Quantitative Measurement of Ligand Exchange with Small-Molecule Ligands on Iron Oxide Nanoparticles via Radioanalytical Techniques

Ligand exchange on the surface of hydrophobic iron oxide nanoparticles is a common method for controlling surface chemistry for a desired application. Furthermore, ligand exchange with small-molecule ligands may be necessary to obtain particles with a specific size or functionality. Understanding to what extent ligand exchange occurs and what factors affect it is important for the optimization of this critical procedure. However, quantifying the amount of exchange may be difficult because of the limitations of commonly used characterization techniques. Therefore, we utilized a radiotracer technique to track the exchange of a radiolabeled ¹⁴C-oleic acid ligand with hydrophilic small-molecule ligands on the surface of iron oxide nanoparticles. Iron oxide nanoparticles functionalized with ¹⁴C-oleic acid were modified with small-molecule ligands with terminal functional groups including catechols, phosphonates, sulfonates, thiols, carboxylic acids, and silanes. These moieties were selected because they represent the most commonly used ligands for this procedure. The effectiveness of these molecules was compared using both procedures widely found in the literature and using a standardized procedure. After ligand exchange, the nanoparticles were analyzed using liquid scintillation counting (LSC) and inductively coupled plasma–mass spectrometry. The labeled and unlabeled particles were further characterized by transmission electron microscopy (TEM) and dynamic light scattering (DLS) to determine the particle size, hydrodynamic diameter, and zeta potential. The unlabeled particles were characterized via attenuated total reflectance–Fourier transform infrared spectroscopy (ATR–FTIR) and vibrating sample magnetometry (VSM) to confirm the presence of the small molecules on the particles and verify the magnetic properties, respectively. Radioanalytical determination of ¹⁴C-oleic acid was used to calculate the total amount of oleic acid remaining on the surface of the particles after ligand exchange. The results revealed that the ligand-exchange reactions performed using widely cited procedures did not go to completion. Residual oleic acid remained on the particles after these reactions and the reactions using a standardized protocol. A comparison of the ligand-exchange procedures indicated that the binding moiety, multidenticity, reaction time, temperature, and presence of a catalyst impacted the extent of exchange. Quantification of the oleic acid remaining after ligand exchange revealed a binding hierarchy in which catechol-derived anchor groups displace the most oleic acid on the surface of the nanoparticles and the thiol group displaces the least amount of oleic acid. Thorough characterization of ligand exchange is required to develop nanoparticles suitable for their intended application

pH Triggered Recovery and Reuse of Thiolated Poly(acrylic acid) Functionalized Gold Nanoparticles with Applications in Colloidal Catalysis

Thiolated poly­(acrylic acid) (PAA-SH) functionalized gold nanoparticles were explored as a colloidal catalyst with potential application as a recoverable catalyst where the PAA provides pH-responsive dispersibility and phase transfer capability between aqueous and organic media. This system demonstrates complete nanoparticle recovery and redispersion over multiple reaction cycles without changes in nanoparticle morphology or reduction in conversion. The catalytic activity (rate constant) was reduced in subsequent reactions when recovery by aggregation was employed, despite unobservable changes in morphology or dispersibility. When colloidal catalyst recovery employed a pH induced phase transfer between two immiscible solvents, the catalytic activity of the recovered nanoparticles was unchanged over four cycles, maintaining the original rate constant and 100% conversion. The ability to recover and reuse colloidal catalysts by aggregation/redispersion and phase transfer methods that occur at low and high pH, respectively, could be used for different gold nanoparticle catalyzed reactions that occur at different pH conditions

Influence of Ligand–Precursor Molar Ratio on the Size Evolution of Modifiable Iron Oxide Nanoparticles

During the synthesis of nanoparticles via thermal decomposition of iron precursors, the capping ligand–precursor ratio influences the resulting size of the iron oxide nanoparticles. As the molar ratio of aliphatic amines to iron precursor is increased, the average diameter of the synthesized iron oxide nanoparticles decreases. This trend is opposite to previously reported results. We investigated this phenomenon by independently varying the ligand chain length, the ligand–precursor molar ratio, and the degree of saturation of the aliphatic chain. Nuclear magnetic resonance spectra of the precursor illustrated the presence of a primary amine peak before heating and the peak absence after heating, potentially indicating that the primary amine acts as reducing agent to promote the decomposition of the iron precursor. We hypothesize that the amine groups play a dominant role in the nucleation of the particles, while the chain length and degree of aliphatic saturation have only a minor effect on particle size. The nanoparticles’ size and crystallinity were characterized with high-resolution transmission electron microscopy, dynamic light scattering, and X-ray diffraction, and the magnetic properties were characterized by magnetometry

Quantitative Measurement of Ligand Exchange on Iron Oxides via Radiolabeled Oleic Acid

Ligand exchange of hydrophilic molecules on the surface of hydrophobic iron oxide nanoparticles produced via thermal decomposition of chelated iron precursors is a common method for producing aqueous suspensions of particles for biomedical applications. Despite the wide use, relatively little is understood about the efficiency of ligand exchange on the surface of iron oxide nanoparticles and how much of the hydrophobic ligand is removed. To address this issue, we utilized a radiotracer technique to track the exchange of a radiolabeled ¹⁴C-oleic acid ligand with hydrophilic ligands on the surface of magnetite nanoparticles. Iron oxide nanoparticles functionalized with ¹⁴C-oleic acid were modified with poly­(ethylene glycol) with terminal functional groups including, l-3,4-dihydroxyphenylalanine, a nitrated l-3,4-dihydroxyphenylalanine, carboxylic acid, a phosphonate, and an amine. Following ligand exchange, the nanoparticles and byproducts were analyzed using liquid scintillation counting and inductively coupled plasma mass spectroscopy. The labeled and unlabeled particles were further characterized by transmission electron microscopy and dynamic light scattering to determine particle size, hydrodynamic diameter, and zeta potential. The unlabeled particles were characterized via thermogravimetric analysis and vibrating sample magnetometry. Radioanalytical determination of the ¹⁴C from ¹⁴C-oleic acid was used to calculate the amount of oleic acid remaining on the surface of the particles after purification and ligand exchange. There was a significant loss of oleic acid on the surface of the particles after ligand exchange with amounts varying for the different functional binding groups on the poly­(ethylene glycol). Nonetheless, all samples demonstrated some residual oleic acid associated with the particles. Quantification of the oleic acid remaining after ligand exchange reveals a binding hierarchy in which catechol derived anchor groups displace oleic acid on the surface of the nanoparticles better than the phosphonate, followed by the amine and carboxylic acid groups. Furthermore, the results show that these ligand exchange reactions do not necessarily occur to completion as is often assumed, thus leaving a residual amount of oleic acid on the surface of the particles. A thorough analysis of ligand exchange is required to develop nanoparticles that are suitable for their desired application

Effect of Postsynthesis Purifications on Gold and Silver Nanoparticle Ligand Coverage

Wet chemical nanoparticle synthesis is commonly employed because of the ability to tailor and control nanoparticle size, shape, polydispersity, and surface chemistry; however, excess ligands or free surfactants in the colloidal dispersion can be detrimental for many nanoparticle applications. Postsynthesis purification using antisolvent precipitation is a widely employed method to remove the excess ligands or precursors; however, there has been little in-depth fundamental investigation of the dynamics between the nanoparticle, ligand, and dispersing media as well as the morphology and fate of the nanoparticle and ligands during nanoparticle processing. In this paper, we investigate the changes in ligand surface coverage for dodecanethiol-stabilized gold and silver nanoparticles in response to repetitive antisolvent precipitation and redispersion using gas chromatography, thermogravimetric analysis, and small-angle neutron scattering. These techniques were each used to determine percent surface coverage and equilibrium ligand partitioning between the nanoparticle surface and bulk solution, which was then modeled with the Langmuir isotherm to determine the binding free energy. The binding free energy for dodecanethiol on 4.2 nm diameter gold nanoparticles was found to be −23 kJ/mol by gas chromatography (GC) and −34 kJ/mol by small-angle neutron scattering (SANS). The binding free energy for dodecanethiol on 7.7 nm diameter silver nanoparticles was found to be −21 kJ/mol by TGA and −29 kJ/mol by SANS. While these numbers demonstrate variability based on the method, they are comparable to literature values. Other notable results from this work demonstrate the optimization of the purification process and avoidance of using excess antisolvent which can lead to coprecipitation of the excess ligand with the nanoparticles, hindering the purification. Finally, multiple techniques for determining ligand binding free energy are demonstrated as well as evaluation of the pros and cons of each method

Iron-Loaded Magnetic Nanocapsules for pH-Triggered Drug Release and MRI Imaging

Magnetic nanocapsules were synthesized for controlled drug release, magnetically assisted delivery, and MRI imaging. These magnetic nanocapsules, consisting of a stable iron nanocore and a mesoporous silica shell, were synthesized by controlled encapsulation of ellipsoidal hematite in silica, partial etching of the hematite core in acid, and reduction of the core by hydrogen. The iron core provided a high saturation magnetization and was stable against oxidation for at least 6 months in air and 1 month in aqueous solution. The hollow space between the iron core and mesoporous silica shell was used to load anticancer drug and a T₁-weighted MRI contrast agent (Gd-DTPA). These multifunctional monodispersed magnetic “nanoeyes” were coated by multiple polyelectrolyte layers of biocompatible poly-l-lysine and sodium alginate to control the drug release as a function of pH. We studied pH-controlled release, magnetic hysteresis curves, and T₁/T₂ MRI contrast of the magnetic nanoeyes. They also served as MRI contrast agents with relaxivities of 8.6 mM^–1 s^–1 (<i>r</i>₁) and 285 mM^–1 s^–1 (<i>r</i>₂)

Monitoring pH-Triggered Drug Release from Radioluminescent Nanocapsules with X‑ray Excited Optical Luminescence

One of the greatest challenges in cancer therapy is to develop methods to deliver chemotherapy agents to tumor cells while reducing systemic toxicity to noncancerous cells. A promising approach to localizing drug release is to employ drug-loaded nanoparticles with coatings that release the drugs only in the presence of specific triggers found in the target cells such as pH, enzymes, or light. However, many parameters affect the nanoparticle distribution and drug release rate, and it is difficult to quantify drug release <i>in situ</i>. In this work, we show proof-of-principle for a “smart” radioluminescent nanocapsule with an X-ray excited optical luminescence (XEOL) spectrum that changes during release of the optically absorbing chemotherapy drug, doxorubicin. XEOL provides an almost background-free luminescent signal for measuring drug release from particles irradiated by a narrow X-ray beam. We study <i>in vitro</i> pH-triggered release rates of doxorubicin from nanocapsules coated with a pH-responsive polyelectrolyte multilayer using HPLC and XEOL spectroscopy. The doxorubicin was loaded to over 5% by weight and released from the capsule with a time constant <i>in vitro</i> of ∼36 days at pH 7.4 and 21 h at pH 5.0, respectively. The Gd₂O₂S:Eu nanocapsules are also paramagnetic at room temperature with similar magnetic susceptibility and similarly good MRI <i>T</i>₂ relaxivities to Gd₂O₃, but the sulfur increases the radioluminescence intensity and shifts the spectrum. Empty nanocapsules did not affect cell viability up to concentrations of at least 250 μg/mL. These empty nanocapsules accumulated in a mouse liver and spleen following tail vein injection and could be observed <i>in vivo</i> using XEOL. The particles are synthesized with a versatile template synthesis technique which allows for control of particle size and shape. The XEOL analysis technique opens the door to noninvasive quantification of drug release as a function of nanoparticle size, shape, surface chemistry, and tissue type

Catalytic Reaction Triggered by Magnetic Induction Heating Mechanistically Distinguishes Itself from the Standard Thermal Reaction

As a recent advancement in reaction engineering, magnetic induction heating (MIH) is utilized to initiate the intended reactions by enabling the self-heating of the ferromagnetic catalyst particles. While MIH can be energy-efficient and industrially scalable, its full potential has been underappreciated in catalysis because of the perception that MIH is merely an alternative heating approach. Unexpectedly, we show that the MIH-triggered reaction could go beyond standard thermal catalysis. Specifically, by probing the representative Pt/Fe3O4 catalysts with CO oxidation in both thermal and MIH modes with consistent temperature profiles and catalyst structures, we found that the MIH mode boosts the reactivity more than 25 times by modifying Pt–FeOx interfacial synergies and promoting facile oxidation of the adsorbed carbonyl species by atomic oxygen. As we preliminarily observed, this beneficial MIH catalysis can be translational to other thermal reactions, potentially paving the way to launch MIH catalysis as a distinct reaction category