
and targeted drug delivery. Systems based on micelles, vesicles, nanospheres and nanocapsules are commonly used for transport of therapeutic agents [5–7]. Nanocapsules are typically colloidal particles with size from 10 to 1000 nm. They consist of colloidal core and polymeric shell. One of the most promising methods to form nanocapsules is the layer-by-layer (LbL) technique. Since 1998 when Shukorukov et al. [8], proposed the methodology of forming polyelectrolyte multilayers on solid particles by the layer by layer approach, it has been the subject of intensive research and further extended to other types of cores including liquid cores e.g. emulsion droplets [9–17]. Various drug targeting strategies has been developed, of which one of the most fascinating is the magnetic targeting, where an active substance or active carrier is bound to magnetic species, injected into a patient’s blood stream, and then it is accumulated with a powerful magnetic field in the target area [18–20]. Polyelectrolyte nanocapsules formed by the LbL technique can also be functionalized by magnetic nanoparticles and that type of magnetically responsive nanocapsules could be guided with magnetic field gradients and therefore, could transport the biologically active components with an optimum therapeutic concentration of the pharmaceuticals to the desired tissue of the organism [21]. There are two general approaches proposed to incorporate magnetic species into polyelectrolyte carriers: the incorporation into polyelectrolyte shell where magnetic nanoparticles are used as building blocks of a shell (deposited via LbL approach or directly synthesized in formed polyelectrolyte layer) [22,23] or their incorporation in a capsule core [24,25]. In our previous work, we functionalized our liquid core—polyelectrolyte shell nanocapsules by incorporation of hydrophilic Fe3 O4 nanoparticles into multilayer shell to form magnetically responsive nanocarriers [26]. Magnetic nanoparticles were embedded in a polyelectrolyte shell through the LbL approach. In this paper we were focused on encapsulation of hydrophobic magnetic nanoparticles (various sizes) in emulsion cores of polyelectrolyte nanocapsules as the alternative way to provide magnetic functionaliy. Furthermore, the obtained magnetic nanocapsules were characterized by size, size distribution, zeta potential and concentration and visualized by Cryo-SEM.
chloride, were obtained from Sigma-Aldrich Poznan, Poland. PLL(20000)-g[3.5]-PEG(5000) PLL-g-PEG copolymer was obtained from SuSoS AG Dübendorf, Switzerland. Toluene and ethanol were obtained from Avantor Performance Materials Gliwice, Poland. All materials were used without further purification. The distilled water used in all experiments was obtained with the three-stage Millipore Direct-Q 5UV purification system. 2.2. Nanocapsules’ synthesis Magnetic nanocapsules cores (MN core) were prepared by a modified method described before by Szczepanowicz et al. [15]. Briefly, nanocapsules were formed by addition of hydrophobic phase containing AOT anionic surfactant (340 g/dm3 ), Fe3 O4 nanoparticles (0.5 g/dm3 for 5 nm and 10 nm nanoparticles and 0.25 g/dm3 for 20 nm nanoparticles) in the mixture of toluene:ethanol (1:100), to polycation solution (PLL in 0.015M NaCl, natural pH) under gentle mixing with a mechanical stirrer. That was used instead of mixing by magnetic stirrers to avoid aggregation of magnetic species. The optimal ratio of surfactant and polycation were determined by measuring zeta potential of emulsion drops and examining their stability. Stable emulsion was obtained when zeta potential of emulsion drops with adsorbed polyelectrolyte layer reached the constant value [27] just after overcharging. The LbL deposition was performed using the saturation procedure, with PLL as the polycation and PGA as the polyanion [28] to form polyelectrolyte multilayer shell. Fixed volume of
2. Experimental 2.1. Material and reagents The toluene suspension of Fe3 O4 nanoparticles (NP) 5 nm, 10 nm and 20 nm at concentration 5 mg/ml, biocompatible polyelectrolytes Poly-l-lysine hydrobromide PLL (MW ∼ 15000–30000), and Poly-l-glutamic acid sodium salt PGA (MW ∼ 15000–50000), oil soluble surfactant docusate sodium salt AOT ≥99%, sodium
Fig. 2. Example of determining the optimal surfactant/polyelectrolyte ratio: the dependence of zeta potential of AOT/PLL-stabilized nanoemulsion droplets—nanocapsules’ cores (MN cores) on PLL/AOT ratio (star denotes the optimal ratio of PLL/AOT used to form a stable polyelectrolyte layer).
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Fig. 3. Example of determining optimal nanocore/polyelectrolyte ratio: the dependence of zeta potential of nanocapsules core on PGA/MN core ratio (star: optimal ratio of PGA/MN core used to form stable second layer).
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Fig. 4. Layer-to-layer variations of zeta potential of MN 5 nm n-layers nanocapsules (n number of layers).
2.4. Nanocapsules’ zeta potential determination nanoemulsion suspension was added to the oppositely charged polyelectrolyte solution (PGA in 0.015M NaCl) under mixing with mechanical stirrer and the shell formation was followed by the measurements of zeta potential of the suspension. The procedure of sequential deposition of PLL and PGA layers was repeated until a required number of polyelectrolyte layers of the shell were formed. After preparation of stable nanocapsules toluene and ethanol were evaporated because of their toxicity. To create pegylated nanocapsules, PGA-terminated hybrid nanocapsules with six layers were coated with the layer of PLL-g-PEG using the same procedure as described above, i.e., by adding nanocapsules (PGA terminated) into filtered PLL-g-PEG polymer solution.
The zeta potential of magnetic nanocapsules and polyelectrolytes was measured by the microelectrophoretic method using Malvern Zetasizer Nano ZS apparatus. Each value was obtained as an average from three consecutive measurements with 20 runs. All experiments were performed at 25 ◦ C in 0.015M NaCl. 2.5. Nanocapsules’ stability studies To evaluate the colloidal stability of magnetic nanocapsules, their freshly prepared suspensions, were stored in 0.015M NaCl at room temperature. Size distribution (hydrodynamic diameter) and zeta potential of nanocapsules were measured just after preparation and after appropriate storage time as described above.
2.3. Nanocapsules’ size and concentration measurements
2.6. Nanocapsules’ visualization
Size distribution (hydrodynamic diameter) of magnetic nanocapsules (MN) was determined by DLS (Dynamic Light Scattering) using Zetasizer Nano Series from Malvern Instruments. Measurements were performed in optically homogeneous square polystyrene cells and with the detection angle of 173◦ . Each value was obtained as average from three runs with at least 20 measurements. Moreover, size distribution and concentration was measured by NTA (Nanoparticle Tracking Analysis) using NanoSight NS500. All measurements were performed at 25 ◦ C in 0.015M NaCl.
For the cryo-SEM imaging a droplet of capsules suspension was put on the cold sample holder. Then the holder was attached to the transfer rod and immediately immersed (frozen) in liquid nitrogen using Quorum PPT2000 cryo-preparation stage (Polaron, Quorum Technologies, United Kingdom). The holder with the frozen sample was cryo-transferred at the temperature of liquid nitrogen vapors to the chamber of the cryo-unit where the sample was subjected to sublimation at −70 ◦ C for 15–30 min. (until all visible ice crystals disappeared). The sample was then sputter coated with platinum (5 nm thickness). Following coating, specimen was transferred to
Fig. 5. Zeta potential distribution of formed pegylated nanocapsules MN 5 nm 6L-PLL-g-PEG.
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Fig. 6. The example of Cryo-SEM micrograph of nanocapsules core containing 5 nm Fe3 O4 nanoparticles.
Fig. 7. Stability of magnetic nanocapsules suspensions: dependence of size and zeta potential of nanocapules (MN core 5 nm and MN 5 nm 6L-PLL-g-PEG) on time.
the cooled stage of the Jeol JSM 7600F field emission scanning electron microscope FESEM (Jeol Ltd., Tokyo, Japan). 3. Results and discussion 3.1. Synthesis of magnetic nanocapsules The results of ours previous studies have indicated that iron oxide nanoparticles can be successfully incorporated in polyelectrolyte shell of nanocapsules [25]. In this paper we decided to propose another approach for the incorporation of iron oxide magnetic particles in our carriers. We encapsulated hydrophobic Fe3 O4 nanoparticles with various sizes (5, 10 and 20 nm) in the liquid cores of nanocapsules (Fig. 1). Nanoemulsion containing hydrophobic iron oxide nanoparticles was prepared according to method proposed previously [26], assisted by ouzo effect [29]. For the preparation of the emulsion of capsule cores, 0.1 ml of hydrophobic phase containing anionic, FDA approved surfactant AOT (34%), hydrophobic Fe3 O4 nanoparticles (5, 10 or 20 nm), toluene and ethanol was added to aqueous solution (0.015M NaCl) of polycation PLL 0.2 g/dm3 . Volume of
polycation PLL solution used to form stable interfacial AOT/PLL complex used as stabilizer for liquid core was determined by zeta potential measurements. The optimal volume of polyelectrolyte was chosen when zeta potential of formed droplets reached constant value close to the value obtained for free polyelectrolyte in solution. In those conditions the amount of free unadsorbed polyelectrolyte in the emulsion was minimized as most of it was consumed to form AOT/PLL interfacial complex [27]. The optimal ratio of polycation PLL to surfactant (AOT) was 1.21 [g/g] (Fig. 2). After 3 h of mixing under mechanical stirrer, nanoemulsion containing magnetic nanoparticles was left to evaporate toxic solvents. The average size of obtained nanocores determined by Dynamic Light Scattering (DLS) and Nanoparticle Tracking Analysis (NTA) was ∼70, 80 and 90 nm for cores with NP 5 nm, 10 nm and 20 nm, respectively, (Table 1) with the polydispersity index (PDI) <0.25. The zeta potential of suspension of nanocores was ∼+60 mV for each type of carrier, which indicated that the surface charge was high enough to prevent aggregation through the electrostatic stabilization. Various encapsulation efficiency of hydrophobic Fe3 O4 nanoparticles was observed for various nanoparticles sizes. For iron oxide magnetic particles with size 5 and 10 nm maximum concentration achieved was 0.0025 mg/ml. Two times lower concentration was achieved for 20 nm magnetic particles 0.00125 mg/ml. Above this values, precipitation of magnetic nanoparticles from nanocapsules suspension was observed. On such prepared nanocores containing magnetic nanoparticles, the sequential adsorption of polyelectrolytes by the saturation method was performed to form a polyelectrolyte multilayer shell. The biocompatible polyelectrolyte pair was used: PGA as the polyanion and PLL as the polycation. Fixed volume of positively charged nanocores suspension was added to the polyanion solutions (2 g/l 0.015M NaCl) under mechanical stirring, to form stable second layer. Volumes of PGA solution used to form a second polyelectrolyte layer were chosen empirically by analyzing the results of the simultaneous zeta potential measurements and were found optimal when the zeta potential of formed capsules reached the constant value just after overcharging (Fig. 3). By applying this approach the amount of unadsorbed PGA in the nanocapsules’ suspension was minimized, as most of it was used to form polyelectrolyte layers on nanocapsules. The zeta potential of formed nanocapsules was reversed to −42 mV. This process was repeated to obtain the desired number of layers. Fig. 4 shows a typical zig-zag dependence of the zeta potential of nanocapsules on the polyelectrolyte deposition cycle, which can be considered as the evidence of the formation of consecutive layers of capsules’ shells. After formation of polyelectrolyte shell with 10 polyelectrolyte layers, size of the nanocapsules increased by ∼30 nm with respect to the initial size of capsules’ cores (cf. Table 1). Polymeric shell was further modified, by PEG-ylation, in order to provide additional steric stabilization in body liquids. Moreover, PEG-ylation prevents nanocapsules from the process of opsonization, thus, the clearance by the immune system and macrophage uptake may be avoided Table 1 Size distribution of nanocores with Fe3 O4 nanoparticles (MN core and MN 10 layers) by DLS and NTA. DLS
NTA
Size Number [nm]
Size Number [nm]
Empty NP 5 nm NP 10 nm NP 20 nm
MN core
MN 10 layers
MN core
67.24 68.66 82.67 94.34
98.2 87.38 119.7 111.5
72.9 79.5 89.2 97.8
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[30,31]. PGA-terminated hybrid nanocapsules with six layers were coated with pegylated PLL (PLL-g-PEG) using the same procedure as for polyelectrolyte layers. Optimal amount of PLL-g-PEG for formation of pegylated layer was achieved when the zeta potential of capsules reached a value similar like for pegylated copolymer in solution, c.a 0 mV. Fig. 5 presents zeta potential distribution of formed pegylated nanocapsules (MN 5 nm 6L-PLL-g-PEG). 3.2. Nanocapsules characterization Concentration of magnetic nanocapsules was determined using NanoSight NS500 and it was ∼1011 nanocapsules/ml. The example of Cryo-SEM micrograph of the core of nanocapsules containing 5 nm Fe3 O4 nanoparticles is shown on Fig. 6. The size of the most of observed particles were ∼80 nm, which is in agreement with the values obtained by DLS and NTA analysis. The observed aggregates can result from the preparation procedure. The stability test for nanocapsules was based on the analysis of the time dependent changes in their size distribution and zeta potential. The freshly prepared suspensions of nanocapsules cores (MN cores with NP 5 nm, 10 nm, 20 nm) and pegylated nanocapsules (MN 5 nm 6L-PLL-g-PEG) had been stored in 0.015M NaCl solution at room temperature for up to one month, during this time we did not observed any significant changes in size and zeta potentials (Fig. 7). A constant magnetic field can be used to concentrate suspension of iron oxide particles, which tend to accumulate at the place with high magnetic field strength [32]. We visualized that effect for freshly prepared nanocapsules cores containing MP with the size 5, 10 and 20 nm as illustrated in Fig. 8. After placing the magnet adjacent to a beakers side we observed changes of nanocapsules distribution in beakers. At the beginning of experiment nanocapsules dispersion was homogeneous in all cases. After 1 h magnetic nanocapsules interacted with the magnetic field and were concentrated next to the magnet at the beaker wall, whereas without strong magnetic field their distribution remained unchanged. Therefore, we demonstrated that encapsulation of magnetic Fe3 O4 nanoparticles in nanocapsules core allowed obtaining nanocapsules sensitive to magnetic field. 4. Conclusions Polyelectrolyte coated magnetically responsive nanocapsules were successfully synthesized by direct encapsulation of nanoemulsion droplets containing hydrophobic Fe3 O4 nanoparticles in the polymer multilayer shell prepared using the layer by layer (LbL) technique. Various sizes of hydrophobic magnetic nanoparticles (5, 10 and 20 nm) were used for the preparation. The average size of synthesized nanocapsules was around 100 nm. For the purpose of biomedical application the nanacapsules shells were pegylated that was evidenced by zeta potential measurements. They maintain colloidal stability for the period not shorter than 30 days. In this paper and our previous study [26], we demonstrated that magnetic nanoparticlesparticles can be easily incorporated into either core or shell of nanocapsules of the size of c.a. 100 nm. Thus, our magnetically responsive nanocapsules may contribute to the further development of new strategies for targeted drug delivery systems. The optimal localization of magnetic nanoparticles depends on their nature (hydrophobic or hydrophilic) and on particular application. In our opinion the magnetic properties of the carriers are less vulnerable to the effect of environment if iron oxide nanoparticles are located in the nanocapsule’s core. On the other hand encapsulation of magnetic nanoparticles in the shell can produce higher loading, thus, higher susceptibility to magnetic field.
Fig. 8. Suspensions of nanocapsules containing Fe3 O4 nanoparticles (with sizes 5 nm (a), 10 nm (b), 20 nm (c), respectively) next to magnet.
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