Metal-oxide Nanoparticles (MONPs) PDF

Metal-oxide Nanoparticles (MONPs)  Introduction The prefix "nano" refers to one-billionth. When applied in the metric scale of linear measurements, a nanometer is one-billionth of a meter. The term "nano-technology” is now commonly used to refer to the creation of new objects with nanoscal...

Metal-oxide Nanoparticles (MONPs)  Introduction The prefix "nano" refers to one-billionth. When applied in the metric scale of linear measurements, a nanometer is one-billionth of a meter. The term "nano-technology” is now commonly used to refer to the creation of new objects with nanoscale dimensions between 1.0 and 100.0 nm. The term "nanoscience" is used to refer to research at a nanoscale. 2  Nanomedicine Nanomedicine involves utilization of nanotechnology for the benefit of human health and wellbeing. The use of nanotechnology in various sectors of therapeutics has revolutionized the field of medicine where nanoparticles are designed and used for diagnostics, therapeutics and as biomedical tools for research. Nanomaterial has been employed significantly in the healthcare sector because of its feature to hold, carry, protect and deliver therapeutic agents, particularly to the targeted tissue and provides safety by reducing dose size and frequency of administrations. Many types of nanomaterials have shown potential effects on the delivery of the drug. 3 MONPs 2024  Nanoparticles’ properties ✓ Nanoparticles have a significant surface-area-to-volume ratio due to their nanoscale size, which allows them to absorb vast amounts of medications and move quickly throughout the bloodstream. ✓ Their increased surface area gives them distinct capabilities, as it increases their mechanical, magnetic, optical, and catalytic qualities, allowing them to be used in more pharmaceutical applications. 4 MONPs 2024  Nanoparticles’ classification Nanoparticles (NPs) are classified into three areas based on their chemical composition: 1. Organic NPs: These nanoparticles are biodegradable and non-toxic. 2. Carbon based NPs: The nanoparticles made completely of carbon are knows as carbon-based nanoparticles. 3. Inorganic NPs: These are non-toxic, hydrophilic, biocompatible, and highly stable compared to organic materials. Inorganic nanoparticles include elemental metals and metal oxides, among others. 5 MONPs 2024 6 MONPs 2024  Inorganic nanoparticles a. Metal based. Nanoparticles that are synthesized from metals to nanometric sizes by different methods are metal based nanoparticles. Almost all the metals can be synthesized into their nanoparticles. The commonly used metals for nanoparticle synthesis are aluminum (Al), copper (Cu), gold (Au), iron (Fe), silver (Ag) and zinc (Zn). b. Metal oxides based The metal oxide-based nanoparticles are synthesized to modify the properties of their respective metal-based nanoparticles, for example nanoparticles of iron (Fe) instantly oxidizes to iron oxide (Fe2O3) in the presence of oxygen at room temperature that increases its reactivity compared to iron nanoparticles 7 MONPs 2024  Metal-oxide NPs Metal oxide nanoparticles are synthesized mainly due to their increased reactivity and efficiency. The commonly synthesized are Iron oxide (Fe2O3), Magnetite (Fe3O4), Silicon dioxide (SiO2), Zinc oxide (ZnO). To be used for a particular application, MONPs should meet certain requirements. For example, the MONPs implemented as drug carriers should have kinetics complying with the requirements for treating a certain infection and they have to be biodegradable to exclude further surgical intervention. Although a broad spectrum of MONPs is available, only TiO2, ZnO, CuO, ferric oxide (Fe2O3) and ferrous oxide (Fe3O4) appeared as comparatively safe for mammals. 8 MONPs 2024  Iron-oxide Nanoparticles (IONPs) 9 MONPs 2024 Iron-oxide Nanoparticles (IONPs) Iron oxide nanoparticles (IONPS), either superparamagnetic iron oxides (SPIO) or ultrasmall superparamagnetic iron oxides (USPIO), are one of the most investigated inorganic particles used for biological applications. The utility and potential of IONPs for clinical use has been proven by the many clinically approved products. The advantages that iron oxide offer stems from their: ✓ innate magnetic responsiveness, which can be controlled in a binary manner to facilitate particle targeting, imaging, and localized heating, the latter of which can be applied towards hyperthermia treatments and tumor ablation. ✓ innate biocompatibility and biodegradability. 10 MONPs 2024  IONPs synthesis methods The magnetic properties of iron oxide nanoparticles depend on their composition and morphology. Thus, the synthetic method needs to be carefully selected, ensuring control over shape, size, size distribution and crystallinity of the particles. SPION can be produced in several different ways, encompassing chemical, physical and biosynthetic methodologies. Chemical approaches (bottom-up approaches) are employed in the vast majority of cases. Physical methods (top-down approaches) suffer from the lack of ability to control the size of particles in the nanometer size range. Biological methods (green synthesis) rely on reduction-oxidation reactions, in which microbial enzymes or plant phytochemicals are responsible for the reduction of salts into SPION. Such biosynthetic routes are generally considered eco-friendly (green chemistry) and the products obtained using such procedures tend to show good biocompatibility. However, the yield of such methods is low and the size distribution is broad. Together, physical and biosynthetic synthesis protocols make up for less than 10% of all SPION synthesis methods. 11 MONPs 2024  IONPs synthesis methods 12 MONPs 2024  IONPs synthesis methods Here are some of the commonly employed chemical synthesis routes: Co-precipitation The co-precipitation technique, which is among the most simple and efficient synthesis procedures, is based on simultaneous precipitation of Fe+2 and Fe+3 aqueous salt solutions via the addition of a weak or strong base. Most of commercially available SPION are synthesized via this method. Many synthetic parameters influence the size, shape and composition of the eventually obtained iron oxide nanoparticles, e.g. Fe+2/Fe+3 ratio, temperature, pH, type of salt used (chloride, nitrate, sulfate, perchlorate), and type of base used (NaOH, NH4OH, Na2CO3). The magnetic nanoparticles obtained by this method are of sizes ranging from 5 to 40 nm. 13 MONPs 2024  IONPs synthesis methods Co-precipitation 14 MONPs 2024  IONPs synthesis methods Thermal decomposition SPION with high control over size and shape, narrow size distribution and good crystallinity can be prepared via thermal decomposition of organoiron precursors in high-boiling point organic solvents in the presence of stabilizing surfactant. Amphiphilic surfactants like oleic acid, allow adjustment of the nucleation and growth kinetics of the nanoparticles. The high reaction temperatures and the presence of the surfactant in the reaction mixture result in high quality samples in terms of size dispersion and crystallinity. Furthermore, because of the presence of a hydrophobic coating on the surface of the magnetic nanoparticles, an additional surface modification step is needed to obtain water-dispersible and biocompatible nanoparticles that are useful for biomedical applications. When employing the thermal decomposition method to prepare SPION, control over morphology and nanoparticle size strongly depends on the reaction time, the reaction temperature and the precursor-to- surfactant ratio. 15 MONPs 2024  IONPs synthesis methods Thermal decomposition 16 MONPs 2024  IONPs synthesis methods Sol-gel technique The sol-gel technique, is based on the formation of colloidal solutions using hydrolysis and condensation of tetraethyl orthosilicate (TEOS) in ethanol and 30% aqueous H2O2 with Fe+3 solutions. The solution is then gelled by solvent removal, to obtain a 3D iron oxide network. To get iron oxide nanoparticles, the formed gel requires an additional crushing step after drying and solvent removal. Adding surfactant prior to gelation results in formation of nano-sized iron oxides without the formation of a 3D network. The size of the resulting spherical IONPs is between 15 and 50 nm. 17 MONPs 2024  IONPs synthesis methods Sol-gel technique 18 MONPs 2024  Functionalization of IONPs The magnetism of IONPs causes intrinsic instability due to agglomeration, forming large particles. In biological systems, the agglomerated nanoparticles are rapidly eliminated by the endoplasmic reticulum. Nevertheless, agglomeration can increase the content of Fe ions causing toxicity in the organism. In addition, IONPs are easily oxidizable by the oxygen of the environment which provokes a significant reduction of their magnetism and dispersibility. According to this, it is necessary to develop bio-functional coatings in IONPs to improve its dispersibility in water, protect therapeutic agents against degradation, and play a significant role in biokinetics and biodistribution of IONPs in the organism. This modification can be performed either during synthesis or afterwards, utilizing chemical function motifs that bind strongly to hydroxides on the nanoparticle surface. 19 MONPs 2024  Functionalization of IONPs Main approaches in IONPs surface functionalization: 1. Ligand Exchange. 2. Ligand Encapsulation. 3. Silanization. 20 MONPs 2024  Functionalization of IONPs 1. ligand-exchange Ligand exchange is a prevalent method for modifying the surface properties of IONPs, converting their hydrophobic nature to hydrophilic, and causing chemical bonding between IONPs and functional groups. This process involves replacing the initial hydrocarbon layer with new functional groups that both bonds tightly to the IONP surface and enhances water solubility. By using ligands such as amines, carboxylic acids, dopamine, or phosphine the colloidal stability of the nanoparticles is achieved. Ligand exchange offers versatility and can be performed under mild conditions, but it may face challenges such as limited long-term stability and difficulties in controlling shell thickness. 21 MONPs 2024  Functionalization of IONPs 2. Ligand Encapsulation For biomedical application, one of the other approaches to creating hydrophilic and biocompatible IONPs is ligand encapsulation which encapsulates nanoparticle in self-assembled polymer. In this innovative approach, IONP unfolds through a series of connections with an encapsulating agent that resides within the solution. Various encapsulation approaches exist, classified based on the encapsulation technique and the type of shell material used. Common shell materials include amphiphilic ligands, hydrophilic inorganic substances, and water-soluble polymer matrices. 22 MONPs 2024  Functionalization of IONPs 2. Ligand Encapsulation This method often utilizes a wide range of both natural and synthetic biodegradable polymers, such as Polysaccharides, Chitosan, Dextran and PEG and inorganic material such as silica can be used. Functional coatings for IONPs can be broadly classified as: organic and inorganic. 23 MONPs 2024  Functionalization of IONPs 3. Silanization Silica is one of the most frequently used compounds for coating the surface of IONPs to reduce their toxicity. Its application is common in functionalizing nanoparticle surfaces, improving stability in water, and providing protection under acidic conditions. Coating with silica typically increases the particle size and modifies the magnetic properties of IONPs. It also enables the attachment of various surface ligands and acts as a protective shield for both drug molecules and the nanoparticle itself. Additionally, small compounds like pharmaceuticals, dyes, or quantum dots can be embedded into the silica layer during its formation. The silica surface allows covalent bonding with ligands and biomolecules, facilitating targeted delivery to specific organs via antibody–antigen interactions. 24 MONPs 2024  Applications of IONPs Of all inorganic nanoparticles, IONPs have been tested in the clinic more than any other type. In fact, many IONPs have been approved for use in the clinic as diagnostic and imaging agents. For example, many IONP formulations have been approved by the FDA for imaging of different pathologies, and even for treatment of iron deficiency. Despite these successes, the majority of approved IONPs have since been discontinued. The specific reasons for discontinuation are not clear for each product. 25 MONPs 2024  Applications of IONPs 1. IONPs in drug delivery, anticancer as an example/ in vitro studies The IONPs target various type of tumor cells and induce tumor cell death without affecting normal cell viability. The toxicity of IONPs in tumor cells is mainly related to the shape, surface modification, size, concentration and valence state. Importantly, an applied external magnetic field, display a synergistic anticancer effect. Many studies investigate the use of magnetic nanoparticles (MNPs) for magnetic hyperthermia since they have high magnetic heating efficiency and display biocompatible properties. MNPs that carry an anticancer drug are administered intravenously in order to localize at the desired location with the use of an external magnetic field. Magnetic targeted treatment is based on the use of magnetic field to produce magnetic force on MNPs. In a drug delivery system, a drug or a therapeutic compound is conjugated (adsorbed, attached, or encapsulated) to a magnetic nanocarrier while later being administered and released. Such nanocarriers, which are stimuli-responsive, have been proven to be improved for in vivo and in vitro drug releases. 26 MONPs 2024  Applications of IONPs 1. IONPs in drug delivery, anticancer as an example/ in vitro studies 27 MONPs 2024  Applications of IONPs 2. Diagnostic and therapeutic applications Currently, the most clinically relevant IONP is ferumoxytol, trade name Feraheme® in the US and Rienso® in Europe. Ferumoxytol is developed and distributed by AMAG Pharmaceuticals®, originally investigated as an MRI contrast agent, but was approved for the treatment of iron deficiency in adults with chronic kidney disease in 2009 by the FDA. Interestingly, ferumoxytol is widely explored in numerous clinical studies for many other applications including additional treatments for anemia and also for imaging. 28 MONPs 2024  Applications of IONPs 2. Diagnostic and therapeutic applications Ferumoxytol are ultrasmall superparamagnetic iron oxide (USPIO) nanoparticles, approximately 17–31 nm in diameter, coated with polyglucose sorbitol carboxymethylether. Intravenous iron treatments are often used in severely anemic patients, though they raise certain safety concerns, are limited by low doses, and are riddled with many systemic side effects which all limit further dosing and therefore treatment. In early clinical trials, ferumoxytol showed advantages over traditional iron treatments, such as improved pharmacokinetic properties and simpler administration methods. Ferumoxytol is also being studied in a number of clinical trials for the imaging of a variety of diseases and conditions, ranging from: multiple sclerosis to numerous cancers (e.g. prostate, bladder, breast, lung, ovarian, to name a few) to heart conditions. 29 MONPs 2024  List of FDA-approved IONPs products 30 MONPs 2024 Silicon dioxide NPs  Silicon dioxide nanoparticles Silicon dioxide (SiO2), is a naturally occurring silicon oxide found in various forms such as quartz. It is versatile and present in both natural minerals and synthetic products. Silica nanoparticles, typically ranging from 55 to 310 nm in diameter, have several significant physicochemical properties that make them useful for various applications, particularly in their mesoporous form (MSNs). MSNs exhibit high surface areas and large pore volumes, allowing them to adsorb and encapsulate large amounts of guest molecules. The pore size of MSNs can be tailored, enabling control over the size of the molecules they can load. Additionally, MSNs demonstrate excellent thermal and chemical stability and generally considered biocompatible, thus have been extensively studied for biomedical applications, such as drug delivery and biosensing. 32 MONPs 2024  Silicon dioxide NPs synthesis methods Silica nanoparticles can be synthesized by a number of protocols, yielding nanoparticles over a size range of 10–500 nm with a variety of shapes and physicochemical properties. The most commonly employed methods for the synthesis of SiNPs are the Stober’s process and the microemulsion method. 33 MONPs 2024  Silicon dioxide NPs synthesis methods 1. Stöber’s method This technique utilizes a silica precursor, tetraethyl orthosilicate (TEOS) which in the presence of ethanol and ammonium hydroxide (NH2OH), undergoes hydrolysis followed by a polycondensation reaction to produce non-porous silica particles with sizes less than 200 nm. This synthesis protocol has now been fine-tuned to suit user-specific requirements. ✓The particle size decrease with an increase in the rate of addition of the TEOS, and precisely controlling the rate of addition produced uniform particles. Further experiments with Stöber type processes have demonstrated that controlling the ratio of solvent/TEOS permits fine control of particle size. Generally, as the solvent to TEOS ratio increases, the diameter of the synthesized particle decreases. 34 MONPs 2024  Silicon dioxide NPs synthesis methods 1. Stöber’s method 35 MONPs 2024  Silicon dioxide NPs synthesis methods 2. Modified Stöber’s method Modified Stober’s method with the incorporation of surfactants such as cetyltrimethylammonium bromide (CTAB) and, site-directing agents is widely used to synthesize MSN with pore sizes ranging between 2 and 50 nm. These porous compartments are widely utilized for loading different drugs and biomolecules such as proteins, peptides, and DNA for various therapeutic and biomedical applications. Tightly controlling the surfactant and TEOS concentrations can yield uniform structured mesoporous nanoparticles. 36 MONPs 2024  Silicon dioxide NPs synthesis methods 2. Modified Stöber’s method 37 MONPs 2024  Silicon dioxide NPs synthesis methods 3. Microemulsion technique Another standard method for the synthesis of SiNPs is the microemulsion technique, which involves the formation of oil-in-water (O/W) micelles or water-in-oil (W/O) reverse micelles. These micelles stabilized by surfactants such as tweens act as nanoreactors for particle synthesis, and therefore, the size of the nanoparticles primarily depends on the volume of these nanoreactors. It is inside these nanoreactors that silica precursors undergo hydrolysis and condensation reactions to form SiNPs. 38 MONPs 2024  SiO2-NPs Functionalization Functionalization is generally used to alter the surface properties of SiO2 nanoparticles. Surfactants and/or polymers are generally used for functionalization of SiO2 nanoparticles. The SiO2 nanoparticles surface properties, such as morphology, size distribution, wettability and surface functional groups are mainly functionalized by these modifiers. The underlying mechanisms are mainly attributed to physical adsorption and chemical bonding. ✓ Although the physical adsorption process generally occurs between SiO2 nanoparticles and surfactants, chemical bonding (covalent modification) might happen between SiO2 nanoparticles with any modifier, either surfactant or polymer. ✓This covalent modification strategy involves either co-condensation or post-synthetic grafting of different functional silanes onto the surface silanol groups 39 MONPs 2024  SiO2-NPs Functionalization ❖The post-synthetic grafting involves conjugation of functional groups, mostly on the surface of the nanoparticle. ❖The co-condensation approach entails the presence of modified functional groups even inside the pores of the nanoparticles. Several studies have shown that PEG, being a hydrophilic polymer, forms a protective layer around the nanoparticles, effectively hiding the reactive surface groups. With a “stealth” mode of action, this modification prevents the binding of non-specific serum proteins, thereby avoiding early clearance from the circulation. 40 MONPs 2024  SiO2-NPs Functionalization 41 MONPs 2024  SiO2-NPs Functionalization 42 MONPs 2024  SiO2-NPs Functionalization 43 MONPs 2024  SiO2-NPs Applications 1. Drug Delivery Mesoporous silica nanoparticles (MSNs) are highly promising for encapsulating diverse therapeutic agents due to their high surface area and tunable pore size. Loading drugs within MSN pores offers several advantages, including an enhanced solubility for poorly soluble drugs, targeted delivery through surface ligand attachment to specific cells or tissues, and controlled release governed by factors such as the pore size, surface functionalization, and external stimuli. This controlled release enables optimized drug delivery with sustained or triggered release profiles. Previous studies have extensively investigated MSNs for delivering various drugs, including anticancer agents, antibiotics, and gene therapy vectors. For example, research has demonstrated that MSNs loaded with doxorubicin, a chemotherapy drug, exhibited improved antitumor activity compared to the free drug. Furthermore, functionalizing MSNs with antibodies has shown efficacy in targeting specific cancer cells, thereby enhancing drug delivery while minimizing systemic exposure. 44 MONPs 2024  SiO2-NPs Applications 2. Bioimaging and biosensing Mesoporous silica nanoparticles (MSNs) offer a versatile platform for functionalization with fluorescent dyes or other imaging agents, enabling their visualization within the body via techniques such as fluorescence imaging or magnetic resonance imaging (MRI). This capability holds significant value for tracking drug delivery, as incorporating imaging moieties into drug- loaded MSNs allows researchers to monitor their biodistribution and release in real-time. Moreover, MSNs functionalized with specific targeting molecules can facilitate the diagnostic imaging of diseased tissues or specific biomarkers. Researchers can also create sensors that can selectively bind to specific analytes (target molecules). This binding event can then be transduced into a measurable signal (e.g., fluorescence change) for detection. 45 MONPs 2024  THANK YOU! 46 MONPS 2024