Bullo Saifullah1, Mohd Zobir B Hussein1. 1. Materials Synthesis and Characterization Laboratory, Institute of Advanced Technology (ITMA), Universiti Putra Malaysia, Serdang, Malaysia.
Abstract
Hydrotalcite-like compounds are two-dimensional inorganic nanolayers also known as clay minerals or anionic clays or layered double hydroxides/layered hydroxy salts, and have emerged as a single type of material with numerous biomedical applications, such as drug delivery, gene delivery, cosmetics, and biosensing. Inorganic nanolayers are promising materials due to their fascinating properties, such as ease of preparation, ability to intercalate different type of anions (inorganic, organic, biomolecules, and even genes), high thermal stability, delivery of intercalated anions in a sustained manner, high biocompatibility, and easy biodegradation. Inorganic nanolayers have been the focus for researchers over the last decade, resulting in widening application horizons, especially in the field of biomedical science. These nanolayers have been widely applied in drug and gene delivery. They have also been applied in biosensing technology, and most recently in bioimaging science. The suitability of inorganic nanolayers for application in drug delivery, gene delivery, biosensing technology, and bioimaging science makes them ideal materials to be applied for theranostic purposes. In this paper, we review the structure, methods of preparation, and latest advances made by inorganic nanolayers in such biomedical applications as drug delivery, gene delivery, biosensing, and bioimaging.
pan class="Chemical">Hydrotalcite-like compounds are two-dimensional al">pan class="Chemical">inorganic nanolayers also known as clay minerals or anionic clays or layered double hydroxides/layeredhydroxy salts, and have emerged as a single type of material with numerous biomedical applications, such as drug delivery, gene delivery, cosmetics, and biosensing. Inorganic nanolayers are promising materials due to their fascinating properties, such as ease of preparation, ability to intercalate different type of anions (inorganic, organic, biomolecules, and even genes), high thermal stability, delivery of intercalated anions in a sustained manner, high biocompatibility, and easy biodegradation. Inorganic nanolayers have been the focus for researchers over the last decade, resulting in widening application horizons, especially in the field of biomedical science. These nanolayers have been widely applied in drug and gene delivery. They have also been applied in biosensing technology, and most recently in bioimaging science. The suitability of inorganic nanolayers for application in drug delivery, gene delivery, biosensing technology, and bioimaging science makes them ideal materials to be applied for theranostic purposes. In this paper, we review the structure, methods of preparation, and latest advances made by inorganic nanolayers in such biomedical applications as drug delivery, gene delivery, biosensing, and bioimaging.
In recent years, pan class="Chemical">inorganic al">pan class="Chemical">metal nanolayers have been receiving increased attention from scientists of various fields, due to their fascinating properties, such as ease of preparation, ability to intercalate variety of anions like inorganic anions, organic anions, biomolecules, and genes, and tendency to protect intercalated anions from physicochemical degradation and sustained release of intercalated anions. These inorganic nanolayers have a hydrotalcite-like structure. The most common class of these inorganic nanolayers is well known as layered double hydroxides (LDHs), and another type is referred to as layered hydroxide salts (LHS). Several books on this research field have provided valuable insight into their functionality and versatile applications. One popular book by Rives1 has presented a great overview of inorganic nanolayers. In addition, Duan and Evans2 clearly explain the inherent molecular dynamics in play, whereas Carillo and Griego et al3 discussed various applications and methods of preparation. Many reviews on LDHs, such as Del Hoyo,4 Khan et al5 (drug-delivery applications of LDHs), Wang and O’Hare6 (synthesis and applications of LDHs), and Rives et al7,8 (drug-delivery applications, drug intercalation of LDHs and sustained release), have been published.
Drug delivery, gene delivery, biosensing science, and bioimaging technology are the key tools of modern-day biomedical sciences. Different materials are used for the application of the aforementioned biomedical tools but there are certain issues related to different materials, such as pan class="Disease">cytotoxicity, lack of biodegradation, and different types of material being used for individual application.9 al">pan class="Chemical">Inorganic nanolayers have many advantages for biomedical applications, such as having been proven to possess very high in vitro and in vivo biocompatibility and biodegradability, and a single material can be applied for drug delivery, gene delivery, biosensing, and in bioimaging sciences. Figure 1 shows the different applications of inorganic nanolayers. This review addresses several aspects, such as structure, preparations, various biomedical sustained-release properties, in vitro and in vivo biocompatibilities, and theranostic applications. There have been many reviews regarding inorganic nanolayers, but most of them have focused on one dimension, ie, their drug-delivery applications.
Figure 1
Applications of inorganic nanolayers.
This is a comprehensive review that provides detailed information about the structure, preparation, and most recent advances in biomedical applications, such as drug delivery, gene delivery, biosensing, and bioimaging, of pan class="Chemical">inorganic nanolayers.
Structure
Structure of brucite
In pan class="Chemical">layered al">pan class="Chemical">magnesium hydroxide (brucite) [Mg(OH)6], the divalent M2+ ions are octahedrally surrounded by hydroxide ions. These octahedral units of magnesium hydroxides share their edges and form infinite layers in which O–H forms the bond perpendicularly to the layers. In these layers, hydroxyl anions are arranged in a closed-packed manner with triangular symmetry in two-dimensional (2-D) planes. The octahedral holes of the O–H alternate planes are occupied by Mg2+ ions, accounting for the triangular lattice similar to the one occupied by O–H ions, resulting in neutral layer.10–14 The structure of brucite is shown in Figure 2.
Figure 2
Schematic representation of the brucite structure.
Notes: (A) Side and (B) top view of the layer. Reprinted from Arizaga GG, Satyanarayana KG, Wypych F. Layered hydroxide salts: synthesis, properties and potential applications. Solid State Ionics. 2007;178:1143–1162, Copyright 2007, with permission from Elsevier.11
Structure of layered double hydroxides
Compositional changes can be made in the pan class="Chemical">brucite structure by the isomorphic replacement of divalent cations with trivalent cations (M3+). This results in overall positive charge in the layer and must be counterbalanced by negatively charged anions. In nature, al">pan class="Chemical">hydrotalcite is a mineral with a similar isomorphic structure. It consists of hydroxycarbonate of magnesium and aluminum, which can be easily crushed to powder. The foliated structure has the formula Mg6Al2 (OH)16CO34H2O.15,16
Substitution of pan class="Chemical">divalent magnesium cations by the trivalent al">pan class="Chemical">Al3+ results in overall positive charge in the hydro-talcite.15 LDHs are often described as hydrotalcite-like compounds, as both hydrotalcite-like compounds and LDHs have isomorphic substitution of the trivalent cations, with a structure similar to brucite, such as layers with positive charge and charge-neutralizing anions and solvent molecules within the interlayer galleries.2,7,8,17,18 The general formula for LDHs is [M2+1−xM3+x(OH)2]x+ (Am−)x/m·nH2O, where M2+ are divalent cations, such as Mg2+, Zn2+, Ni2+, and Ca2+, M3+ are trivalent cations, ie, Al3+, Fe3+, and Cr3+, and A is a counter anion with negative charge (m).2,8,10,12,18 They have an octa hedral structure, in which metal cations are accommodated in the centers of the edge-sharing octahedral; each cation contains six OH− ions that are pointed toward the corners and form infinite 2-D sheets.1,2,7,8
Figure 3 shows the schematic structure of LDHs with side view and top view.
Figure 3
Schematic representation of the structure of layered double hydroxide.
Notes: (A) Side and (B) top view of the layer. Reprinted from Arizaga GG, Satyanarayana KG, Wypych F. Layered hydroxide salts: synthesis, properties and potential applications. Solid State Ionics. 2007;178:1143–1162, Copyright 2007, with permission from Elsevier.11
Structure of layered hydroxides
One way of modification of pan class="Chemical">brucite-like structures is by induction of trivalent cations similar to al">pan class="Chemical">LDHs. Another way of structure modification is by replacing the hydroxyl group (OH−1) with suitable anions or water molecules. These types of compounds are called layered hydroxides or LHS, with the general formula M2+ (OH−)2 × (Am−)x/m·nH2O, where M2+ is the metal cation (eg, Mg2+, Zn2+, Ca2+, Cd2+, Co2+, Ni2+, and Cu2+) and Am− is the counterion. In the layered hydroxide structure, additional anions must be located in the second coordination sphere.2,11,18
Figure 4 shows the structure of LHS with both the side view (Figure 4A) and top view (Figure 4B).
Figure 4
Structures of zinc hydroxide nitrate.
Notes: (A) Side view and (B) top view. Reprinted from Arizaga GG, Satyanarayana KG, Wypych F. Layered hydroxide salts: synthesis, properties and potential applications. Solid State Ionics. 2007;178:1143–1162, Copyright 2007, with permission from Elsevier.11
Preparation methods of layered double hydroxides
pan class="Chemical">LDHs can easily be preal">pared by a number of methods, such as:
coprecipitation (direct method)ion exchange (indirect method)reconstruction (memory-effect method)sol–gel synthesispreparation of pan class="Chemical">LHS.
Coprecipitation (direct method)
A coprecipitation technique is most commonly applied for direct one-pot synthesis of pan class="Chemical">LDHs with a variety of divalent and trivalent cations and different anions ranging from al">pan class="Chemical">inorganic anions, such as Cl−, NO3−, and CO3− and a variety of organic molecule dyes and even large biomolecules have been intercalated.1,2,8,10,11 Moreover, coprecipitation methods can be applied for the large-scale production of the material of interest.2
In coprecipitation, both the divalent cations and trivalent cations along with the anions to be intercalated are mixed in aqueous solution, and pH is increased by adding basic solution.2,18 Coprecipitation is often the preferred method of pan class="CellLine">choice over other methods, as most of the anions can easily be intercalated using this method.2 The coprecipitation of cations is ensured by applying a supersaturation condition, which can be easily real">pan class="Gene">ached by controlling the pH of the solution.15 Thermal treatment is often performed after coprecipitation to ensure maximum yield and to improve the crystallinity of the sample. Thermal treatment can be done by aging the solution at 25°C–100°C. Alternatively, it can be performed by hydrothermal methods, wherein the sample is subjected to high pressure ranging from 10 to 150 MPa and high temperature in autoclave bombs with duration ranging from a few hours a to few days.2,19,20
Ion exchange (indirect method)
Ion exchange is also commonly used for pan class="Chemical">LDH synthesis, and has been successfully applied for the intercalation of a number of different types of anions.1,2,8,11 It is also known as an indirect method, in which the first al">pan class="Chemical">LDHs are prepared with host anions, most commonly NO3−, CO32−, and Cl− In the later stages, anions present in the interlayer region are exchanged with the desired anions.1,2 The host–guest exchange mainly depends on the electrostatic forces between positively charged LDH layers and the exchanging anions, and Figure 5 shows the typical ion-exchange process.21
Figure 5
Schematic representation of ion-exchange process.
Anions of interest can be intercalated in two possible ways, as described in the equations:
orIn the first example, the anions to be deintercalated are univalent, such as Cl−, pan class="Gene">NO3−, or al">pan class="Chemical">ClO4−. There exists weak electrostatic interaction with layers, and hence these anions can be easily replaced by anions with higher electrostatic interaction with layers.
In the second example, there is strong interaction between the positive layers and anions, as they have higher negative charge, such as pan class="Chemical">CO32− or al">pan class="Chemical">carboxylate. But these divalent anions are susceptible to acid attack, and can be easily exchanged with univalent anions, such as (Cl−), (NO3−), or (ClO4−).1,2 Different anions have been intercalated by ion-exchange methods, such as the inorganic anions Cl−, NO3−, SO42−, CrO42−, HAsO42−, HPO42−, and CO32−, pharmaceutical agents like para-aminosalicylic acid (PAS), and cetirizine.1,2,22–25
Regeneration of layered double hydroxides by structural memory effect
pan class="Chemical">LDHs can be completely transferred to the respective al">pan class="Chemical">metal oxide by heating the LDHs at high temperature, a process known as calcination. In this method, LDHs are heated at between 500°C and 600°C. As a consequence, interlayer water molecules, intercalated anions, and hydroxyl groups of LDHs are completely removed, leaving behind mixed metal oxides.23,26–28 It should be noted that preferably LDHs should be heated at about 400°C–550°C; heating at higher temperature will affect the regeneration of LDHs.2,18 When these mixed metal oxides are exposed to water and anions of interest, LDHs are reformed. However, due to the structural memory effect, if only the metal oxides that are not formed from LDHs are used, they will not generate LDHs.2,18,26–28 Calcination and anions of interest can be introduced after calcination and rehydration process.2,18 This is a very useful method, especially for the intercalation of organic molecules, and many different anions have been successfully incorporated in LDHs, such as caprolactam, organic chromospheres, dyes, surfactants, and metal complex anions, and this is even a very useful method for the intercalation of nonionized species, eg, sugar molecules like pentoses.29–33 The whole process of rehydration should be carried out under an inert nitrogen atmosphere.2,18
Hydrothermal method
In the hydrothermal method, pan class="Chemical">metals either in al">pan class="Chemical">hydroxide forms or in the form of salts or anions of choice are mixed, and the pH of the solution is raised to the desired level. For Mg/Al LDHs, for example, the pH is usually set at 9–10 and for Zn/Al LDHs, the pH is set at 7–7.5.20,34,35 After rising the pH, the sample solution is enclosed in stainless steel autoclave hydrothermal bombs, then the sample is either heated to a certain temperature ranging from 50°C to 180°C or it is subjected to simultaneous rotations.34–36 This method is particularly useful for the intercalation of anions with low affinity for LDHs compared to the competing anions of starting salts, such as Cl− and NO3−2. Intercalation of low-affinity anions into LDHs using the hydrothermal procedure can be more effective by the application of insoluble hydroxides, such as magnesium hydroxides and aluminum hydroxides, instead of their salts, which contain counteranions like Cl− and NO3−36. By this method, very fine LDHs are formed. Zhao et al synthesized very fine nickel/aluminumLDH nanorods with a size range of 15–40 nm.34 By this method, properties of LDHs can easily be tuned by controlling the temperature, pressure, and contact time.35
Preparation of metal layered hydroxides
pan class="Chemical">Metal layered hydroxides (al">pan class="Chemical">layered hydroxyl salts [LHS]) can be prepared in two ways: by using salt of the chosen metal and by using metal oxide.37–39 In the first method, salt is used as the starting material, which is dissolved in aqueous solution and its pH is increased by the slow addition of basic solutions, such as sodium hydroxides, aqueous solution of ammonia, or aqueous carbonate, until precipitation occurs.40 This method is very much similar to the coprecipitation method used in LDH preparation, where aqueous salt solutions are coprecipitated with counteranions of interest.23,24
pan class="Chemical">Metal layered hydroxides can also be preal">pared using al">pan class="Chemical">metal oxide as the starting material. In this method, metal oxide is dissolved in the solution of the desired anions, and the pH is raised until precipitation occurs.37,39 The results are more fruitful if the desired anion solution is acidic in nature.37,39 Varieties of organic and inorganic anions have been intercalated using these two methods.39–42
Application of layered double hydroxides
Catalytic
pan class="Chemical">LDHs have been used as catalysts as well as catalyst support in a number of reactions.43 They have been applied in the oxidation of al">pan class="Chemical">ethanol, methanol, selective oxidation of glycerol, selective oxidative halogenations, and oxidation of water for oxygen production and several other applications.43–49
Environmental remediation
pan class="Chemical">LDHs are considered to be an ideal material for the removal of toxic material from al">pan class="Chemical">water and also from the atmosphere.50,51 Motor vehicles, such as cars and motorcycles, are now integral to modern requirements. However, their increased use has also deteriorated our environment, due to the toxic gases being released as a by-product of combustion. Nitrogen oxides and soot exhaust from our vehicles are the most common causes of environmental and health problems.50 LDHs with different metal compositions have been applied in the adsorption of nitrogen oxides and soot.52–57 Removal of toxic material, both organic and inorganic, is very difficult task, which LDHs have successfully accomplished.58
Moreover, pan class="Chemical">LDHs have been successfully applied in the removal of toxic al">pan class="Chemical">metals in the form of their oxides, such as selenium, arsenic, chromium in wastewater, and radioactive uranium (VI), and have also been utilized for the removal of other heavy metals.58–61 Also, halogen anions and perchlorate anions have been removed by LDH application.62–65 Organic toxins are very difficult to remove from water, but this has been rendered possible by LDH application. Another study on the removal of guar gum and humic acid demonstrated very positive removal from water with the application of LDHs.66 LDHs have also been successfully utilized in the removal of many organic compounds from water, such as N,N-dimethyl aniline, 2-chlorophenol, phenolic compounds, dodecylbenzenesulfonate, and Remazol Blue 19. Even bacteria and viruses have been removed from water by the application of LDHs.32,67–70
In pan class="Chemical">water-treatment plants, disinfection is an important procedure, and currently al">pan class="Chemical">halogens and ozone are employed as disinfectants. However, there are certain issues with respect to these disinfectants, such as the fact that they can form genotoxic and carcinogenic by-products in the presence of organic compounds.71 Nowadays, scientists are looking for alternative disinfectants. One of the important disinfectants is lysozyme (LYZ), also called muramidase, which can break down the bacterial cell wall, resulting in bacterial eradication.72 Yang et al developed a novel disinfectant by the intercalation of LYZ into LDHs (LYZLDHs), and its antibacterial capability was evaluated against Staphylococcus aureus. The antibacterial activity of LYZLDHs was found to be consistently above 94% in the pH range of 3–9, which was much higher compared to free LYZ. This was due to the double action of LYZLDHs, ie, adsorption of LDHs and antibacterial action of LYZ.73 The LYZLDH formulation is considered to be a green antibacterial agent, as it does not produce any by-product.
Flame retardancy
One of the important characteristics of pan class="Chemical">LDHs is their high thermal stability, which makes them an ideal al">pan class="Chemical">halogen-free retardant material.74 They have been applied alone and in combination with polymers for fire control.74,75 Gao et al developed flame-retardant nanocomposite-based LDHs with different anions like nitrate, carbonate, chloride, and sulfonate, and combined them with a high-density polyethylenepolymer.75 There are many other LDHs and polymer composites that have been developed and applied as flame retardants.74,76–79
Layered double hydroxides in biosensing
Biosensing is an emerging technology that has a number of applications in biomedical diagnosis, pan class="Disease">food sciences, and enval">pan class="Chemical">ironmental sciences. The sensors are small devices that can detect chemical or biochemical changes in the medium around them and can convert them into the analytically useful signal. The sensor contains two basic components: 1) a receptor that can recognize the occurrences of events in the analytes of interest and 2) a transducer that converts the events into measurable signals.80 In biosensors, transducers are attached with biological materials (enzymes, affinity ligands, antibody, oligonucleotides, receptors, peptides, etc), which can serve as a biological recognizer.81
The high thermal stability and tendency of pan class="Chemical">inorganic nanolayers to protect immobilized bioactive molecules and their biocomn class="Chemical">al">patibility make them ideal material to be applied in biosensing technology. In this section, the application of al">pan class="Chemical">LDHs in biosensing technology is highlighted.
Zhang et al designed a chemiluminescence (CL) flow cell sensor by immobilizing pan class="Gene">Co(II)-ethylenediaminetetraacetic acid (al">pan class="Chemical">EDTA)-intercalated Mg/Al LDHs on a clear quartz tube. The developed microcell enhanced the CL signal from the luminol–H2O2 reaction, and has the strong potential to be applied in chemical/biological sensing for H2O2, as well as for other oxidase-based reactions producing H2O2. The limit of detection for H2O2 was found to be 0.14 μM with a signal-to-noise ratio of 3 (S/N =3).82
The likely mechanism of CL in the enhanced pan class="Chemical">luminol–al">pan class="Chemical">H2O2 system-based Co(II)-EDTA complex-intercalated LDHs is shown in Figure 6. There is an equilibrium between the Co(II) and EDTA, accompanied by a constant source of Co(II) ions to the luminol–H2O2 system. The Co(II) ions released then react with H O, producing lots of OH− and O2− ions, which can further react with luminol to emit light.82–84
Figure 6
Possible chemiluminescence mechanism for the Co(II)-ethylenediaminetetraacetic acid (EDTA)-intercalated Mg/Al layered double hydroxide (LDH)-enhanced luminol–H2O2 system.
Note: Reprinted from Zhang LJ, Chen YC, Zhang AM, Lu C. Highly selective sensing of hydrogen peroxide based on cobalt-ethylenediaminetetraacetate complex intercalated layered double hydroxide-enhanced luminol chemiluminescence. Sens Actuators B Chem. 2014;193:752–758, Copyright 2014, with permission from Elsevier.82
Hemoglobin and DNA-fabricated layered double hydroxide-based biosensor
Liu et al designed a biosensor by fabricating hemoglobin, deoxyribonucleic acid (DNA), and Ni/Alpan class="Chemical">LDHs. The hemoglobin-DNA al">pan class="Chemical">LDH-based biosensor showed sensitivity toward H2O and NO2 in the linear range of 4.85–10−7 to 1.94–10−4 M and 2.5–10−7 to 3.0–10−5 M, respectively.85
Gong et al designed highly sensitive amperometric biosensors for the biosensing of pan class="Chemical">organophosphate pesticides by the fabrication of al">pan class="Chemical">LDHs with acetylcholinesterase (AChE). They found that LDHs facilitate a biocompatible microenvironment that assists in maintaining the bioactivity of AChE because of the intrinsic properties of LDHs, specifically regular structure, good chemical, mechanical, and thermal stability, and swelling properties. They found that AChELDH-based electrodes greatly enhanced catalysis, oxidation producing thiocholine, and facilitated improved sensitivity with a detection limit of 0.6 ng·mL−1 (S/N =3).86
Luminol-layered double hydroxide-based biosensor for glucose detection
Wang et al developed a biosensor by the fabrication of Mg/Alpan class="Chemical">LDHs with al">pan class="Chemical">luminol for glucose detection in human serum. They combined the Mg/Al LDH–luminol with silica gel-fabricated glucose oxidase. The concentration was determined by CL, which can detect glucose in a linear range of 0.005–1.0 mM. The detection limit for glucose was found to be 0.1 mM, with S/N =3.87 Colombari et al designed a biosensor for the amperometric detection of glucose by combining Mg/Al LDHs with glassy electrode carbon.88
Ionic liquid: layered double hydroxide-based biosensor for protein detection
Lou et al developed a biosensor based on pan class="Chemical">ionic liquid al">pan class="Chemical">1-carboxyl-methyl-3-methylimidazolium tetrafluoroborate (CMMIMBF4) and LDHs for redox protein detection. The designed biosensor facilitated faster electron transfer in the redox process and was highly suitable for the detection of redox proteins.89
Gold-layered double hydroxide-based biosensor for toxic nitrite compound
pan class="Chemical">Nitrite is the most commonly found compound in foods and the enval">pan class="Chemical">ironment. It has been reported to be toxic and carcinogenic, and can even block oxygen supply via the blood by irreversible oxidation of hemoglobin to methemoglobin.90,91 Yin et al developed a biosensor by the fabrication of the gold electrode with Cu-Mg-AlLDHs, which were able to detect the nitrite amperometrically. The designed LDH-based bio-sensor showed excellent bioelectrocatalytic activity for nitrite oxidation in a linear range of 0.75–123 μM, with a detection limit of 2×10−7 M and S/N =3. The biosensor successfully determined nitrite content in food samples.81
Layered double hydroxide-based biosensor for cysteine sulfoxide detection in food samples
Anifantaki et al designed a biosensor by fabricating alliinase with pan class="Chemical">LDHs for al">pan class="Chemical">cysteine sulfoxide detection. The developed biosensor has the strong potential to be applied in food science.92 Mansouri et al designed a conductometric biosensor for polypeptide biosensing by the intercalation of trypsin into Zn/Al LDHs and Mg/Al LDHs.93
Layered double hydroxides in bioimaging
Bioimaging is one of the latest scientific techniques applied for disease diagnosis and examination of disease, and is also being applied in medical science to study normal physiology and anatomy. In bioimaging techniques, different processes are used to develop pan class="Species">human body image, tissues, and anatomical area down to the molecular level.
pan class="Chemical">LDHs can be ideal material to be applied in bioimaging science, due to their proven high biocomn class="Chemical">al">patibility (both in vitro and in vivo studies), positively charged surface, and ease of interaction with negatively charged cell membranes, which improve the efficiency of transfer.94 al">pan class="Chemical">LDHs are most recently explored in the bioimaging science and only few studies are carried out using LDHs in bioimaging science.
Layered double hydroxide-based upconversion fluorescence for bioimaging and drug delivery in cancer therapy
Chen et al designed a multifunctional nanodelivery system for drug delivery to and bioimaging of pan class="Disease">tumors by the fabrication of al">pan class="Chemical">Y2O3:Er3+ Yb3+ nanoparticles (NPs; near-infrared fluorescent nanophosphors) and fluorouracil (5-FU; anticancer drug) intercalated into Mg/Al LDHs, collectively abbreviated as (Y2O3:Er3+,Yb3+@SiO2@LDH-5FU).95 The developed nanodelivery systems showed powerful red upconversion fluorescence upon excitation with a 980 nm laser, which permitted the easy tracking of the nanodelivery system after internalization in cancer cells. The resultant nanodelivery system showed better anticancer efficacy and stronger red fluorescence, as shown in Figure 7. The better therapeutic outcome with the nanodelivery system compared to the free 5-FU can be attributed to the better internalization of positively charged NPs (due to LDHs’ positive surface) in the cell membrane.95
Figure 7
CytoViva microscopy images of MCF-7 cells incubated with Y2O3:Er3+, Yb3+@SiO2@LDH-5-FU at 100 mg·mL−1 for different time durations of 0.5 hour, 4 hours, and 24 hours.
Note: Reproduced from Chen C, Yee LK, Gong H, Zhang Y, Xu R. A facile synthesis of strong near infrared fluorescent layered double hydroxide nanovehicles with an anticancer drug for tumor optical imaging and therapy. Nanoscale. 2013;5:4314–4320, with permission of The Royal Society of Chemistry.95
Layered double hydroxide-based multifunctional core/shell nanospheres for bioimaging and targeted delivery in cancer
Li et al designed novel biodegradable multifunctional core/shell nanospheres with targeted, controlled release and pan class="Chemical">fluorescent properties for al">pan class="Disease">cancer therapy. First, they prepared a core based on iron magnetic supraparticles (MSPs), which were then coated with a shell of Ni/Al LDH. Next, the doxorubicin (anticancer drug)-carboxyl group, modified (DOX-COOH), was loaded on the shell of MSP LDH nanospheres. In addition, they immobilized the iminodiacetic acid-modified folate over MSP LDH-(DOX-COOH) in order to target cancer cells. Fluorescence microscopy found that the designed nanospheres targeted the cancerous cells and were highly cytotoxic to the cancerous cells compared to normal HEK 293T cells.96
Layered double hydroxide-based luminescent systems for bioimaging
Yan et al designed a highly luminescent nanocomposite by the fabrication of pan class="Chemical">sodium fluorescein dye with Mg/Al al">pan class="Chemical">LDHs. The nanocomposite was found to exhibit excellent fluorescence intensity, maintain fluorescence even in the form of dry powder, and was able to form transparent free-standing film (fluorescence active in ultraviolet [UV] light).
Tanaka et al intercalated a pan class="Chemical">fluorescent compound al">pan class="Chemical">fluores-cein (Fluo) into Mg/Al LDHs and studied their internalization and intracellular behavior in mammalian cells. They found that the FluoLDHs displayed high green fluorescence in whole cells, including the nucleus. Furthermore, the study revealed that anion fluorescein was released from FluoLDHs and endosomes by the proton-assisted dissolution of FluoLDHs.97
Musumeci et al fabricated pan class="Chemical">LDHs with different organic dyes for understanding the biological interactions and their biocomn class="Chemical">al">patibility with al">pan class="Chemical">LDHs. They intercalated LDHs with organic dyes, namely fluorescein isothiocyanate (FITC), fluorescein, 8-aminopyrene-1,3,6-trisulfonic acid, and 8-ami-nonaphthelene-1, 3,6-trisulfonic acid. Confocal imaging after incubation of LDH–dye nanocomposites with cells revealed that for biological tracking and labeling purposes, organic dyes were suitable in the following order: 1) fluorescein, 2) sulfonic acid-derived pyrene, and 3) naphthalene-based dyes.98
Posati et al doped Zn/Alpan class="Chemical">LDHs with europium (III) ions via microemulsion methods, and luminescence measurements revealed that the resulting material, europium (III)–Zn/Al al">pan class="Chemical">LDHs, was found to be very luminescent.99
Layered double hydroxides in UV protection and sunscreen formulations
Most pan class="Disease">skin cancers are caused by solar UV radiation, and al">pan class="Disease">skin cancer is responsible for human deaths. According to the World Health Organization, about 60,000 people died from cancer in the year 2000.100 We are exposed to sunrays every day; visible light is beneficial for us, but at the same time we are also exposed to UV (carcinogenic) radiation. Sunscreen formulation is the most commonly applied defense against UV radiation, but these sunscreen formulations contain organic UV absorbers that have certain limitations, eg, they cannot cover the whole UV region (200–400 nm). These organic UV absorbers undergo photodegradation under UV radiation, and the degradation products are toxic.42 Therefore, there is a need to design new sunscreen protection formulations free from the aforementioned demerits. The photostability of these organic UV absorbers can be achieved by intercalating them with inorganic nanolayers. Inorganic nanolayers are highly biocompatible, and most importantly they also absorb in the UV region, resulting in a hybrid material to cover the larger UV region (200–400 nm).
Mohsin et al designed an efficient sunscreen formulation by the intercalation of an organic UV absorber – n class="Chemical">cinnamate anion – into al">pan class="Chemical">zinc layered hydroxides (ZnLHs). The developed formulation covered the whole UV region, and was found to be biocompatible with HDF cells. In addition, cinnamate anion was thermally stabilized in the interlayers of ZnLHs.42
Mohsin et alalso recently designed three UV-absorbing nanocomposites by separate intercalation of three organic UV absorbers, namely pan class="Chemical">cinnamic acid (CA), al">pan class="Chemical">benzophenone-4, and Eusolex® 232, into Zn/Al LDHs. The study revealed that the UV-absorption range of all of the nanocomposites was longer compared to the free individual organic absorbers. Figure 8 shows the UV-absorption spectrum of CA, Zn/Al-CA, and Zn/Al LDHs. It can be easily seen that Zn/Al-CA covered a larger UV region compared to the CA alone. Likewise, the UV absorption of the two other nanocomposites showed similar trends. Most importantly, a cytotoxic study revealed that all three nanocomposites were found to be biocompatible with HDF cells.101
Figure 8
Solid-state absorbance spectra of Zn/Al-NO3, organic sunscreen guest cinnamic acid (CA), and the corresponding nanocomposite.
Mohsin et al have recently also developed a UV-absorbing nanohybrid (sunscreen formulation) by intercalating the strong UV absorber pan class="Chemical">benzophenone-9 into Zn/Al al">pan class="Chemical">LDHs. The sunscreen formulation was found to be stable in deionized water, artificial seawater, and in skin pH conditions. The UV-absorption spectrum was found to be broader compared to the free benzophenone-9, and the nanocomposite was also determined to be biocompatible with HDF cells.102
Wang et al designed novel UV-absorbing thin film by doping pan class="Chemical">Fe3+ with Mg/Al al">pan class="Chemical">LDHs, and the resulting material covered the whole UV region (200–400 nm). Furthermore, the thin film was easily fabricated with highly transparent polymerpolysiloxanes and UV-blocking composite material. The designed transparent UV-blocking composite can potentially be applied in protective coatings for glass curtain walls, automotive glass, outdoor wood objectives, priceless scrolls of calligraphy, cultural relic paintings, and some UV-sensitive materials.100
Li et al designed a UV-absorber organic–pan class="Chemical">inorganic nanocomposite by the intercalation of al">pan class="Chemical">2,4-dihydroxybenzophe-none into dodecylbenzenesulfonate-fabricated LDHs. The UV-absorption capability of the designed nanocomposite was extended over the entire UV region, which suggests it can be potentially applied as a UV absorber.103
Drug-delivery applications of layered double hydroxides
pan class="Chemical">LDHs have been the focus of several researchers, due to their potential applications in the biomedical field, and the research trends have proved that al">pan class="Chemical">LDHs are the ideal material for this field. In this section, recent advances in drug-delivery application for the cure of various diseases are discussed.
Also in this section, the latest developments in the drug-delivery applications of pan class="Chemical">inorganic nanolayers are discussed. Many nonsteroidal anti-inflammatory drugs have been intercalated into al">pan class="Chemical">inorganic nanolayers; Rives et al comprehensively reviewed the application of LDHs to the delivery of nonsteroidal anti-inflammatory drugs.8 Many other drugs, such as antidiabetes, cardiovascular, antibiotics, antioxidants, antiosteoporosis, vitamins, amino acids, and peptides, have been intercalated into inorganic nanolayers, which were comprehensively reviewed by Rives et al recently.7
Layered double hydroxides in anticancer formulations
pan class="Disease">Cancer has been threatening al">pan class="Species">humans for centuries, and despite technological advancements, cancer claims millions of human lives every year, with about 8.2 million deaths in 2012.104,105 The statistics of increasing cancer cases suggest that by the year 2025, cancer-related deaths will increase by up to 80% in less developed countries.104 Cancer is a set of diseases caused by the uncontrolled growth of abnormal cells and spread of these abnormal cells. It has been reported that if the spread of these abnormal cells is not controlled, they ultimately lead to death.110 Of drugs, such as decrease in bloodstream cell count, hair loss, cardiac dysfunction and heart failure, hyperglycemia, bone marrow depression, vomiting, nausea and diarrhea, tiredness, mouth soreness, constipation or diarrhea, loss of appetite, skin changes or reactions, pain or nerve changes, and changes in fertility and sexuality.106–109 Resistance of cancer cells toward effective therapeutic drugs is another major issue in cancer therapy.110,111
Drug-delivery systems could be very handy in reducing the adverse side effects of antipan class="Disease">cancer drugs, and could target al">pan class="Disease">cancer cells and release the drugs in a sustained manner. All of these factors would enhance therapeutic efficacy.
Methotrexate layered double hydroxides
pan class="Chemical">Methotrexate (al">pan class="Chemical">MTX) is an anticancer drug that can deactivate the metabolism of diseased cells effectively via programmed cell death (apoptosis), and is being used against different humancancers, eg, osteosarcoma (bone cancer) and leukemia.112 Jae-Min et al evaluated the anticancer efficacy of free MTX and MTXLDHs against bone cancer cell lines (Saos-2 and MG-63), and found that MTXLDHs were more effective in suppressing the cancer cells compared to free MTX. Oh et al revealed that LDHs were highly cytocompatible with human fibroblast cells even up to 500 μg·mL−1.113
Zhang et al recently pan class="CellLine">chose al">pan class="Chemical">MTX LDHs as a model nanohybrid to study the effect of different hydrothermal conditions on particle size and the effect of particle size on control release and suppression of cancer cells.114 They found a direct relationship between the diameter of LDHs and prolonged hydrothermal treatment at higher temperatures. In addition, hydrothermal treatment had no effect on percentage drug loading.114 Furthermore, they studied the effect of particle size on in vitro drug release, and found a direct relation between the size of LDHs and sustained release: the bigger the size, the longer the release. They considered the shelf life of MTXLDHs, and found that release was excellent even after 18 months, which makes LDHs suitable for drug delivery.114
Ifosfamide layered double hydroxides
The intercalation of neutral or nonpan class="Chemical">ionic molecules into al">pan class="Chemical">LDHs is very difficult and challenging, because the positive layers of LDHs have very low affinity for neutral molecules. Alternative methods for neutral species intercalation are either the memory-effect method or the direct assembly of neutral molecules with negatively charged surfactants like sodium dodecyl sulfate, sodium dodecylbenzenesulfonate, cholate, and deoxycholate.
pan class="Chemical">Ifosfamide (al">pan class="Chemical">IFO) is an anticancer agent commonly applied for the treatment of many pediatric and adult tumors, including soft-tissue sarcomas and lymphomas.115,116 IFO is a nonionic drug, and nonionic drugs are difficult to intercalate into LDHs. Nie and Hou intercalated IFO into Mg/Al LDHs by the surfactant-assisted method, in which they applied sodium dodecyl sulfate and sodium dodecyl-benzenesulfonate.117 They intercalated IFO into surfactant-modified Mg/Al LDHs separately. They conducted in vitro release in phosphate-buffered saline (PBS, pH 7.5), and found that IFO release was much more sustained from the LDH-surfactant-IFO nanohybrid compared to the physical mixture of free IFO and LDHs. The kinetic study of IFO release from LDHs was revealed to follow a pseudo-second order process.117
Camptothecin-layered double hydroxides
pan class="Chemical">Camptothecin (al">pan class="Chemical">CPT) is highly potent against a variety of cancers, such as lung cancer, ovarian cancer, pancreatic cancer, and stomach cancer.118,119 However, the chemical instability of CPT and its poor water solubility limit its clinical applications.118,119
Recently, Wu et al successfully intercalated the neutral antipan class="Disease">cancer drug al">pan class="Chemical">CPT into Mg/Al LDHs by coassembling it with sodium cholate, and then intercalated the CPT-sodium cholate by the delaminating method.120 The loading of CPT was found to be 13%, and PBS solution of pH 7.4 was found to be much more sustained compared to the physical mixture of CPT and sodium cholateLDHs.120 In addition, they also determined release kinetic models, which satisfactorily adopted the parabolic kinetic model, which suggests that release possibly follows a diffusion mechanism. However, ironically, they did not study the anticancer effect, which is crucially important for drug-delivery applications.
Protocatechuic acid layered double hydroxides
pan class="Chemical">Protocatechuic acid (al">pan class="Chemical">PA; 3,4-dihydroxybenzoic acid) is an anticancer agent widely used for the treatment of different types of cancers, namely cervix, breast, humanleukemia (pa-2000-leukemia), liver, lung, and prostate cancers.121 Barahuie et al intercalated PA into Mg/Al LDHs (PA–Mg/Al LDHs) by coprecipitation and ion-exchange methods, and studied various drug-delivery aspects.122 Anticancer assay revealed that PA–Mg/AL LDHs had higher anticancer activity compared to the free PA against the HeLa cervical cancer cell line and MCF-7 breast cancer cells. In addition, nanocomposites did not show any cytotoxicity to normal 3T3 fibroblast cells. The in vitro release study revealed that PA release from PA–Mg/Al LDHs was much more sustained compared to their physical mixture.122 The in vitro release of PA from Mg/Al LDHs was found to follow a second-order kinetic model more satisfactorily.122
Etoposide layered double hydroxides
pan class="Chemical">Etoposide (al">pan class="Chemical">VP16) is a derivative of podophyllotoxin, and has been reported to have significant anticancer activities against various cancer cells, such as small-cell lung carcinoma, gastric cancer cells, hematologic malignancies, childhood malignancies, and germ cell tumors.123–127
pan class="Gene">Qin et al preal">pared a nanohybrid formulation of al">pan class="Chemical">VP16 by intercalating it into Mg/Al LDHs (VP16–Mg/Al LDHs).128 They found that the nanohybrid (VP16–Mg/Al LDHs) possessed better antitumor activity against MKN45 and SGC-7901 cells. The release of VP16 from LDHs was found to be sustained and followed a diffusion mechanism, as it followed the parabolic kinetic model.28
Ciprofloxacin zinc layered hydroxides
Latip et al designed a antipan class="Disease">cancer nanodelivery formulation by intercalating al">pan class="Chemical">ciprofloxacin into ZnLHs. The release of ciprofloxacin was found to sustain in human body-simulated PBS of pH 7.4. The ciprofloxacinZnLH nanocomposite showed stronger anticancer effect against A549 cancer cells compared to free ciprofloxacin.129 The enhanced anticancer effect can be attributed to the nanoscale size of the nano-composite and sustained release of the ciprofloxacin. Many other anticancer drugs have been intercalated into LDHs, such as ferulic acid,130 cetirizine,131 ellagic acid (EA),41 5-FU–cyclodextrin complex,132 and doxifluridine.133
Layered double hydroxides in antimicrobial formulations
pan class="Chemical">Inorganic nanolayers have been applied in designing antimicrobial formulations by intercalating a variety of antimicrobials into them. Here, we discuss some of the latest developments made in the application of al">pan class="Chemical">inorganic nanolayers in antimicrobial formulations.
Ciprofloxacin layered double hydroxides
Hesse et al intercalated the antimicrobial drug pan class="Chemical">ciprofloxacin into Mg/Al al">pan class="Chemical">LDHs and evaluated its in vivo antimicrobial effect in rabbit ears against the bacterium Pseudomonas aeruginosa, and the material was found to show excellent antimicrobial effect even after 1 week.134
Hippuric acid zinc layered hydroxides
pan class="Chemical">Hippuric acid has been reported to have antimicrobial and anti-al">pan class="Disease">tumor properties.39,135 Hussein Al Ali et al developed nanocomposite formulations by the intercalation of hippuric acid into ZnLHs.136 The antimicrobial study revealed that hippuric acidZnLHs showed strong activity against P. aeruginosa, and most importantly hippuric acidZnLHs showed better antimicrobial properties against drug-resistant bacteria, namely methicillin-resistant S. aureus, compared to free hippuric acid.136
Benzylpenicillin layered double hydroxides
Wang et al designed an antimicrobial film by intercalating pan class="Chemical">benzylpenicillin (antimicrobial agent) into Mg/Al al">pan class="Chemical">LDHs, and then fabricated that nanohybrid with graphene oxide.137 They found that sustained release of benzylpenicillin from the film was directly related to the thickness of the film, and the film showed strong antimicrobial activity against Micrococcus lysodeikticus and sulfate-reducing bacteria.137
Amino acid layered double hydroxides
Wang et al designed antimicrobial formulations by intercalating different complex amino acids based on the pan class="Chemical">Schiff base ligands al">pan class="Chemical">salicylidene with alanine, phenylalanine, glycine, tyrosine, aspartic acid, and glutamic acid for complexes and gallium ion (G3+).138 The designed nanocomposites retained antimicrobial activity against P. aeruginosa, with a very good minimum inhibitory concentration (65–137 μmol·L−1).1380Many different antimicrobial agents, eg, amoxicillin139 and cefazolin,140 have been successfully intercalated into LDHs.
Layered double hydroxides as antimicrobial biomaterial
The development of biomaterial with antimicrobial properties is another fascinating area of research, as many diseases are caused by microbes. Biomaterial with antimicrobial properties finds a variety of applications, such as in medical implants, medical devices, food packaging, and pan class="Chemical">household products.141 al">pan class="Chemical">Inorganic nanolayer composition based on metals is renowned for its antimicrobial effect. Some compounds, such as silver, zinc, and copper, can be very useful for the production of different LDH-based ceramic materials in floor tiles, kitchens, and even bathrooms.142 In this section, we discuss applications of LDH-based biomaterial as antimicrobial agents.
Silver-based layered double hydroxides with antimicrobial properties
Mishra et al incorporated pan class="Chemical">silver into Zn/Al al">pan class="Chemical">LDHs and compared their antibacterial activity with Zn/Al LDHs, silver-based LDHs, and their calcined product. They found that Ag LDHs before and after calcination remained active against the bacterial species Escherichia coli and S. aureus.142 The antimicrobial effect of calcined Ag LDHs (spinel form) would be a useful property that can be applied in household items to prevent microbes, which in itself is an important avenue of research in the field of ceramics. In addition, the antimicrobial drugs intercalated into this type of LDH would result in a synergetic antimicrobial effect.
pan class="Chemical">Silver NPs have been reported to have strong antimicrobial properties, but al">pan class="Disease">toxicity associated with them limits their applications.143–145 In order to make silver NPs more biocompatible, Marcato et al fabricated biogenic silver NPs (AgNPbio) with Mg/Al LDHs.146 They evaluated the biocompatibility of free AgNPbio, LDHs, and AgNPbio LDHs against a lung fibroblast cell line (V79), and found that AgNPbio caused 50% cell death at a concentration of 45 μmol·L−1. However, even at a concentration of 45 μmol·L−1, LDHs alone and AgNPbio LDHs did not show any toxicity.146 In addition, AgNPbio LDH hybrid material was found to retain the antimicrobial effect, as the minimum inhibitory concentration of AgNPbio remained unchanged against Gram-positive (S. aureus) and Gram-negative (E. coli) bacteria: 6.6 μg·mL−1 and 12 μg·mL−1, respectively.146 This fascinating hybrid material is suitable to be applied in biomedical devices, cosmetics, and household items.
Carja et al previously adopted a similar approach, and developed hybrid material by fabricating AgNPs on the surface of pan class="Chemical">LDHs (AgNP al">pan class="Chemical">LDHs).147 They evaluated the antimicrobial effect of AgNPs alone and hybrid AgNP LDHs with respect to time, and found that AgNP LDHs retained the inhibition zone against the Gram-positive S. aureus (American Type Culture Collection [ATCC] 25923) and the Gram-negative E. coli (ATCC 35218). However, the AgNP zone of inhibition was found to almost disappear with time.147
Titanium-based layered double hydroxides with antimicrobial properties
Zhao et al designed nanoscale material with photocatalytic activity.141 They developed Zn-Ti pan class="Chemical">LDH nanosheets in the size range of 40–80 nm with a band gap of about 2.3 eV.141 They found that photochemical activity and nanosize confer antimicrobial activity under visible light. The material was found to possess a strong antimicrobial effect against al">pan class="Species">Saccharomyces cerevisiae (85% inhibition), S. aureus (65% inhibition), and E. coli (100% inhibition).141
ZnO nanoparticle-fabricated layered double hydroxides with antimicrobial properties
Zhang et al designed antimicrobial nanocomposite by combining Zn/Alpan class="Chemical">LDHs, al">pan class="Chemical">waterborne polyurethane, and ZnO NPs. The designed nanocomposite showed strong antimicrobial activity against the Gram-negative E. coli and the Gram-positive S. aureus.148
Layered double hydroxides in antituberculosis nanodelivery formulations
pan class="Disease">Tuberculosis (TB) is an al">pan class="Disease">airborne infectious disease caused by the bacterium Mycobacterium tuberculosis (MTB). It can be classified as pulmonary TB when MTB infects the lungs, and the other form is extrapulmonary TB, in which MTB attacks other organs of the human body, namely the liver, kidneys, intestines, bones, tonsils, spleen, and brain.149 TB has been intimidating humans for centuries, and in the Global Tuberculosis Report 2013 by the World Health Organization, there were approximately 8.6 million people infected with TB, and about 1.3 million died in the year 2012.150
There are several issues in TB treatment, such as longer treatment duration (6–24 months), multidrug prescription, frequent dosage of anti-TB drugs, and adverse effects of anti-TB drugs, and all of these factors result in pan class="Species">patients’ noncompliance with the treatment. al">pan class="Species">Patient noncompliance is the most common reason for the failure of TB chemotherapy.151 There has been no new anti-TB drug that has been introduced in the market, and in a situation like this, biocompatible drug-delivery systems with sustained release seem to be the best option.
Saifullah et al designed an anti-TB nanocomposite formulation with sustained-release properties by intercalation of the anti-TB drug pan class="Chemical">PAS into al">pan class="Chemical">ZnLHs using zinc oxide as a precursor.37 They have also designed a similar sustained-release PASZnLH nanocomposite with higher drug loading by using zinc nitrate as a precursor.152 Both of these nanocomposite formulations were found to be highly biocompatible with normal human lung fibroblast cells (MRC-5) and 3T3 fibroblast cells. In addition, the nanocomposites showed higher efficacy against bacteria MTB compared to the free drug PAS. The nanocomposites showed antimicrobial activities against S. aureus, P. aeruginosa, E. coli, and Candida albicans.152,153
Saifullah et alalso reported the development of anti-TB nanocomposite formulations by intercalating pan class="Chemical">PAS into Zn/Al al">pan class="Chemical">LDHs by coprecipitation and ion-exchange methods.23 The developed nanodelivery formulation was found to release the PAS in a sustained manner in human body-simulated PBS solutions. They also reported better biocompatibility of the nanocomposites with human normal lung cells (MRC-5) and fibroblast cells (3T3). The nanocomposites were found to be more effective in eradicating MTB compared to free PAS, and were also found to show antimicrobial activities against S. aureus, P. aeruginosa, E. coli, and C. albicans.23,153
Figure 9 sows the anti-tuberculosis formulations based on inorganic nanolayers and anti-TB drugs.
Figure 9
Various antituberculosis nanodelivery formulations based on antituberculosis drugs, para-aminosalicylic acid, and isoniazid with various inorganic nanolayers.
Saifullah et al recently designed an anti-TB nanodelivery formulation based on the anti-TB drug pan class="Chemical">isoniazid (INH) and Mg/Al al">pan class="Chemical">LDHs with sustained-release properties. The designed nanodelivery formulation of INH–Mg/Al LDHs was found to be very effective in eradicating the MTB, and most importantly the formulation was found to be more biocompatible when compared to free INH.154 Saifullah et al also designed another anti-TB sustained-nanodelivery formulation by intercalating INH into Zn/Al LDHs. The designed INH–Zn/Al LDHs showed better therapeutic results against MTB compared to free INH. The as-synthesized INH–Zn/Al LDHs were also found to be more biocompatible with human normal lung cells (MRC-5) and fibroblast cells (3T3).155 INH-based Zn/Al LDHs and Mg/Al LDHs were also found to show antimicrobial activities against S. aureus, P. aeruginosa, E. coli, and C. albicans.154,155
The better therapeutic efficacy against pan class="Species">MTB, high biocomn class="Chemical">al">patibility with al">pan class="Species">human normal lung cells, and sustained release of the anti-TB drugs will reduce adverse effects as well as dosing frequency, and will shorten the treatment duration. The sustained-release biocompatible nanodelivery formulation will make TB chemotherapy more patient-friendly.
Layered double hydroxides in gene delivery
The genes are the hereditary units being transferred from parents to pan class="Species">children, and are responsible for transporting the characteristics of al">parents to the al">pan class="Species">children. There are instances where parents with defective genes can pass the disease to their children.156 Gene therapy is a modern scientific technique that uses genes to prevent and treat disease. It is believed that in the future, this technique will revolutionize medical science in the treatment of all diseases by introducing genes into patient cells instead of drugs and surgery.157 Scientists are adopting several different approaches in gene therapy, such as the replacement of a defective gene (responsible for disease) with a healthy one, and the introduction of new genes into the body to fight disease.157 The in vitro and in vivo delivery of bioactive molecules, such as proteins, peptides, and nucleic acids, with the specific focus to transfer these biomolecules into the cytoplasm/nucleus by passing the cell membrane is an important area of biomedical research. There are many issues related to the direct delivery of biomolecules, such as poor solubility and enzymatic degradation. Though there are many hurdles in the development of efficient gene carriers, it is an exciting area of modern biomedical research. Many viral and nonviral carriers have been designed traditionally.158 If the gene of interest is introduced into the body directly, it will not work. Therefore, certain carriers are required, which can transfer the gene safely without harming the gene or the human body. Some viruses are currently being tested for the delivery of genes, and these viruses are modified in such a way that they do not harm the body.157
pan class="Chemical">LDHs offer several advantages over other gene carriers, such as easy preal">paration, easy intercalation of the biomolecules, targeted delivery, easier removal from the body after delivery wital">pan class="Chemical">hout accumulation, high biocompatibility, and the ability to enter the cell via clathrin-mediated mechanism.159–161
Layered double hydroxides in pEGFP-N1-DNA transfection mouse neuron cells
Li et al studied the cellular uptake of pan class="Chemical">LDHs into al">pan class="Species">mouse motor neuron cells (NSC 34) and determined the effect of LDH concentration, size, and incubation time by labeling the LDHs with FITC.162 The study revealed that cellular uptake was directly proportional to LDH concentration and incubation time. They also found that LDHs of 20 nm size were better at internalizing in the cell cytoplasm and cell nucleus; however, LDHs greater than 20 nm were internalized in the cell cytoplasm.162 They fabricated LDHs of 20 nm size with plasmid enhanced green fluorescent protein (pEGFP)-N1 DNA, and then successfully transfected them to NSC 34 cells. The found 20 nm LDHs did not cause any cytotoxicity to NSC 34 cells up to 200 mg·mL−1.
Figure 10 shows a confocal image depicting the cytoplasm in green pan class="Chemical">fluorescence after incubation of 6.25 mg·mL−1 of al">pan class="Chemical">CO3 LDH-FITC for 2.5 hours. Some of the particles have also entered the nucleus, as can be seen in green fluorescence in Figure 10A.162 The free FITC anions showed very weak green fluorescence at a much higher concentration of 6.25 mg·mL−1 compared to CO3 LDH-FITC. The lower free FITC cytoplasm entrance can be attributed to the mechanism of entrance: free FITC entrance takes place due to diffusion and not by endocytosis.162
Figure 10
Confocal microscopic images of intracellular localization in NSC 34 cells.
Notes: (A) 6.25 mg·mL−1 CO3 layered double hydroxide (LDH)–fluorescein isothiocyanate (FITC), incubated for 2.5 hours; (B) free 6.25 mg·mL−1 FITC anions incubated for 4 hours. Reproduced from Li SD, Li JH, Wang CL, et al. Cellular uptake and gene delivery using layered double hydroxide nanoparticles. J Mater Chem B. 2013:61–68, with permission of The Royal Society of Chemistry.162
Layered double hydroxides in plasmid DNA delivery
Hu et al modified the surface of pan class="Chemical">LDHs and studied the effect of surface change on the transfected properties of al">pan class="Chemical">LDHs. They tailored the LDH surface by fabricating it with 2-(dimethylamino) ethyl methacrylate, and designed a series of surface-modified LDHs for gene delivery.163 The surface-modified LDHs showed better tendency to conjugate with plasmid DNA and a higher level of gene delivery in different cell lines, including COS7 and HepG2, compared to free LDHs.163
Layered double hydroxides as gene-protective biomaterial
Wu et al investigated the suitability of pan class="Chemical">LDHs as a gene-protective agent in the adverse enval">pan class="Chemical">ironment of a Cd2+/Pb2+ solution.164 They intercalated DNA into LDHs and subjected both unprotected DNA and LDHs-DNA separately to the Cd2+/Pb2+ solution. The study revealed that the unprotected DNA structure was damaged, while LDH-protected DNA remained unaffected.164 Previously, Swadling et al also proved the higher stability of DNA after intercalation by molecular dynamic simulation.165 Zhang et al studied the structural stability of ribonucleic acid (RNA) before and after intercalation into LDHs by molecular simulation, and their study revealed that RNA had higher stability in LDHs compared to its free form.166
Codelivery of 5-flourouracil and siRNAs by intercalation in layered double hydroxides
The emergence of multidrug-resistant pan class="Disease">cancer is one of the major drawbacks of longer chemotherapy duration for al">pan class="Disease">cancer.167,168 High-concentration doses are administered to multidrug-resistant cancerpatients, causing adverse side effects to healthy tissue.169 A useful strategy being applied is the coadministration of two different types of anticancer drugs, specifically 5-FU and small interfering RNAs (siRNAs), which have been in use for over 40 years.170–172 The sustained and simultaneous codelivery of the 5-FU and siRNAs will improve the therapeutic outcome against cancer.
Li et al designed a novel antipan class="Disease">cancer formulation by co-intercalation of al">pan class="Chemical">5-FU and siRNAs into LDHs for the effective cancer treatment.173 The LDH-based sustained codelivery of 5-FU and siRNAs markedly enhanced anticancer activity in comparison to single treatment of either of the two against three cancer cell lines, namely human breast (MCF-7), osteosarcoma (U2OS), and colorectal (HCT-116).173 This codelivery formulation has the strong potential to overcome the emergence of drug-resistant cancer.
Transfection of siRNA into cytoplasm by layered double hydroxides
pan class="Chemical">LDHs are suitable vectors to facilitate the uptake and transfection of siRNA, due to their ability to dissolve in an endosomal enval">pan class="Chemical">ironment (acidic condition) and buffer the environment.158 Ladewig et al designed a siRNA-delivery system based on LDHs, and successfully transfected siRNA into the cytoplasm, because of their tremendous ability of escape endosomal environment.161 The cellular uptake study revealed that siRNA LDHs successfully entered HEK293T cells; however, free siRNA failed to enter HEK293T cells. The developed formulation was found to be highly biocompatible with humanembryonic kidney cells (HEK 293T) at very high concentrations (up to 0.200 mg·mL−1).161
Many other studies have been conducted on pan class="Chemical">LDHs for their application in gene therapy, such as Ladewig et al (transfected plasmid DNA al">pan class="Chemical">LDHs into different cells, namely HEK 293T, NIH 3T3, COS-7, and CHO-K1),161 Xu et al (supercoiled pEF-eGFP plasmid LDHs transfected to HEK 293T cells),174 Hu et al (intercalated mononucleotides and DNA). Table 1 summarizes the biomedical applications of inorganic nanolayers.175
Table 1
Biomedical application of layered double hydroxides (LDHs)
Sample
Type of formulation
Name of formulation
Type of disease
Reference(s)
1
Anticancer formulation
Methotrexate LDHs
Bone cancer, leukemia, etc
Zhang et al,114 Oh et al113
2
Ifosfamide LDHs
Pediatric, adult tumors, soft-tissue sarcomas and lymphomas
Nie and Hou117
3
Camptothecin LDHs
Lung cancer, ovarian cancer, pancreatic cancer, stomach cancer
Wu et al120
4
Protocatechuic acid LDHs
Cervix, breast, human leukemia (pa-2000-leukemia), liver, lungs, prostate
The key parameter in designing drug-delivery systems is their tendency to release the active agents (drugs/genes/biomolecules, etc) in a sustained manner at the target site. The tendency of pan class="Chemical">inorganic nanolayers (al">pan class="Chemical">LDHs/LHS) to release the drug in a desired manner makes them superior to other drug-delivery systems. The drug release from inorganic nanolayers (LDHs/LHS) can be tuned for the desired applications, such as for delivery of the drug in a two-phase manner, initially fast followed by a slower release.37,176
The ability of pan class="Chemical">inorganic nanolayers to protect, release in the desired manner, and release at the target site would avoid the physicochemical degradation of the drug, with a reduction in adverse effects and dosing concentration and frequency, and in general would improve the bioavailability of the drug. All of these characteristics would improve al">pan class="Species">patients’ compliance with treatment, particularly in the management of cancer, TB, and Parkinson’s disease, whose drugs have a lot of side effects.130,177–179 Here, we discuss the effect of different parameters, such as pH, types of anions present in the release media, and mechanisms involved in drug release from LDHs.
Release in phosphate-buffered saline of pH 7.4 and pH 4.8
In vitro release studies are conducted in various solutions simulating different routes of the delivery. In some cases, the release is carried out in pan class="Chemical">PBS of pH 7.4 to check the suitability of the drug-delivery system for intravenous application, as al">pan class="Chemical">PBS 7.4 simulates blood.23 The condition of PBS 7.4 is most commonly applied to evaluate the release behavior of any newly designed drug-delivery system, and the release of different drugs from LDHs/LHS have been conducted in PBS 7.4. The drug release in PBS 7.4 from LDHs/LHS has been found to be highly sustained compared to acidic pH conditions.22,24,37 The in vitro release is also most commonly conducted in PBS 4.8 to mimic the release in lysosomal conditions. Lysosomes are membrane-enclosed organelles present in the cell, and function as the digestive system of the cell.180 A great deal of in vitro release studies of LDHs have revealed that LDH release in PBS at pH 4.8 is sustained, but relatively faster compared to pH 7.4.22,23,37,39,41
Kura et al intercalated the antipan class="Disease">parkinsonian drug al">pan class="Chemical">levodopa into LDHs and conducted in vitro release in PBS pH 7.4, wherein the drug release was found to be sustained until 8,500 minutes.178 The release of levodopa in PBS solution of pH 4.8 was completed in 2,400 minutes; this release was still considered sustained, but was relatively faster than the release at pH 7.4. Figure 11 shows the release of levodopa from LDHs in PBS of pH 7.4 and pH 4.8.178
Figure 11
Release profiles of levodopa from the nanocomposite at pH 7.4 (A) and pH 4.8 (B).
Notes: Inset shows the release profiles of levodopa from the nanocomposite at pH 4.8 from 0 to 2,000 minutes. Reproduced with permission from Kura AU, Hussein Al Ali SH, Hussein MZ, Fakurazi S, Arulselvan P. Development of a controlled-release anti-parkinsonian nanodelivery system using levodopa as the active agent. Int J Nanomedicine. 2013;8:1103–1110.178
The release at pH 7.4 is for the evaluation of the oral route pan class="Chemical">PBS, with pH 6.8 being used to mimic the intestinal enval">pan class="Chemical">ironment, and pH 4.8 is used as the simulator for a lysosomal environment. Rives et al comprehensively reviewed release studies on LDHs.7,8 Rojas et al studied the drug release from LDHs using ibuprofen as a model drug in an intestinal-simulated PBS solution of pH 6.8 and a gastric-simulated solution (HCl in 0.05 mol·L−1 NaCl) of pH 1.2.176 They found the release at pH 6.8 was relatively similar with PBS 4.8 lysosomal pH. However, release in the gastric environment at pH 1.2 was much faster, such that the complete release took only about 200 minutes.176 The dissimilar pattern of drug release from LDHs in unlike conditions is due to different release mechanisms. The drug can be released in two different ways: 1) an ion-exchange mechanism and 2) weathering mechanisms. The drug is released by an ion-exchange mechanism under basic or neutral PBS medium, whereas under acidic conditions the drug is released by both ion exchange and by the weathering of inorganic nanolayers.181,182
Biocompatibility of layered double hydroxides
The most important characteristic of the ideal material for drug-delivery systems is biocompatibility with the pan class="Species">human body, cells, and tissues. Biocomn class="Chemical">al">patibility can be evaluated by two means: in vitro and in vivo cytotoxic studies. In the in vitro studies, the compounds of interest are treated with different cell lines, and their viability is determined by different assays. Many cytotoxic studies are carried out over al">pan class="Chemical">LDHs to evaluate their biocompatibility.
In vitro environment
pan class="Gene">Qin et al intercalated antial">pan class="Disease">tumor drug VP16 into LDHs and evaluated its antitumor effect, as well as its cytocompatibility with the human GES-1 cell line. They found that free VP16 was toxic to GES-1. On the other hand, LDH-intercalated VP16 did not show any cytotoxicity, and the therapeutic effect was maintained against the tumor cell lines MKN45 and SGC-7901.128
Hussein AlAli et al developed a formulation for the inhibition of pan class="Gene">angiotensin-converting enzyme by intercalating al">pan class="Chemical">perindopril erbumine (PE) into LDHs. The study revealed that PE LDHs showed better enzyme-inhibition activity against angiotensin-converting enzyme, and the PE LDHs were found to be highly biocompatible with a human liver cell line.24 Xu et al designed a gene-delivery system based on supercoiled pEF-eGFP plasmid and LDHs, and evaluated its cytocompatibility against HEK 293T cells. They found that pEF-eGFP LDHs were highly biocompatible with HEK 293T cells, even at the highest concentration of 500 μg/mL.174 The protein gene LDHs have been reported to be biocompatible with kidney (Vero3) cells of monkeys by Masarudin et al, and Ramli et al reported ZnLH–salicylic acid biocompatibility with kidney (Vero3) cells of monkeys.183,184
Marcato et al fabricated AgNPbio with pan class="Chemical">Mg-Alal">pan class="Chemical">LDHs (LDH-AgNPbio), and evaluated their biocompatibility against a permanent lung fibroblast cell line (V79).146 The developed nanohybrid LDH-AgNPbio was found to be highly biocompatible with the permanent lung fibroblast cell line (V79).146 Saifullah et al developed an anti-TB nanocomposite formulation based on PAS and ZnLHs and Zn/AL LDHs. The cytotoxic study revealed that the anti-TB nanocomposites were highly biocompatible with human normal lung cells (MRC-5) and fibroblast cells (3T3).23,37 Barahuie et al designed an anticancer nanohybrid by intercalating PA into Mg/Al LDHs, and found the nanohybrid possessed strong anticancer activity against MCF-7humanbreast cancer and human cervical cancer cell lines. At the same time, the nanohybrid did not show any cytotoxicity against fibroblast cells (3T3).122 Mohsin et al designed a sunscreen protection formulation that was able to cover the whole UV regions of A, B, and C by cointercalating the UV absorber CA, benzophenone-4, and Eusolex 232. The cytotoxic study of the UV-protection LDH formulation was found to be biocompatible with HDF cells.101 Hussein et al designed nanohybrid-based EA into ZnLHs and evaluated the cytotoxicity of the nanohybrid EA ZnLHs against the normal cell lines 3T3 and MCF-10A. The EA ZnLHs were found to be highly biocompatible with these normal cells, and at the same time EA ZnLHs were effective in killing two humancancer cell lines (breast cancer MCF-7 and liver cancerHepG2).185
Kura et al studied the pan class="Disease">toxicity of a nanohybrid based on the antial">pan class="Disease">parkinsonian drug levodopa and Zn/Al LDHs on the PC12 cell model. They found the nanohybrid did not induce any toxicity to the PC12 cells at a concentration of 100 μg/mL; however, levodopa in the free form was found to be extremely toxic, causing 80% cell death at 100 μg/mL.178
In vivo environment
Clay minerals have been applied in pharmaceutical products. pan class="Chemical">Hydrotalcite is used as an antacid and antipepsin agent under the brand names Almax, Bemolan, and Talcid. It is also used in cosmetic products, such as dentifrices and deodorants, as an excipient.186,187
Indomethacin LDH in vivo biocompatibility
pan class="Chemical">Indomethacin is an important anti-inflammatory drug applied for the treatment of al">pan class="Disease">ulcers, but it has gastrointestinal side effects. Del Arco et al intercalated indomethacin into Mg/Al LDHs and carried out a comparative pharmacological study of free indomethacin and Mg/Al LDH–indomethacin on Swiss mice of both sexes.187 They found Mg/Al LDHs were able to reduce side effects and improve therapeutic outcomes against ulcers, and were much better compared to free indomethacin.187
Ketoprofen LDH in vivo biocompatibility
pan class="Chemical">Ketoprofen (al">pan class="Chemical">Ket; 2-[3-benzoylphenyl]-propionic acid) is antipyretic, analgesic, and a nonsteroidal anti-inflammatory drug that is being applied for the cure of rheumatoid arthritis, osteoarthritis, and other chronic musculoskeletal conditions.188,189 Its application is limited by the side effects associated with it, such as peptic ulceration, anorexia, and bleeding.190,191 Silion et al intercalated Ket into Mg/Al LDHs and Zn/Al LDHs and conducted an in vivo comparative biocompatibility study with free Ket in mice. Their study revealed that KetLDHs reduced the ulcerogenic effect to a greater extent compared to free Ket.192
Acetylsalicylic acid–dextran-coated LDH in vivo biocompatibility
Dong et al designed drug-delivery systems based on pan class="Chemical">dextran-coated al">pan class="Chemical">LDHs for acetylsalicylic acid, and conducted a pharmacokinetic study with rabbits as the model animal.160 They found the LDH-based delivery system increased the bioavailability and half-life and reduced the side effects of acetylsalicylic acid.160
Table 2 summarizes the in vitro cytotoxic studies of inorganic nanolayers.
Table 2
In vitro biocompatibility studies of layered double hydroxides (LDHs) toward various cell lines
Sample
Type of LDH
Biocompatibility with cell type
Reference
1
Etoposide (VP16)–Mg/Al LDHs
Human GES-1 cells
Qin et al128
2
Perindopril erbumine LDHs
Human liver cell line
Hussein et al24
3
pEF-eGFP LDHs
HEK 293T cells
Xu et al174
4
Protein gene LDHs
Monkey kidney (Vero3) cells
Masarudin et al183
5
Salicylic acid ZnLHs
Monkey kidney (Vero3) cells
Ramli et al184
6
LDH-AgNPbio
Permanent lung fibroblast cell line (V79)
Marcato et al146
7
Para-aminosalicylic acid–Zn/Al LDHs
Fibroblast 3T3 cells and human normal lung cells (MRC-5)
Saifullah et al23
8
Para-aminosalicylic acid ZnLH
Fibroblast 3T3 cells and human normal lung cells (MRC-5)
Saifullah et al153
9
Isoniazid–Mg/Al LDHs
Fibroblast 3T3 cells and human normal lung cells (MRC-5)
Saifullah et al154
10
Isoniazid–Zn/Al LDHs
Fibroblast 3T3 cells and human normal lung cells (MRC-5)
Saifullah et al155
11
Cinnamic acid ZnLH
Fibroblast cells (3T3)
Mohsin et al42
12
Cinnamic acid into Zn/Al LDHs
HDF cells
Mohsin et al101
13
Benzophenone-4–Zn/Al LDHs
HDF cells
Mohsin et al101
Eusolex® 232–Zn/Al LDHs
HDF cells
Mohsin et al101
14
Benzophenone-9–Zn/Al LDHs
HDF cells
Mohsin et al101
15
Ellagic acid ZnLH
Normal human breast epithelial MCF-10A cells and murine fibroblast 3T3 cells
Yu et al evaluated acute pan class="Disease">oral toxicity and kinetic behaviors of al">pan class="Chemical">LDH NPs by using mice as the model animal. They found that LDH NPs did not cause any abnormal behaviors, mortality, symptoms, body-weight loss, or any symptoms at the very high concentration of 2,000 mg/kg for 14 days. Furthermore, their study revealed that LDH NPs did not cause any injury to the liver or kidneys.193 Flesken-Nikitin et al evaluated the toxicity of Mg/Al LDH NPs and used different routes in mice, namely subcutaneous, intraperitoneal, and intravenous injections. The LDH NPs showed only minor in vivo toxicity, and their results were highly encouraging, with a high percentage of mouse survival.194
Kura et al recently evaluated the subacute pan class="Disease">oral toxicity of al">pan class="Chemical">levodopa–Zn/Al LDHs in rats of 5–500 mg/kg body weight. The study revealed that there was no significant change in body-weight gain, water intake, or percentage of survival between groups of rats treated with nanocomposites and the control group. In addition, the liver, spleen, and brain histology was similar with the control group.195
In vivo biocompatibility is the most important characteristic of any material considered for biomedical application. The aforementioned in vivo biocompatibility studies are highly encouraging, but there is still need for further in vivo studies on pan class="Chemical">LDHs in order to establish that they are safe for biomedical applications. Table 3 summarizes the in vivo cytotoxic studies of al">pan class="Chemical">Inorganic nanolayers.
Table 3
In vivo biocompatibility of layered double hydroxides (LDHs) using animal models
Sample
Type of LDH
Animal model
Reference
1
Indomethacin–Mg/Al LDHs
Both sexesSwiss mice
Del Arco et al187
2
Ketoprofen–Mg/Al LDHs
Mice
Silion et al192
3
Ketoprofen–Zn/Al LDHs
Mice
Silion et al192
4
Acetylsalicylic acid–dextran LDHs
Rabbits
Dong et al160
5
LDH nanoparticles
Mice
Yu et al193
6
Mg/Al LDH nanoparticles
Mice
Flesken-Nikitin et al194
7
Levodopa–Zn/Al LDHs
Rats
Kura et al195
Conclusion
There are varieties of materials being studied for biomedical and other applications. However, pan class="Chemical">inorganic nanolayers are unique and very useful in many aspects, such as their easy preal">paration and proven in vitro and in vivo biocomn class="Chemical">al">patibility. Their tendency to intercalate a variety of anions, such as al">pan class="Chemical">inorganic and organic acids, organic dyes, pharmaceutical drugs, and biopolymers, and being able to be fabricated with other metallic materials like silver and ceramics either by intercalation or by surface interactions, resulting in fabulous material with numerous applications, makes them all the more advantageous.
The development of drug-delivery science is an important avenue in modern biomedical research. pan class="Chemical">Inorganic nanolayers have been continuously exploited for the delivery of a number of drugs, and have been found to be the best material to be applied as a delivery system. For a material to be suitable for drug delivery, it sal">pan class="Chemical">hould meet some important criteria: 1) it should be biocompatible with normal cells and tissues, 2) have a tendency to encapsulate/intercalate different pharmaceutical drugs, 3) be easy to prepare, 4) be cost-effective, 5) be able to release the drug in a sustained manner, 6) be able to deliver the drug at the disease site, and 7) be biodegradable and easily excreted from the body after releasing the drugs. This review has categorically proved the ability of nanolayers to meet these criteria, and hence these are an ideally suitable biomaterial to be applied for drug-delivery purposes.
Gene therapy is another revolutionary modern technique of biomedical science in which defective genes are replaced by healthy genes. Previously, viruses were being employed as gene carriers, but due to the risk of adverse health effects, scientists are looking for nonviral gene carriers. pan class="Chemical">Inorganic nanolayers have been applied as nonviral gene carriers recently in gene delivery. Our review has shown that al">pan class="Chemical">inorganic nanolayers have successfully transfected genes. Their positive surface charge assists them to cross the negatively charged cell membrane. Gene delivery is also one of the most important characteristics of nanolayers along with drug delivery.
The diagnosis of disease is another important research area of modern biomedical science. Previously, pan class="Species">people needed to submit samples from the al">pan class="Species">human body (such as blood, urine, and bone marrow) and wait for hours to days to get the reports. In modern medical diagnosis, a shorter time to reach diagnosis can be the difference between life and death. Biosensing technology has made it possible to diagnose diseases in a matter of seconds. Most importantly, a layman can easily understand the output of the results by eliminating the need of a laboratory expert to interpret the results.
Recently, pan class="Chemical">inorganic nanolayers have been applied in biosensors, and are considered to be a suitable material, as they can easily intercalate the biosensing receptor biomolecules, are highly biocomn class="Chemical">al">patible, and provide a high surface area to facilitate faster electron transfer during biosensing activity. The application in the biosensors enhances the versatility of the al">pan class="Chemical">inorganic nanolayers and further widens horizons for biomedical science. Inorganic nanolayers have the tendency to perform dual functions as a biosensor and drug-delivery system. This simultaneous dual-function characteristic has made it possible to identify the disease site and deliver the drug there. This has opened up a new research dimension in biomedical sciences.
The diagnosis of disease and therapy is collectively called theranostic science, and this has been facilitated by the use of pan class="Chemical">inorganic nanolayers, which are fabulous biomaterials applied in theranostic science.
Bioimaging is also an important area of biomedical science that can be applied in the diagnosis of disease, monitoring the disease condition, and applying to the study of normalpan class="Species">human physiology and anatomy. Most recently, al">pan class="Chemical">inorganic nanolayers have been applied in bioimaging science, and results suggest that there are many fascinating biomaterial applications to be applied in bioimaging science. Inorganic nanolayers are suitable for bioimaging science, because of their proven high biocompatibility, ability to be intercalated with fluorescent organic material that can glow, and ability to be fabricated with metals that can confer the glow to them. Furthermore, the positively charged surface of the inorganic nanolayers would assist in internalization inside the cell. Only a few studies have been carried out recently on bioimaging applications of inorganic nanolayers. The initial results of these are highly encouraging.
The application of pan class="Chemical">inorganic nanolayers in biosensors, drug delivery, gene delivery, and bioimaging biomaterial will enable us to diagnose the disease, release the drug at the target site, and help in monitoring therapeutic progress. It can be concluded that al">pan class="Chemical">inorganic nanolayers are an excellent biomaterial for various biomedical applications, such as cosmetics, drug delivery, biosensing, and bioimaging technology.
Authors: M Del Arco; E Cebadera; S Gutiérrez; C Martín; M J Montero; V Rives; J Rocha; M A Sevilla Journal: J Pharm Sci Date: 2004-06 Impact factor: 3.534
Authors: Nahidah Ibrahim Hammadi; Yusuf Abba; Mohd Noor Mohd Hezmee; Intan Shameha Abdul Razak; Alhaji Zubair Jaji; Tijani Isa; Saffanah Khuder Mahmood; Md Zuki Abu Bakar Zakaria Journal: Pharm Res Date: 2017-04-05 Impact factor: 4.200
Authors: Vanessa Roberta Rodrigues Cunha; Rodrigo Barbosa de Souza; Ana Maria Cristina Rebello Pinto da Fonseca Martins; Ivan Hong Jun Koh; Vera Regina Leopoldo Constantino Journal: Sci Rep Date: 2016-08-02 Impact factor: 4.379
Authors: Ahmed Hamidu; Ajat Mokrish; Rozaihan Mansor; Intan Shameha Abdul Razak; Abubakar Danmaigoro; Alhaji Zubair Jaji; Zuki Abu Bakar Journal: Int J Nanomedicine Date: 2019-05-20
Authors: Muhammad Sani Usman; Mohd Zobir Hussein; Sharida Fakurazi; Mas Jaffri Masarudin; Fathinul Fikri Ahmad Saad Journal: Nanomaterials (Basel) Date: 2017-08-31 Impact factor: 5.076
Authors: Muhammad Sani Usman; Mohd Zobir Hussein; Sharida Fakurazi; Mas Jaffri Masarudin; Fathinul Fikri Ahmad Saad Journal: PLoS One Date: 2018-07-25 Impact factor: 3.240
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