Magnetite Nanocontainers: Toward Injectable Highly Magnetic

Subscriber access provided by the Library Service | Stellenbosch University

Letter

Magnetite Nanocontainers: Towards Injectable Highly Magnetic Materials for Targeted Drug Delivery Elizaveta I. Anastasova, Artur Prilepskii, Anna Fakhardo, Andrey Drozdov, and Vladimir Vinogradov ACS Appl. Mater. Interfaces, Just Accepted Manuscript • DOI: 10.1021/acsami.8b10129 • Publication Date (Web): 23 Aug 2018 Downloaded from http://pubs.acs.org on August 25, 2018

Just Accepted “Just Accepted” manuscripts have been peer-reviewed and accepted for publication. They are posted online prior to technical editing, formatting for publication and author proofing. The American Chemical Society provides “Just Accepted” as a service to the research community to expedite the dissemination of scientific material as soon as possible after acceptance. “Just Accepted” manuscripts appear in full in PDF format accompanied by an HTML abstract. “Just Accepted” manuscripts have been fully peer reviewed, but should not be considered the official version of record. They are citable by the Digital Object Identifier (DOI®). “Just Accepted” is an optional service offered to authors. Therefore, the “Just Accepted” Web site may not include all articles that will be published in the journal. After a manuscript is technically edited and formatted, it will be removed from the “Just Accepted” Web site and published as an ASAP article. Note that technical editing may introduce minor changes to the manuscript text and/or graphics which could affect content, and all legal disclaimers and ethical guidelines that apply to the journal pertain. ACS cannot be held responsible for errors or consequences arising from the use of information contained in these “Just Accepted” manuscripts.

is published by the American Chemical Society. 1155 Sixteenth Street N.W., Washington, DC 20036 Published by American Chemical Society. Copyright © American Chemical Society. However, no copyright claim is made to original U.S. Government works, or works produced by employees of any Commonwealth realm Crown government in the course of their duties.

Page 1 of 15 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

ACS Applied Materials & Interfaces

Magnetite Nanocontainers: Towards Injectable Highly Magnetic Materials for Targeted Drug Delivery. Elizaveta I. Anastasova, Artur Y. Prilepskii, Anna F. Fakhardo, Andrey S. Drozdov, and Vladimir V. Vinogradov∗ Laboratory of Solution Chemistry of Advanced Materials and Technologies, ITMO University, St. Petersburg, 197101, Russian Federation E-mail: [email protected] Abstract Nanocontainers based solely on magnetite NPs have been synthesized by indirect gelation of stable magnetite hydrosol at ambient temperature using the microemulsionassisted sol-gel method. Containers synthesized have adjustable size and consist of ∼10 nm magnetite nanoparticles linked by Fe-O-Fe interparticle bonds. The material demonstrates high magnetization values up to 60 emu/g and low cytotoxicity against both HeLa and postnatal human fibroblast (up to 260 µg/mL). The systems developed are perspective as a drug depot, particularly for magnetically controlled thrombolysis.

Keywords Magnetite, microemulsion, tPA, thrombolysis, targeted delivery. Magnetic micro- and nanocapsules are the emerging class of nanoformulations that can be applied for targeted drug delivery, 1,2 localization of small molecules, 3–5 tissue engineer1

ACS Paragon Plus Environment

ACS Applied Materials & Interfaces 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

ing 6,7 or single cell manipulations. 8–10 Magnetic properties allow to perform non-invasive manipulations on the systems with application of external magnetic fields that are known to have relatively good penetration capabilities in tissues and biosamples and weak interaction with biological systems. 11 While the main functional properties of magnetic capsules are their drug loading capacity, biocompatibility, magnetization value and release profile, such aspects as easiness of synthesis, structure organization and composition should also be taken into account. Among all magnetic materials only two of them are considered biocompatible and regarded as safe to be applied for biomedical applications, namely magnetite and maghemite. 12 In the ideal situation, the magnetic nanocapsule consists of only magnetic material, but due to the chemical nature and surface properties of these two oxides, difficulties in covalent condensation of iron oxide nanoparticles, they cannot be used directly for the creation of magnetic capsules. Hence, various approaches are applied for the synthesis of magnetic carriers, such as polyelectrolytes-mediated self-assembly, bioscaffold-based formulations, or microemulsion synthesis of magnetic NPs doped organic or inorganic polymers. 13–15 While hybrid materials have variable sizes and structures, the presence of foreign molecules reduces specific magnetization values of such materials, so their magnetization rarely reaches 40 emu/g. On the other hand, the introduction of additional components can increase cytotoxicity of these hybrid materials or interfere with their legal status and application potential of such systems as the materials listed for oral or parenteral administration. 16 In this article we present a facile and universal method to synthesize single-component magnetite-based nanocontainers (designated as MNCs) by template-promoted formation of magnetite gel using the microemulsion (ME) technique and demonstrate the potential of such systems as drug carriers for biomedical applications, particularly for thrombolytic treatment. For this aim, the formation of the magnetite hydrogel (designated as ferria gel) was provided by the proton scavengers as described in our previous paper. 17 The resulting material consists of 10 nm magnetite nanoparticles linked by interparticle Fe-O-Fe bonds. The nanocontainers were synthesized in the reverse ME system (W/O) comprising cyclohexan, Triton X-15 and

2


Page 2 of 15

Page 3 of 15 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


hexanol as an oil phase, 18 and magnetite hydrosol as water phase. The synthesis of MNCs includes three stages: formation of ME, gelation of magnetite hydrosol by the addition of a deprotonating agent and washing with water and ethanol to remove organic components from the surface of magnetite nanocontainers formed (Figure 1).

Figure 1: Scheme of the synthesis of magnetite nanocontainers. The process of magnetite gelation can be described as follows: the surface of magnetite NPs, constituents hydrosol, is covered with OH- groups that play a key role in its colloidal stability. 19 Upon addition of proton scavenger propylene oxide, its oxirane-ring oxygen is attacked by a proton from an inorganic aqua-complex with the subsequent nucleophilic SN2 attack on a magnetite particle. This results in the formation of a covalent Fe-O-Fe bond between individual particles ending up the formation of the porous solid ferria gel (Figure 1). It is possible to obtain spheres with a different size distribution conducting the process in the constricted environmental conditions of a microemulsion and varying the emulsion parameters (Table 1). The experiments were performed to study the correlation between the size of the spheres and the ratio of the components (see the experimental part and SI for details). The table 1 shows the dependence of the amount of magnetite sol added to 3



Page 4 of 15

the cyclohexane/triton/hexanol system at a volume ratio of 4/2/1 on the dimensions of the magnetite spheres obtained (measured by both DLS and SEM). As seen, there is an approximately linear correlation between the particle size of the product (range 65-250 nm) and the amount of the Mixture introduced, as measured with SEM. With 200:1 ratio of the Mixture volume to Fe3 O4 sol, the size of the spheres formed was 65 nm according to SEM, while the increase of the hydrosol volume fraction up to 20:1 resulted in a larger diameter of gel spheres, up to 250 nm. The increased diameter of the spheres measured with DLS can be explained by the fact that finer particles tend to aggregate into larger agglomerates. The largest size of the spheres measured by SEM and DLS is within the reference accuracy. Table 1: Synthesis conditions and size parameters of MNCs. Sample

Mixture : Fe3 O4 sol volume ratio

MNCs 65 MNCs 155 MNCs 201 MNCs 250 MNCs 30000

200:1 80:1 40:1 20:1 0.5:1

The average size of the MNCs by DLS, nm 130±20 177±25 235±35 255±37 n/a

The average size of the MNCs by SEM, nm 65±3 155±7 201±10 250±12 30000±1500

Since it is feasible to use nanocontainers of less than 300 nm 20 for magnetic drug delivery, the further studies were performed on the systems with size less than 300 nm. Figure 2 shows the results of SEM and TEM images for MNCs synthesized. Their size corresponds to 250 nm, and size distribution is quite narrow (the data are presented in Figure S2). Nitrogen adsorption and desorption isothermal lines (Figure S3) have Type IV behavior with an extensive hysteresis corresponding to Type H1, which is characterized by the presence of globules of the same size and same package. 21 The MNCs have a distinctly developed porous structure with a high specific surface area( SBET = 135 m2 /g for MNCs compared to 120 m2 /g for magnetite NPs 22 ). High surface area values can be explained by the presence of a large number of pores with 19 nm average diameter (Figure S3). Such pore size is optimal for both loading low-molecular drug compounds and proteins. 23,24 The nanocapsules consist of ˜10 nm nanoparticles and demonstrate diffraction peaks typical for the spinel cubic crystalline of magnetite according to XRD (Figure S4). To address the question of MNCs organization, 4


Page 5 of 15 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


Raman spectra were recorded and analyzed. As it can be concluded from the Raman spectra, the characteristic broad band of magnetite at 667 cm−1 was also found (Figure S7-B). The magnetization curve of the dried sample (Figure S5) shows a superparamagnetic behavior of the material with no hysteresis and a high coercivity value. The saturation magnetization for MNCs is 60 emu/g, which is close to bulk magnetite. 25 It is also the highest value which has been achieved for magnetite-based drug carriers. A comparative analysis of the saturation magnetization of other magnetite-based materials is presented in Table S1.

Figure 2: A - SEM image and particle size distributions measured by SEM, C-B - TEM image and particle size distributions measured by TEM and D - HR TEM images of synthesized 250 nm magnetite nanocontainers. The MNCs consist of linked magnetite nanoparticles and show a high degree of biocompatibility in accordance with the cytotoxicity study performed on the HeLa, because HeLa response to different toxicants is quite similar to that of other normal cell types and postnatal human fibroblast cell lines. There was no significant decrease in cell viability after 72-hour exposure to magnetite containers (260 µg/mL) (Figure 3). Hence, the MNCs toxicity does not exceed values in our data on the cytotoxicity of magnetite nanoparticles, the exposure at equal doses caused similar effects in the cells. 26 Since nanoparticles are known for being capable of causing a strong oxidative stress in 5



Figure 3: Cytotoxicity of the magnetite nanocontainers. The influence of the MNCs on the viability of HeLa (A) and postnatal human fibroblast cells (B). Shown are mean of 3 measurements with standard deviations. cells, which leads to their death, 27,28 an additional study to determine the active forms of oxygen were performed on the MNCs synthesized. The cells were stained with non-fluorescent DCFDA which were converted to highly fluorescent DCF upon oxidation. We observed no reactive oxygen species generation in IMR-32 cells after incubation with MNCs in high concentration or in negative control (Figure 4a,b). The treated cells with H2 O2 as positive control 29 showed concentration dependent increase of FDA-positive cells (Figure 4c,d). To identify MNCs uptake by cells we used so-called multi-focus technique (Figure 4e-g). The cells were washed at least three times with PBS to remove extracellular nanoparticles. By adjusting focal length, we observed that MNCs localized within the cells and accumulated predominantly around the nucleus. The accumulation of MNCs starts after at least 240 min of incubation, after 24 hours almost all cells have MNCs in their cytoplasm (Figure S8). A confluence reaches almost 100% after 24 hours and indicates that accumulation of MNCs doesn’t effect on cell viability and grow rate. Low cytotoxic effect and absence of pro-oxidative activity renders the MNCs as a promising candidate to be used for injectable

6


Page 6 of 15

Page 7 of 15 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


theraputical purposes. Furthermore, to assess the stability of the resulting material in a biological environment, the particle size was analyzed during the time by DLS. As can be seen, during first 60 minutes after the start of the experiment, an increase of hydrodynamic diameter from 250 to almost 285 nm is observed due to the adsorption of proteins from the medium. Aggregation of particles in larger clusters was not observed.

Figure 4: Staining of IMR-32 cells with DCFDA. a- negative control, b MNCs at concentration 250 µg/mL (black areas on image is MNCs aggregates), c- H2 O2 at concentration 0.03%, D - H2 O2 at concentration 0.15%; E-G Phase contrast images of IMR-32 cells after 4 hours of incubation with MNCs at concentration 250 µg/mL. Brown areas are aggregates of MNCs. By altering focus, we clearly observed nanoparticles inside the cell. In order to evaluate the potency of magnetic NCs for the targeted drug delivery, magnetic thrombolytic composites were prepared by the entrapment of thrombolytic enzyme within a magnetite cage and tested for their ability to destroy model thrombi made of human plasma clots. To prepare such materials, tissue plasminogen activator (a protein belonging to the group of secreted proteases (tPA)) was added to the ME system and gelled together with the magnetite hydrosol. This resulted in the formation of composite magnetite NCs with protein captured within the pores of the gel structure (designated as tPA@MNCs). The enzyme capture can be either complete or partial depending on the weight fraction of the enzyme in the tPA@MNCs. The release was controlled spectrophotometrically using the Bradford protein assay by measuring the dependence of free tPA concentration in the 7



supernatant solution during the time period. As seen from the studies conducted, when the mass fracture of the captured enzyme in the composite was less than 10% mass, only 2% of the total amount of immobilized tPA was released from the composite within 12 hours. Taking into account the curve shape, it can be assumed that this amount is a part of uncaptured enzyme, which also does not react with the surface of MNCs. Therefore, we used only composites with the enzyme concentration not exceeding 10% w/w in further studies. Yet another proof, commonly used for analyzing hybrid materials, is IR spectroscopy, which should clearly show a superposition of the typical absorption bands of the matrix and the dopant. This was indeed confirmed, and a representative example tPA@MNCs is given in Figure S7-A, where it is seen that the IR spectrum of the composite is indeed a superposition of the spectra of MNCs and tPA; detailed spectral assignment of the various peaks is given in the SI as well. In order to evaluate the thrombolytic activity of tPA@MNCs, a study was performed on plasma clots (Figure 5). The model plasma clots were obtained from human control plasma with known amounts of fibrinogen and plasminogen (plasminogen concentration is 102 mg/mL and fibrinogen is 2.8 mg/mL). To evaluate the thrombolytic activity of the composite material, tPA@MNCs nanocontainers were added to the model clot formed, and the dynamic of lysis was monitored via optical microscope. Specially for this experiment particles with the size of 30 microns were synthesized. A model plasma clot was placed on the slide, further MNCs were added and the behavior of the clot was observed via a microscope. It should be noted that lysis was observed only in the case when MNCs were delivered to the clot by magnet. Without a magnet changes in the clot did not occur within 24 hours (Figure S1). The process of thrombolysis by tPA@MNCs began in 60 minutes after the components contact under static conditions as it can be seen from the alternations in the plasma clot structure, while full lysis of the clot was observed after 620 min of the experiment. The mechanism of the clot lysis can be described as follows: tPA, entrapped within MNCs,

8


Page 8 of 15

Page 9 of 15 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


Figure 5: Thrombolysis provided by targeted tPA@MNCs (the content of tPA is 10 w%). Changes in the thrombus periphery are clear seem immediately after the containers were delivered by the magnet (A), after 60 (B), 245 (C), 620 (D) min. The thrombus is completely destroyed after 620 minutes under static conditions. interacts with plasminogen presented in human plasma and converts it into plasmin (the main fibrinolytic protease). Once plasmin is formed, it disintegrates fibrin with the formation of soluble degradation products. The process of plasminogen and plasmin diffusion within magnetite gel matrix might face some diffusion limitations. The localization of tPA buried within the nanocage have its benefits such as prolonged period of action and prolonged period of half-life in human plasma. 30 At the end, we would like to propose a mechanism of removal magnetite from the body. According to available data 31 magnetic nanoparticles remain in the rat liver for 7-10 days after i.v. injection of 20 µmol Fe/kg (∼ 1.1 mg/kg). It was showed that after i.v. injection of 1 mg/kg of the drug composed of the nanoparticles ∼80 nm, 82% of nanoparticles were captured by the liver and 6% by the spleen within 1 h. However, the half-life of the

59

Fe

isotope in the liver was 3 days, in the spleen 4 days. This indicates that the nanoparticles undergo metabolic changes and transform into other forms of iron. According to several studies carried out on animals, it is generally suggested that MNPs in the liver is gradually transformed into the other iron compounds such as hemoproteins and other iron-containing proteins. 32

9



Thus, for the first time we have developed the new method for synthesizing biocompatible nanocontainers consisting of solely magnetic phase by propylene oxide mediated gelation of stable magnetite hydrosol in microemulsion. The diameter of NCs can be varied in a wide range by the regulation of microemulsion composition and emulsifying conditions. The MNCs exhibit a developed microstructure and textural properties with total surface area up to 135 m2 /g, excellent magnetization up to 60 emu/g and high degree of biocompatibility. Synthesis conditions allow to immobilize molecules of various nature, including complex and labile biomolecules such as thrombolytic enzymes and other proteins, thus opening doors to the creation of injectable drug carriers with low cytotoxicity and high magnetization value. This work was supported by Russian Science Foundation, grant No. 16-13-00041. The authors are grateful to Danilovich D. P. for comprehensive support and to engineering center of Saint-Petersburg Technological Institute for research assistance with IR measurements. SEM images of MNCs, size distribution of synthesized MNCs by DLS and SEM, the magnetization curves, N2 adsorptiondesorption isotherms, pore size distribution curves, IR spectra of free tPA, MNCs and tPA@MNCs, Raman spectrum of MNCs, XRD pattern, accumulation of MNCs in IMR-32 cell over time are provided in the Supporting Information.

References (1) Blanco, E.; Shen, H.; Ferrari, M. Principles of Nanoparticle Design for Overcoming Biological Barriers to Drug Delivery. Nat. Biotechnol. 2015, 33, 941. (2) Huang, J.; Shu, Q.; Wang, L.; Wu, H.; Wang, A. Y.; Mao, H. Layer-by-layer Assembled Milk Protein Coated Magnetic Nanoparticle Enabled Oral Drug Delivery with High Stability in Stomach and Enzyme-Responsive Release in Small Intestine. Biomaterials 2015, 39, 105–113. (3) Nakamura, T.; Sugihara, F.; Matsushita, H.; Yoshioka, Y.; Mizukami, S.; Kikuchi, K.

10


Page 10 of 15

Page 11 of 15 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


Mesoporous Silica Nanoparticles for 19 F Magnetic Resonance Imaging, Fluorescence Imaging, and Drug Delivery. Chem. Sci. 2015, 6, 1986–1990. (4) Wu, W.; Wu, Z.; Yu, T.; Jiang, C.; Kim, W.-S. Recent Progress on Magnetic Iron Oxide Nanoparticles: Synthesis, Surface Functional Strategies and Biomedical Applications. Sci. Technol. Adv. Mater. 2015, 16, 023501. (5) Andrey S. Drozdov, V. V. V. V. V. V., Katerina V. Volodina Biocomposites for Woundhealing based on Sol–Gel Magnetite. RSC Adv. 2015, 5, 82992–82997. (6) Silva, E. D.; Gon¸calves, A. I.; Santos, L. J.; Rodrigues, M. T.; Gomes, M. E. Smart Materials for Tissue Engineering; 2016; pp 491–519. (7) Santos, L. J.; Reis, R. L.; Gomes, M. E. Harnessing Magnetic-mechano Actuation in Regenerative Medicine and Tissue Engineering. Trends Biotechnol. 2015, 33, 471–479. (8) Shields IV, C. W.; Reyes, C. D.; L´opez, G. P. Microfluidic Cell Sorting: a Review of the Advances in the Separation of Cells from Debulking to Rare Cell Isolation. Lab Chip 2015, 15, 1230–1249. (9) Qiu, F.; Fujita, S.; Mhanna, R.; Zhang, L.; Simona, B. R.; Nelson, B. J. Magnetic Helical Microswimmers Functionalized with Lipoplexes for Targeted Gene Delivery. Adv. Funct. Mater. 2015, 25, 1666–1671. (10) Sitaras, C. C.; Ehrlicher, A. J. Mechanical Relaxation of Alpha-Actinin in the Cellular Cytoplasm Probed with Magnetic Tweezers. Biophys. J. 2018, 114, 517a–518a. (11) Stanley, S. A.; Sauer, J.; Kane, R. S.; Dordick, J. S.; Friedman, J. M. Remote Regulation of Glucose Homeostasis in Mice Using Genetically Encoded Nanoparticles. Nat. Med. (N. Y., NY, U. S.) 2015, 21, 92. (12) Bobo, D.; Robinson, K. J.; Islam, J.; Thurecht, K. J.; Corrie, S. R. Nanoparticle-based

11



Medicines: a Review of FDA-Approved Materials and Clinical Trials to Date. Pharm. Res. 2016, 33, 2373–2387. (13) Barbe, C.; Bartlett, J.; Kong, L.; Finnie, K.; Lin, H. Q.; Larkin, M.; Calleja, S.; Bush, A.; Calleja, G. Silica Particles: a Novel Drug-delivery System. Adv. Mater. (Weinheim, Ger.) 2004, 16, 1959–1966. (14) Malik, M. A.; Wani, M. Y.; Hashim, M. A. Microemulsion Method: a Novel Route to Synthesize Organic and Inorganic Nanomaterials: 1st Nano Update. Arabian J. Chem. 2012, 5, 397–417. (15) Sanghvi, P. G.; Devi, S. Synthesis of Nanoparticles by Microemulsion Polymerization and Their Application in a Drug Delivery System. Int. J. Polym. Mater. 2005, 54, 293–303. (16) H¨ormann, K.; Zimmer, A. Drug Delivery and Drug Targeting with Parenteral Lipid NanoemulsionsA Review. J. Controlled Release 2016, 223, 85–98. (17) Anastasova, E. I.; Ivanovski, V.; Fakhardo, A. F.; Lepeshkin, A. I.; Omar, S.; Drozdov, A. S.; Vinogradov, V. V. A Pure Magnetite Hydrogel: Synthesis, Properties and Possible Applications. Soft Matter 2017, 13, 8651–8660. (18) Eastoe, J.; Robinson, B. H.; Steytler, D. C.; Thorn-Leeson, D. Structural Studies of Microemulsions Stabilised by Aerosol-OT. Adv. Colloid Interface Sci. 1991, 36, 1–31. (19) Drozdov, A. S.; Ivanovski, V.; Avnir, D.; Vinogradov, V. V. A Universal Magnetic Ferrofluid: Nanomagnetite Stable Hydrosol with No Added Dispersants and at Neutral pH. J. Colloid Interface Sci. 2016, 468, 307–312. (20) Kim, J.; Kim, H. S.; Lee, N.; Kim, T.; Kim, H.; Yu, T.; Song, I. C.; Moon, W. K.; Hyeon, T. Multifunctional Uniform Nanoparticles Composed of a Magnetite Nanocrys-

12


Page 12 of 15

Page 13 of 15 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


tal Core and a Mesoporous Silica Shell for Magnetic Resonance and Fluorescence Imaging and for Drug Delivery. Angew. Chem., Int. Ed. 2008, 47, 8438–8441. (21) Tanev, P. T.; Vlaev, L. T. An Attempt at a More Precise Evaluation of the Approach to Mesopore Size Distribution Calculations Depending on the Degree of Pore Blocking. J. Colloid Interface Sci. 1993, 160, 110–116. (22) Shapovalova, O. E.; Drozdov, A. S.; Brushkova, E. A.; Morozov, M. I.; Vinogradov, V. V. Room-temperature Fabrication of Magnetite-Boehmite Sol-Gel Composites for Heavy Metal Ions Removal. Arabian J. Chem. 2018, (23) Drozdov, A. S.; Shapovalova, O. E.; Ivanovski, V.; Avnir, D.; Vinogradov, V. V. Entrapment of Enzymes within Sol–Gel-Derived Magnetite. Chem. Mater. 2016, 28, 2248– 2253. (24) Shabanova, E. M.; Drozdov, A. S.; Ivanovski, V.; Suvorova, I. I.; Vinogradov, V. V. Collagenase@ Magnetite: Proteolytic Composite for Magnetically Targeted Minimally Invasive Surgery. RSC Adv. 2016, 6, 84354–84362. (25) Han, D.; Wang, J.; Luo, H. Crystallite Size Effect on Saturation Magnetization of Fine Ferrimagnetic Particles. J. Magn. Magn. Mater. 1994, 136, 176–182. (26) Andreeva, Y. I.; Drozdov, A. S.; Fakhardo, A. F.; Cheplagin, N. A.; Shtil, A. A.; Vinogradov, V. V. The Controllable Destabilization Route for Synthesis of Low Cytotoxic Magnetic Nanospheres with Photonic Response. Sci. Rep. 2017, 7, 11343. (27) Burello, E.; Worth, A. P. A Theoretical Framework for Predicting the Oxidative Stress Potential of Oxide Nanoparticles. Nanotoxicology 2011, 5, 228–235. (28) Wang, H.; Kou, X.; Pei, Z.; Xiao, J. Q.; Shan, X.; Xing, B. Physiological Effects of Magnetite (Fe3O4) Nanoparticles on Perennial Ryegrass (Lolium Perenne L.) and Pumpkin (Cucurbita Mixta) Plants. Nanotoxicology 2011, 5, 30–42. 13



(29) Kalyanaraman, B.; Darley-Usmar, V.; Davies, K. J.; Dennery, P. A.; Forman, H. J.; Grisham, M. B.; Mann, G. E.; Moore, K.; Roberts II, L. J.; Ischiropoulos, H. Measuring Reactive Oxygen and Nitrogen Species with Fluorescent Probes: Challenges and Limitations. Free Radical Biol. Med. 2012, 52, 1–6. (30) Vinogradov, V. V.; Drozdov, A. S.; Mingabudinova, L. R.; Shabanova, E. M.; Kolchina, N. O.; Anastasova, E. I.; Markova, A. A.; Shtil, A. A.; Milichko, V. A.; Starova, G. L. Composites Based on Heparin and MIL-101 (Fe): the Drug Releasing Depot for Anticoagulant Therapy and Advanced Medical Nanofabrication. J. Mater. Chem. B 2018, 6, 2450–2459. (31) Weissleder, R. a.; Stark, D. D.; Engelstad, B. L.; Bacon, B. R.; Compton, C. C.; White, D. L.; Jacobs, P.; Lewis, J. Superparamagnetic Iron Oxide: Pharmacokinetics and Toxicity. Am. J. Roentgenol. 1989, 152, 167–173. (32) Weinstein, J. S.; Varallyay, C. G.; Dosa, E.; Gahramanov, S.; Hamilton, B.; Rooney, W. D.; Muldoon, L. L.; Neuwelt, E. A. Superparamagnetic Iron Oxide Nanoparticles: Diagnostic Magnetic Resonance Imaging and Potential Therapeutic Applications in Neurooncology and Central Nervous System Inflammatory Pathologies, a Review. J. Cereb. Blood Flow Metab. 2010, 30, 15–35.

14


Page 14 of 15

Page 15 of 15 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


15


Magnetite Nanocontainers: Toward Injectable Highly Magnetic

Recommend Documents