Iron oxide nanoparticles for treatment and diagnosis of chronic inflammatory diseases: A systematic review.

Chronic inflammatory conditions are among the most prevalent diseases worldwide. Several debilitating diseases such as atherosclerosis, inflammatory bowel disease, rheumatoid arthritis, and Alzheimer's are linked to chronic inflammation. These conditions often develop into complex and fatal conditions, making early detection and treatment of chronic inflammation crucial. Current diagnostic methods show high variability and do not account for disease heterogeneity and disease-specific proinflammatory markers, often delaying the disease detection until later stages. Furthermore, existing treatment strategies, including high-dose anti-inflammatory and immunosuppressive drugs, have significant side effects and an increased risk of infections. In recent years, superparamagnetic iron oxide nanoparticles (SPIONs) have shown tremendous biomedical potential. SPIONs can function as imaging modalities for magnetic resonance imaging, and as therapeutic agents due to their magnetic hyperthermia capability. Furthermore, the surface functionalization of SPIONs allows the detection of specific disease biomarkers and targeted drug delivery. This systematic review explores the utility of SPIONs against chronic inflammatory disorders, focusing on their dual role as diagnostic and therapeutic agents. We extracted studies indexed in the Web of Science database from the last 10 years (2013-2023), and applied systematic inclusion criteria. This resulted in a final selection of 38 articles, which were analyzed for nanoparticle characteristics, targeted diseases, in vivo and in vitro models used, and the efficacy of the therapeutic or diagnostic modalities. The results revealed that ultrasmall SPIONs are excellent for imaging arterial and neuronal inflammation. Furthermore, novel therapies using SPIONs loaded with chemotherapeutic drugs show promise in the treatment of inflammatory diseases. This article is categorized under: Therapeutic Approaches and Drug Discovery > Emerging Technologies Diagnostic Tools > In Vivo Nanodiagnostics and Imaging.

Pharmaceutical Quality by Design Approach to Develop High-Performance Nanoparticles for Magnetic Hyperthermia.

Magnetic hyperthermia holds significant therapeutic potential, yet its clinical adoption faces challenges. One obstacle is the large-scale synthesis of high-quality superparamagnetic iron oxide nanoparticles (SPIONs) required for inducing hyperthermia. Robust and scalable manufacturing would ensure control over the key quality attributes of SPIONs, and facilitate clinical translation and regulatory approval. Therefore, we implemented a risk-based pharmaceutical quality by design (QbD) approach for SPION production using flame spray pyrolysis (FSP), a scalable technique with excellent batch-to-batch consistency. A design of experiments method enabled precise size control during manufacturing. Subsequent modeling linked the SPION size (6-30 nm) and composition to intrinsic loss power (ILP), a measure of hyperthermia performance. FSP successfully fine-tuned the SPION composition with dopants (Zn, Mn, Mg), at various concentrations. Hyperthermia performance showed a strong nonlinear relationship with SPION size and composition. Moreover, the ILP demonstrated a stronger correlation to coercivity and remanence than to the saturation magnetization of SPIONs. The optimal operating space identified the midsized (15-18 nm) Mn0.25Fe2.75O4 as the most promising nanoparticle for hyperthermia. The production of these nanoparticles on a pilot scale showed the feasibility of large-scale manufacturing, and cytotoxicity investigations in multiple cell lines confirmed their biocompatibility. In vitro hyperthermia studies with Caco-2 cells revealed that Mn0.25Fe2.75O4 nanoparticles induced 80% greater cell death than undoped SPIONs. The systematic QbD approach developed here incorporates process robustness, scalability, and predictability, thus, supporting the clinical translation of high-performance SPIONs for magnetic hyperthermia.

Magnetoresponsive fluorescent core-shell nanoclusters for biomedical applications.

Nowadays, superparamagnetic iron oxide nanoparticles (SPIONs) have a dominant role in many subfields of biomedicine. Owing to their peculiar properties, they can be employed for magnetic separation, drug delivery, diagnostics, and hyperthermia treatments. However, these magnetic nanoparticles (NPs) suffer from low unit magnetization due to size constraints (up to 20-30 nm) to exhibit superparamagnetic character. In this work, we have designed and synthesized superparamagnetic nanoclusters (SP-NCs) with diameters of up to 400 nm with high unit magnetization for enhanced loading capacity. These were synthesized with conventional or microwave-assisted solvothermal methods, in the presence of either of the two biomolecules (citrate or l-lysine) as the capping agent. Primary particle size, SP-NC size, surface chemistry, and the resultant magnetic properties were observed to be significantly influenced by the choice of synthesis route and capping agent. Selected SP-NCs were then coated with a fluorophore-doped silica shell to provide fluorescence properties, in the near-infrared spectrum region, while silica provided high chemical and colloidal stability. Heating efficiency studies were performed under alternating magnetic field on the synthesized SP-NCs, highlighting their potential in hyperthermia treatment. We envision that their enhanced magnetically-active content, fluorescence, magnetic property, and heating efficiency will pave the way to more effective uses in biomedical applications.

Hyperthermia-Induced In Situ Drug Amorphization by Superparamagnetic Nanoparticles in Oral Dosage Forms.

Superparamagnetic iron oxide nanoparticles (SPIONs) generate heat upon exposure to an alternating magnetic field (AMF), which has been studied for hyperthermia treatment and triggered drug release. This study introduces a novel application of magnetic hyperthermia to induce amorphization of a poorly aqueous soluble drug, celecoxib, in situ in tablets for oral administration. Poor aqueous solubility of many drug candidates is a major hurdle in oral drug development. A novel approach to overcome this challenge is in situ amorphization of crystalline drugs. This method facilitates amorphization by molecular dispersion of the drug in a polymeric network inside a tablet, circumventing the physical instability encountered during the manufacturing and storage of conventional amorphous solid dispersions. However, the current shortcomings of this approach include low drug loading, toxicity of excipients, and drug degradation. Here, doped SPIONs produced by flame spray pyrolysis are compacted with polyvinylpyrrolidone and celecoxib and exposed to an AMF in solid state. A design of experiments approach was used to investigate the effects of SPION composition (Zn0.5Fe2.5O4 and Mn0.5Fe2.5O4), doped SPION content (10-20 wt %), drug load (30-50 wt %), and duration of AMF (3-15 min) on the degree of drug amorphization. The degree of amorphization is strongly linked to the maximum tablet temperature achieved during the AMF exposure (r = 0.96), which depends on the SPION composition and content in the tablets. Complete amorphization is achieved with 20 wt % Mn0.5Fe2.5O4 and 30 wt % celecoxib in the tablets that reached the maximum temperature of 165.2 °C after 15 min of AMF exposure. Furthermore, manganese ferrite exhibits no toxicity in human intestinal Caco-2 cell lines. The resulting maximum solubility of in situ amorphized celecoxib is 5 times higher than that of crystalline celecoxib in biorelevant intestinal fluid. This demonstrates the promising capability of SPIONs as enabling excipients to magnetically induce amorphization in situ in oral dosage forms.

Design of Gadoteridol-Loaded Cationic Liposomal Adjuvant CAF01 for MRI of Lung Deposition of Intrapulmonary Administered Particles.

Designing effective and safe tuberculosis (TB) subunit vaccines for inhalation requires identification of appropriate antigens and adjuvants and definition of the specific areas to target in the lungs. Magnetic resonance imaging (MRI) enables high spatial resolution, but real-time anatomical and functional MRI of lungs is challenging. Here, we describe the design of a novel gadoteridol-loaded cationic adjuvant formulation 01 (CAF01) for MRI-guided vaccine delivery of the clinically tested TB subunit vaccine candidate H56/CAF01. Gadoteridol-loaded CAF01 liposomes were engineered by using a quality-by-design approach to (i) increase the mechanistic understanding of formulation factors governing the loading of gadoteridol and (ii) maximize the loading of gadoteridol in CAF01, which was confirmed by cryotransmission electron microscopy. The encapsulation efficiency and loading of gadoteridol were highly dependent on the buffer pH due to strong attractive electrostatic interactions between gadoteridol and the cationic lipid component. Optimal gadoteridol loading of CAF01 liposomes showed good in vivo stability and safety upon intrapulmonary administration into mice while generating 1.5-fold MRI signal enhancement associated with approximately 30% T1 relaxation change. This formulation principle and imaging approach can potentially be used for other mucosal nanoparticle-based formulations, species, and lung pathologies, which can readily be translated for clinical use.