Ultrasmall Iron Oxide Research Articles

PEGylated Ultrasmall Iron Oxide Nanoparticles as MRI Contrast Agents for Vascular Imaging and Real-Time Monitoring.

Accurate imaging evaluations of pre- and post-treatment of cardiovascular diseases are pivotal for effective clinical interventions and improved patient outcomes. However, current imaging methods lack real-time monitoring capabilities with a high contrast and resolution during treatments. This study introduces PEGylated ultrasmall iron oxide nanoparticles (PUSIONPs), which have undergone comprehensive safety evaluations, boasting an r1 value of 6.31 mM-1 s-1, for contrast-enhanced magnetic resonance angiography (MRA). Systematic comparisons against common clinical methods in rabbits reveal that PUSIONPs-enhanced MRA exhibited improved vascular contrast, clearer vascular boundaries, and superior vessel resolution. Moreover, owing to their nanosize, PUSIONPs demonstrate significantly prolonged blood circulation compared to small molecular contrast agents such as Magnevist and Ultravist. This extended circulation enables captivating real-time monitoring of thrombolysis treatment for up to 4 h in rabbit models postsingle contrast agent injection. Additionally, in larger animal models such as beagles and Bama minipigs, PUSIONPs-enhanced MRA also showcases superior contrast effects, boundary delineation, and microvessel visualization, underscoring their potential to transform cardiovascular imaging, particularly in real-time monitoring and high-resolution visualization during treatment processes.

A novel water-soluble polymer nanocomposite containing ultra-small Fe3O4 nanoparticles with strong antibacterial and antibiofilm activity.

A novel water-soluble polymer nanocomposite containing ultra-small iron oxide nanoparticles, intercalated into a biocompatible matrix of 1-vinyl-1,2,4-triazole and N-vinylpyrrolidone copolymer has been synthesized for the first time. The use of an original polymer matrix ensured effective stabilization of the crystalline phase of iron oxides at an early stage of its formation in an ultra-small (2-8 nm, average diameter is 4.8 nm) nanosized state due to its effective interaction with the functional groups of copolymer macromolecules. At the same time, the copolymer ensures the long-term stability of iron oxide nanoparticles in a nanosized dispersion. The structure and physicochemical properties of the copolymer and nanocomposite were studied by elemental analysis, 1H and 13C NMR spectroscopy, gel permeation chromatography, Fourier-transform infrared spectroscopy, transmission and scanning electron microscopy, dynamic light scattering, thermogravimetric analysis and differential scanning calorimetry. The nanocomposite exhibits high antibacterial and antibiofilm activity against both Gram-negative and Gram-positive bacteria. The nanocomposite at a concentration of 500 and 1000 μg mL-1 leads to complete death of Escherichia coli cells after 24 and 3 hours of incubation, respectively. The nanocomposite at a concentration of 100 μg mL-1 leads to complete death of Staphylococcus aureus cells after 24 hours of incubation. Which indicates the potential of using the nanocomposite for the treatment of superficial wounds and purulent-inflammatory complications.

Designing iron oxide & silver nanocomposites with phyto- and fungo chemicals for biomedicine: lessons learned.

Multifunctional nanoparticles for biomedical applications are widely researched and constantly developed because they provide wider possibilities for therapy and diagnostics. This work aims to summarise our findings towards the design of multifunctional complex iron oxide and silver nanoparticles (NPs) produced from the plants Zingiber officinale and Hypericum perforatum and mushrooms Amanita muscaria and Sparassis crispa. It was revealed that the antimicrobial and anticancer properties of the NPs were a consequence of the combination of silver and phyto- and fungo-chemicals originating from natural species. Moreover, the photoactive properties of the complex iron oxide and silver nanoparticles promoted photodynamic therapy (λexc = 405 nm) that significantly improved the antibacterial (E. coli, S. aureus, B. pumilus, P. fluorescence) and anticancer (HeLa, U2OS cells) effects. Notably, the gel formulations of the NPs based on hyaluronic and alginic acids had advantages over the aqueous dispersions of the NPs. For instance, being embedded into a hyaluronic acid gel, the NPs were more effective against cancer cells due to the improved uptake of hyaluronic acid by cancer cells. Another advantage of gel formulations of the NPs was connected with their microstructural properties; the nanocomposite gel adjusted its microstructure to the substrate topology, mimicking the substrate scale and pattern. Thus, complex ultrasmall iron oxide and silver nanoparticle NPs synthesized with natural extracts and their gel formulations may find diverse applications in the biomedical field, particularly for local cancer treatment and as post-operative bone or tissue scaffold after cancer or chronic osteomyelitis surgery.

Single cell combined with laser ablation ICP-MS to study cisplatinum (IV) loaded nanoparticles penetration pathways in osteosarcoma spheroids

Background3D cellular structures have been considered the following step in the evaluation of drugs penetration after 2D cultures since they are more physiologically representative in cancer cell biology. Here the penetration capabilities of Pt (IV)-loaded ultrasmall iron oxide nanoparticles in 143B osteosarcoma multicellular spheroids of different sizes is conducted by a multidimensional quantitative approach. Single cell (SC) and imaging techniques (laser ablation, LA) coupled to inductively coupled plasma-mass spectrometry (ICP-MS) are used to visualize their penetration pathways and distribution in comparison to those of cisplatin. ResultsThe analysis of Pt in disaggregated individual cells from spheroids shows levels of incorporation dependent on the spheroid surface to volume ratio and considerably higher than those observed for cisplatin. These results in combination with the total Pt determination in the complete spheroids reveal a preferential transcellular incorporation pathway of the Pt(IV)-loaded NPs. Elemental imaging by LA-ICP-MS shows the co—localization of Pt/Fe in hot spots at distances up to 100 μm from the spheroid surface reaching concentrations of Pt up to 200 μg g−1 when exposed to Pt(IV)-loaded NPs. A more homogeneous distribution all along the spheroid is observed in the cisplatin-treated models. SignificanceThe multidimensional ICP-MS based analytical methodology developed through this work offers a generalizable approach to quantitatively study the tissue penetration of nano-transported drugs to be applied in the design of nanoparticles with high accumulation at a target site.

Magnetic nanoradiotracers for targeted neutrophil detection in pulmonary arterial hypertension

BackgroundPulmonary arterial hypertension (PAH) is a severe disease characterized by elevated blood pressure in the pulmonary artery that can ultimately damage the right ventricle of the heart. PAH is pathophysiologically heterogeneous, which makes early diagnosis and treatment difficult. Inflammation is thought to be an important factor in the development and progression of this disease and may explain some of the observed interindividual differences. In the context of both acute and chronic inflammation, neutrophil recruitment to the lung has been suggested as a potential biomarker for studying PAH progression. However, there are currently no specific probes for its non-invasive in vivo detection. The imaging-based gold standard for assessing inflammation is [18F] fluorodeoxyglucose (18F-FDG), which is not cell specific. This highlights the urgent need for more specific molecular probes to support personalized medicine.MethodsThis study investigated the potential of magnetic nanoradiotracers based on ultrasmall iron oxide nanoparticles, functionalized with N-cinnamoyl-F-(D)L-F-(D)L-F peptide, to detect increased neutrophil infiltration in vivo in different PAH animal models via positron emission tomography. These nanoprobes target formyl peptide receptor 1, which is abundantly expressed in the cell membrane of neutrophils. To assess the benefit of these nanoprobes, their biodistribution was first assessed via magnetic resonance imaging and histology. Then, their lung uptake was compared by positron emission tomography with that of 18F-FDG in two types of PAH animal models with different profiles of inflammation and neutrophil infiltration: monocrotaline and double-hit Sugen-chronic hypoxia PAH rat models.ResultsOur targeted magnetic nanoradiotracer detected an increase in pulmonary neutrophil infiltration in both PAH models and distinguished between them, which was not possible with 18F-FDG PET.ConclusionsThis study underscores the importance of targeted imaging in providing an individualized and longitudinal evaluation of heterogeneous and multifactorial diseases such as PAH. The use of targeted multimodal nanoprobes, for magnetic resonance/positron emission tomography imaging has the potential to facilitate the diagnosis and monitoring of diseases, as well as the development of novel therapies.Graphical abstract

Clustered ultra-small iron oxide nanoparticles as potential T1/T2 dual–modal magnetic resonance imaging contrast agents and application to tumor model

Many studies have been conducted on the use of ultra-small iron oxide nanoparticles (USIONs) (d < 3 nm) as potential positive magnetic resonance imaging (MRI)-contrast agents (CAs); however, there is dearth of research on clustered USIONs. In this study, nearly monodispersed clustered USIONs were synthesized using a simple two-step one-pot polyol method. First, USIONs (d = 2.7 nm) were synthesized, and clustered USIONs (d = 27.9 nm) were subsequently synthesized through multiple cross-linking of USIONs with poly(acrylic acid-co-maleic acid) (PAAMA) polymers with many -COOH groups. The clustered PAAMA-USIONs exhibited very weak ferromagnetism owing to the magnetic interaction between superparamagnetic USIONs; this was evidenced by their appreciable r1= 3.9 s‒1mM‒1and high r2/r1ratio of 14.6. Their ability to function as a dual-modal T1/T2MRI-CA in T1-weighted MRI was demonstrated when they simultaneously exhibited positive and negative contrasts in T1-weighted MRI of tumor model mice after intravenous injection. They displayed positive contrasts at the kidneys, bladder, heart, and aorta and negative contrasts at the liver and tumor.&#xD.

Using Adaptive Imaging Parameters to Improve PEGylated Ultrasmall Iron Oxide Nanoparticles-Enhanced Magnetic Resonance Angiography.

The PEGylated ultrasmall iron oxide nanoparticles (PUSIONPs) exhibit longer blood residence time and better biodegradability than conventional gadolinium-based contrast agents (GBCAs), enabling prolonged acquisitions in contrast-enhanced magnetic resonance angiography (CE-MRA) applications. The image quality of CE-MRA is dependent on the contrast agent concentration and the parameters of the pulse sequences. Here, a closed-form mathematical model is demonstrated and validated to automatically optimize the concentration, echo time (TE), repetition time (TR) and flip angle (FA). The pharmacokinetic studies are performed to estimate the dynamic intravascular concentrations within 12h postinjection, and the adaptive concentration-dependent sequence parameters are determined to achieve optimal signal enhancement during a prolonged measurement window. The presented model is tested on phantom and in vivo rat images acquired from a 3T scanner. Imaging results demonstrate excellent agreement between experimental measurements and theoretical predictions, and the adaptive sequence parameters obtain better signal enhancement than the fixed ones. The low-dose PUSIONPs (0.03mmol kg-1 and 0.05mmol kg-1) give a comparable signal intensity to the high-dose one (0.10mmol kg-1) within 2h postinjection. The presented mathematical model provides guidance for the optimization of the concentration and sequence parameters in PUSIONPs-enhanced MRA, and has great potential for further clinical translation.

Trapped in Endosome PEGylated Ultra-Small Iron Oxide Nanoparticles Enable Extraordinarily High MR Imaging Contrast for Hepatocellular Carcinomas.

The early diagnosis of hepatocellular carcinomas (HCCs) remains challenging in the clinic. Primovist-enhanced magnetic resonance imaging (MRI) aids HCC diagnosis but loses sensitivity for tumors <2cm. Therefore, developing advanced MRI contrast agents is imperative for improving the diagnostic accuracy of HCCs in very-early-stage. To address this challenge, PEGylated ultra-small iron oxide nanoparticles (PUSIONPs) are synthesized and employed as liver-specific T1 MRI contrast agents. Intravenous delivery produces simultaneous hyperintense HCC and hypointense hepatic parenchyma signals on T1 imaging, creating an extraordinarily high tumor-to-liver contrast. Systematic studies uncover PUSIONP distribution in hepatic parenchyma, HCC lesions at the organ, tissue, cellular, and subcellular levels, revealing endosomal confinement of PUSIONP without aggregation. By mimicking such situations, the dependency of relaxometric properties on local PUSIONP concentration is investigated, emphasizing the key role of different endosomal concentrations in liver and tumor cells for high tumor-to-liver contrast and clear tumor boundaries. These findings offer exceptional imaging capabilities for early HCC diagnosis, potentially benefiting real HCC patients.

Three-Dimensional Label-Free Observing of the Self-Assembled Nanoparticles inside a Single Cell at Nanoscale Resolution.

Understanding the intracellular behavior of nanoparticles (NPs) plays a key role in optimizing the self-assembly performance of nanomedicine. However, conducting the 3D, label-free, quantitative observation of self-assembled NPs within intact single cells remains a substantial challenge in complicated intracellular environments. Here, we propose a deep learning combined synchrotron radiation hard X-ray nanotomography approach to visualize the self-assembled ultrasmall iron oxide (USIO) NPs in a single cell. The method allows us to explore comprehensive information on NPs, such as their distribution, morphology, location, and interaction with cell organelles, and provides quantitative analysis of the heterogeneous size and morphologies of USIO NPs under diverse conditions. This label-free, in situ method provides a tool for precise characterization of intracellular self-assembled NPs to improve the evaluation and design of a bioresponsive nanomedicine.

Erythrocyte-Membrane-Camouflaged Magnetic Nanocapsules With Photothermal/Magnetothermal Effects for Thrombolysis.

Venous/arterial thrombosis poses significant threats to human health. However, drug-enabled thrombolysis treatment often encounters challenges such as short half-life and low bioavailability. To address these issues, the design of erythrocyte-membrane (EM) camouflaged nanocapsules (USIO/UK@EM) incorporating ultra-small iron oxide (USIO) and urokinase (UK) drug, which exhibits remarkable photothermal/magnetothermal effects and drug delivery ability for venous/arterial thrombolysis, is reported. USIO, UK, and EM are coextruded to fabricate USIO/UK@EM with average sizes of 103.7nm. As USIO/UK@EM possesses wide photoabsorption and good magnetic properties, its solution demonstrates a temperature increase to 41.8-42.9°C within 5min when exposed to an 808nm laser (0.33mW cm-2) or alternating magnetic field (AMF). Such photothermal/magnetothermal effect along with UK confers impressive thrombolytic rates of 82.4% and 74.2%, higher than that (≈15%) achieved by UK alone. Further, the EM coating extends the circulating half-life (t1/2 = 3.28h). When USIO/UK@EM is administered to mice and rabbits, tail vein thrombus in mice and femoral artery thrombus in rabbits can be dissolved by the synergetic effect of thermothrombolysis and UK. Therefore, this study not only offers insights into the rational design of multifunctional biomimetic nanocapsules but also showcases a promising thrombolysis strategy utilizing nanomedicine.

Acidic tumor microenvironment-activated MRI nanoprobes for modulation and visualization of anti-PD-L1 immunotherapy

Tumor acidity has emerged as a pivotal regulator of immune checkpoint blockade (ICB). However, acidity-based therapy presents challenges of low efficiency and lack of reliable imaging technology for assessing the immune response. Here we report a magnetic resonance imaging (MRI)-guided ICB therapy (MRGIT) strategy to modulate and visualize the efficacy of anti-PD-L1 in pancreatic ductal adenocarcinoma (PDAC). MRGIT was achieved by a pH responsive nanoprobe (APPAM@U-104) composed of ultrasmall iron oxide nanoparticles (USIONs) and a tumor pH regulator (U-104). Notably, the nanoprobes exhibited a T1 “ON” MR signal in acidic tumors but switched to a T2 “ON” MR signal in a neutralized tumor microenvironment, resulting in a switchable MR signal from T1 to T2 during real-time MRI monitoring. Moreover, the switch of MR signals can serve as an indicator for alleviating tumor immune suppression, thus guiding the timing of anti-PD-L1 therapy. Our results revealed that the MRGIT strategy can potentiate the antitumor efficacy of anti-PD-L1 against pancreatic tumors. Collectively, this strategy sensitively regulates and recognizes tumor acidosis, thus paving the way for the modulation and noninvasive monitoring of anti-PD-L1 efficacy in PDAC.

Pilot-scale co-precipitation synthesis of a novel active ingredient made of ultrasmall iron (oxyhydr)oxide nanoparticles for the treatment of hyperphosphatemia.

Due to its simplicity, co-precipitation is the most commonly used method for producing iron (oxyhydr)oxide nanoparticles. However, it is reported to be sensitive to changes in process parameters, which complicates scale-up and is why only volumes up to 1.2 L have been described in the literature. This study aims to demonstrate the scale-up of a co-precipitation synthesis to 100 L using the example of a new phosphate-binding active ingredient based on iron (oxyhydr)oxide. The synthesis was shown to be very robust to changes in synthesis parameters and stirrer geometries. The in vitro phosphate-binding efficacy and the yield were maintained in all five scales tested. Only the content of the components in the nanoparticles varied slightly. However, Mössbauer spectroscopy, dynamic light scattering (DLS), and attenuated total reflection Fourier transform infrared spectroscopy (FT-IR) revealed no evidence of structural changes, but a reduction in the size of the iron (oxyhydr)oxide cores and the total core-shell nanoparticle sizes. Overall, this study has successfully demonstrated that ultrasmall iron (oxyhydr)oxide nanoparticles can be produced on a pilot scale by co-precipitation with a yield of >40 g L-1.

Ultrasmall Mn-doped iron oxide nanoparticles with dual hepatobiliary and renal clearances for T1 MR liver imaging.

Although magnetic nanoparticles demonstrate significant potential as magnetic resonance imaging (MRI) contrast agents, their negative contrasts, liver accumulation, and limited excretion hinder their application. Herein, we developed ultrasmall Mn-doped iron oxide nanoparticles (UMIOs) with distinct advantages as T1 MRI contrast agents. Exceptionally small particle sizes (ca. 2 nm) and magnetization values (5 emu gMn+Fe-1) of UMIOs provided optimal T1 contrast effects with an ideally low r2/r1 value of ∼1. Furthermore, the use of Mn as a dopant facilitated hepatocyte uptake of the particles, allowing liver imaging. In animal studies, UMIOs exhibited significantly enhanced contrasts for sequential T1 imaging of blood vessels and the liver, distinguishing them from conventional magnetic nanoparticles. UMIOs were systematically cleared via dual hepatobiliary and renal excretion pathways, highlighting their safety profile. These characteristics imply substantial potential of UMIOs as T1 contrast agents for the accurate diagnosis of liver diseases.

Macrophage membrane-camouflaged nanoclusters of ultrasmall iron oxide nanoparticles for precision glioma theranostics.

Developing effective nanomedicines to cross the blood-brain barrier (BBB) for efficient glioma theranostics is still considered to be a challenging task. Here, we describe the development of macrophage membrane (MM)-coated nanoclusters (NCs) of ultrasmall iron oxide nanoparticles (USIO NPs) with dual pH- and reactive oxygen species (ROS)-responsivenesses for magnetic resonance (MR) imaging and chemotherapy/chemodynamic therapy (CDT) of orthotopic glioma. Surface citrate-stabilized USIO NPs were solvothermally synthesized, sequentially modified with ethylenediamine and phenylboronic acid, and cross-linked with gossypol to form gossypol-USIO NCs (G-USIO NCs), which were further coated with MMs. The prepared MM-coated G-USIO NCs (G-USIO@MM NCs) with a mean size of 99.9 nm display tumor microenvironment (TME)-responsive gossypol and Fe release to promote intracellular ROS production and glutathione consumption. With the MM-mediated BBB crossing and glioma targeting, the G-USIO@MM NCs can specifically inhibit orthotopic glioma in vivo through the gossypol-mediated chemotherapy and Fe-mediated CDT. Meanwhile, USIO NPs can be dissociated from the NCs under the TME, thus allowing for effective T1-weighted glioma MR imaging. The developed G-USIO@MM NCs with simple components and drug as a crosslinker are promising for glioma theranostics, and may be extended to tackle other cancer types.

Ultrasmall iron oxide nanoparticles with MRgFUS for enhanced magnetic resonance imaging of orthotopic glioblastoma.

Ultrasmall iron oxide nanoparticles (USIO NPs) are expected to become the next generation T1 contrast agents; however, their diagnostic and therapeutic potential for primary brain tumors (such as glioblastoma multiforme, GBM) is yet to be explored. At present, the main challenge is the effective hindering of biological barriers, including the blood-brain barrier (BBB) and the blood-brain tumor barrier (BBTB). Herein, we aimed to investigate whether the USIO NPs, in combination with MR-guided focused ultrasound (MRgFUS), could intensify MR imaging of GBM. In this study, we presented zwitterionic USIO NPs for enhanced MR imaging of both xenografted and orthotopic GBM mouse models. We first synthesized citric-stabilized USIO NPs with a size of 3.19 ± 0.76 nm, modified with ethylenediamine, and decorated with 1,3-propanesultone (1,3-PS) to form USIO NPs-1,3-PS. The obtained USIO NPs-1,3-PS exhibited good cytocompatibility and cellular uptake efficiency. MRgFUS, in combination with microbubbles, provided a non-invasive and safe technique for BBB opening, which, in turn, promoted the delivery of USIO NPs-1,3-PS in orthotopic GBM. This developed USIO NP nanoplatform may improve the precision imaging of solid tumors and therapeutic efficacy in the central nervous system.

Process development for pilot-scale spray drying of ultrasmall iron (oxyhydr)oxide nanoparticles

In manufacturing iron (oxyhydr)oxide nanoparticles, drying is often necessary to increase stability or to enable granulation and tableting. Lyophilization is a simple drying method, although it is characterized by high energy consumption and high cost. This study aims to demonstrate that spray drying is a suitable alternative for preparing iron (oxyhydr)oxide nanoparticles. A Design of Experiment approach was used varying the inlet air temperature, feed flow rate, and feed concentration. Especially a low feed flow rate was beneficial for low residual moisture (< 7%) and high yield (> 80%). The process was subsequently transferred to pilot scale at a feed flow rate of 2.3 kg/h. The nanomaterial had comparable properties and efficacy to the freeze-dried product. However, about 15% lower yield and 35% lower energy consumption were found for spray drying the nanoparticles. This study shows that spray drying is a suitable alternative to freeze drying for iron (oxyhydr)oxide nanoparticles.

Exploring atherosclerosis imaging with contrast-enhanced MRI using PEGylated ultrasmall iron oxide nanoparticles.

Plaque rupture is a critical concern due to its potential for severe outcomes such as cerebral infarction and myocardial infarction, underscoring the urgency of noninvasive early diagnosis. Magnetic resonance imaging (MRI) has gained prominence in plaque imaging, leveraging its noninvasiveness, high spatial resolution, and lack of ionizing radiation. Ultrasmall iron oxides, when modified with polyethylene glycol, exhibit prolonged blood circulation and passive targeting toward plaque sites, rendering them conducive for MRI. In this study, we synthesized ultrasmall iron oxide nanoparticles of approximately 3nm via high-temperature thermal decomposition. Subsequent surface modification facilitated the creation of a dual-modality magnetic resonance/fluorescence probe. Upon intravenous administration of the probes, MRI assessment of atherosclerotic plaques and diagnostic evaluation were conducted. The application of Flash-3D sequence imaging revealed vascular constriction at lesion sites, accompanied by a gradual signal amplification postprobe injection. T1-weighted imaging of the carotid artery unveiled a progressive signal ratio increase between plaques and controls within 72h post-administration. Fluorescence imaging of isolated carotid arteries exhibited incremental lesion-to-control signal ratios. Additionally, T1 imaging of the aorta demonstrated an evolving signal enhancement over 48h. Therefore, the ultrasmall iron oxide nanoparticles hold immense promise for early and noninvasive diagnosis of plaques, providing an avenue for dynamic evaluation over an extended time frame.

Stimuli-Responsive Codelivery System Self-Assembled from in Situ Dynamic Covalent Reaction of Macrocyclic Disulfides for Cancer Magnetic Resonance Imaging and Chemotherapy.

Supramolecular self-assembly has gained increasing attention to construct multicomponent drug delivery systems for cancer diagnosis and therapy. Despite that these self-assembled nanosystems present surprising properties beyond that of each subcomponent, the spontaneous nature of co-self-assembly causes significant difficulties in control of the synthesis process and consequently leads to unsatisfactory influences in downstream applications. Hence, we utlized an in situ dynamic covalent reaction based on thiol-disulfide exchange to slowly produce disulfide macrocycles, which subsequently triggered the co-self-assembly of an anticancer drug (doxorubicin, DOX) and a magnetic resonance imaging (MRI) contrast agent of ultrasmall iron oxide nanoparticles (IO NPs). It showed concentration regulation of macrocyclic disulfides, DOX, and IO NPs by a dynamic covalent self-assembly (DCS) strategy, resulting in a stable codelivery nanosystem with high drug loading efficiency of 37.36%. More importantly, disulfide macrocycles in the codelivery system could be reduced and broken by glutathione (GSH) in tumor cells, thus leading to disassembly of nanostructures and intellgent release of drugs. These stimuli-responsive performances have been investigated via morphologies and molecular structures, revealing greatly enhanced dual-modal MRI abilities and smart drug release under the trigger of GSH. Moreover, the codelivery system conjugated with a targeting molecule of cyclic Arg-Gly-Asp (cRGD) exhibited significant biocompatibility, MR imaging, and chemotherapeutic anticancer effect in vitro and in vivo. These results indicated that in situ dynamic covalent chemistry enhanced the control over co-self-assembly and paved the way to develop more potential drug delivery systems.

Single-Cell ICP-MS in Combination with Fluorescence-Activated Cell Sorting for Investigating the Effects of Nanotransported Cisplatin(IV) Prodrugs.

The combined use of fluorescence-activated cell sorting (FACS) and single-cell inductively coupled plasma mass spectrometry (SC-ICP-MS) is reported, for the first time, in this work. It is applied to evaluate the differences between the cellular uptake of ultrasmall iron oxide nanoparticles (FeNPs) loaded with cisplatin(IV) prodrug (FeNPs-Pt(IV)) and cisplatin regarding cell viability. For this aim, FACS is applied to separate viable, apoptotic, and necrotic A2780 ovarian cancer cells after exposing them to the nanotransported prodrug and cisplatin, respectively. The different sorted cell populations are individually analyzed using quantitative SC-ICP-MS to address the intracellular amount of Pt. The highest Pt intracellular content occurs in the apoptotic cell population (about 2.1 fg Pt/cell) with a narrow intercellular distribution when using FeNPs-Pt(IV) nanoprodrug and containing the largest number of cells (75% of the total). In the case of the cisplatin-treated cells, the highest Pt content (about 1.6 fg Pt/cell) could be determined in the viable sorted cell population. The combined methodology, never explored before, permits a more accurate picture of the effect of the intracellular drug content together with the cell death mechanisms associated with the free drug and the nanotransported prodrug, respectively, and opens the door to many possible single-cell experiments in sorted cell populations.

Scalable diafiltration process for the purification of a colloidal dispersion of ultrasmall iron (oxyhydr)oxide-based nanoparticles

The process description for large-scale production of iron (oxyhydr)oxide nanoparticles is currently receiving greater attention, with cost-effective industrial production usually crucial for economic application. In this context, the purification step is often price-determining in the production process. Dialysis as membrane-assisted purification is one of the most widely used methods in the case of iron (oxyhydr)oxide nanoparticles but has very limited suitability for large-scale production. This study aims to demonstrate for the first time that cross–flow filtration is a suitable alternative for the industrial production of ultrasmall iron (oxyhydr)oxide nanoparticles. This study includes the development of a concentration and diafiltration process for ultrasmall iron (oxyhydr)oxide nanoparticles on a laboratory scale, upscaling for the purification of 75 kg nanoparticle suspension, and comparison with dialysis purification.In summary, the optimized filtration process is characterized by a consistent and high product quality and high product yield, comparable to dialysis purification and suitable for pilot-scale production. Finally, the results demonstrated that the developed process is an economically attractive alternative to dialysis. The processing time is reduced by 79 %, the water consumption is 96 % lower, and 66 % of the material costs are saved.