T1 Contrast Agents Research Articles

Hybrids of manganese oxide and lipid liquid crystalline nanoparticles (LLCNPs@MnO) as potential magnetic resonance imaging (MRI) contrast agents.

Due to the health risks associated with the use of Gd-chelates and the promising effects of using nanoparticles as T1 contrast agents (CAs) for MRI, Mn-based nanoparticles are considered a highly competitive alternative. The use of hybrid constructs with paramagnetic functionality of Mn-based nanoparticles is an effective approach, in particular, the use of biocompatible lipid liquid crystalline nanoparticles (LLCNPs) as a carrier of MnO nanoparticles. LLCNPs possess a unique internal structure ensuring a payload of different polarity MnO nanoparticles. In view of MRI application, the surface properties including the polarity of MnO are crucial factors determining their relaxation rate and thus the MRI efficiency. Two novel hybrid constructs consisting of LLCNPs loaded with hydrophobic MnO-oleate and hydrophilic MnO-DMSA NPs were prepared. These nanosystems were studied in terms of their physico-chemical properties, positive T1 contrast enhancement properties (in vitro and in vivo) and biological safety. LLCNPs@MnO-oleate and LLCNPs@MnO-DMSA hybrids exhibited a heterogeneous phase composition, however with differences in the inner periodic arrangement and structural parameters, as well as in the preferable localization of MnO NPs within the LLCNPs. Also, these hybrids differed in terms of particle size-related parameters and colloidal stability, which was found to be strongly dependent on the addition of differently functionalized MnO NPs. Embedding both types of MnO NPs into LLCNPs resulted in high relaxivity parameters, in comparison to bare MnO-DMSA NPs and also commercially developed CAs (e.g. Dotarem and Teslascan). Further biosafety studies revealed that cell internalization pathways were dependent on the prepared hybrid type, while viability, effects on the mitochondria membrane potential and cytoskeletal networks were rather related to the susceptibility of the particular cell line. The high relaxation rates achieved with the developed hybrid LLCNPs@MnO enable them to be possibly used as novel and biologically safe MRI T1-enhancing CAs in in vivo imaging.

Curcumin Coated Ultra-Small Iron Oxide Nanoparticles as T1 Contrast Agents for Magnetic Resonance Imaging of Cancer Cells.

The application of nanotechnology in the molecular diagnosis and treatment of cancer is essential. This study aimed to investigate the influence of curcumin-coated ultra-small superparamagnetic iron oxide (USPIO) as a T1 contrast agent in Magnetic Resonance Imaging (MRI). In this experimental study, the influence of curcumin-coated USPIO (Fe3O4@C) on the diagnosis of the cancer cell line was investigated. After synthesis, characterization, and relaxation of Fe3O4@C, the contrast changes in T1-weight MRI to mouse colon carcinoma 26 cell line were evaluated in vitro. Fe3O4@C nanoparticles (NPs) are good at imaging; based on a relaxometry test, the r1 and r2 relaxivities of Dotarem were 3.139 and 0.603 mM-1s-1, respectively. Additionally, the r1 and r2 relaxivities of Fe3O4@C were 3.792 and 1.3 mM-1s-1, respectively, with the rate of 2.155 of r2/r1 NPs. The NPs can be identified as a positive contrast agent with a weight of T1 in MRI. The coresh-ell Fe3O4@C NPs can be effective in cancer treatment and diagnosis because of the therapeutic effects of curcumin and the properties of USPIO.

A tumor-targeting and ROS-responsive iron-based T1 magnetic resonance imaging contrast agent for highly specific tumor imaging.

T1 contrast agents (CAs) exhibit outstanding capacity in enhancing the magnetic resonance imaging (MRI) contrast between tumor tissues and normal tissues for generating bright images. However, the clinical application of representative gadolinium(III) chelate-based T1 CAs is limited due to their potential toxicity and low specificity for pathological tissues. To obtain MRI CAs with a combination of low toxicity and high tumor specificity, herein, we report a reactive oxygen species (ROS)-responsive T1 CA (GA-Fe(II)-PEG-FA), which was constructed by chelating Fe(II) with gallic acid (GA), and modified with tumor-targeted folic acid (FA). The resultant CA could accumulate in tumor tissues via the affinity between FA and their receptors on the tumor cell membrane. It realized the switch from Fe(II) to Fe(III), and further enhancing the longitudinal relaxation rate (r1) under the stimuli of ROS in the tumor microenvironment. The r1 of GA-Fe(II)-PEG-FA on a 0.5 T nuclear magnetic resonance analyzer increased to 2.20 mM-1 s-1 under ROS stimuli and was 5 times greater than the r1 (0.42 mM-1 s-1) before oxidation. The cell and in vivo experiments demonstrated that GA-Fe(II)-PEG-FA exhibited good biocompatibility and significant targeting specificity to tumor cells and tumor tissues. Furthermore, in vivo MRI studies demonstrated that the enhanced T1 contrast effect against tumors could be achieved after injecting the CA for 3 h, indicating that GA-Fe(II)-PEG-FA has the potential as an ideal tumor MRI CA to increase the contrast and improve the diagnostic precision.

ATP-responsive Mn(II)-based T1 contrast agent for MRI.

A novel diacetylpyridylcarbohydrazide-DAPyCOHz-based manganese(II) chelate with dipicolylamine/zinc(II) (DPA/Zn2+) arms (MnLDPA-Zn2) was developed for adenosine triphosphate (ATP) responsive magnetic resonance imaging (MRI) T1 contrast applications. Compound 2 shows enhanced relaxivity (r1 = 11.52 mM-1 s-1) upon selective ATP binding over other phosphates.

Amine-assisted catechol-based nanocoating on ultrasmall iron oxide nanoparticles for high-resolution T1 angiography.

Surface engineered iron oxide nanoparticles (IONPs) with catecholic ligands have been investigated as alternative T1 contrast agents. However, complex oxidative chemistry of catechol during IONP ligand exchange causes surface etching, heterogeneous hydrodynamic size distribution, and low colloidal stability because of Fe3+ mediated ligand oxidation. Herein, we report highly stable and compact (∼10 nm) Fe3+ rich ultrasmall IONPs functionalized with a multidentate catechol-based polyethylene glycol polymer ligand through amine-assisted catecholic nanocoating. The IONPs exhibit excellent stability over a broad range of pHs and low nonspecific binding in vitro. We also demonstrate that the resultant NPs have a long circulation time (∼80 min), enabling high resolution T1 magnetic resonance angiography in vivo. These results suggest that the amine assisted catechol-based nanocoating opens a new potential of metal oxide NPs to take a step forward in exquisite bio-application fields.

Hypoxia-Responsive Aggregation of Iron Oxide Nanoparticles for T1-to-T2 Switchable Magnetic Resonance Imaging of Tumors

Magnetic resonance imaging (MRI), one of the most general imaging techniques in the clinic, is widely employed for tumor diagnosis with the assistance of contrast agents (CAs). However, currently available CAs in the clinic suffer from shortcomings of a short blood circulation time, lack of specificity to pathological location, insufficient imaging window, and potential biotoxicity of the gadolinium ion. To overcome these problems, on the basis of extremely small iron oxide nanoparticles (ESIONPs), a hypoxia-responsive T1-to-T2 switchable MRI contrast agent was designed and constructed. In detail, polyacrylic acid-modified ESIONPs (ESIONPs-PAA) were first synthesized, and then, nitroimidazole derivatives and cysteine molecules were sequentially coupled on the surface of ESIONPs-PAA to obtain a hypoxia-responsive MRI contrast agent (HR-ESIONPs). Since 2-nitroimidazole and cysteine molecules on the surface of HR-ESIONPs can form an irreversible bond induced by the nitroreductase in the hypoxic tumor microenvironment, monodispersed HR-ESIONPs could transform into the nanocluster form, which can specially provide T2 contrast enhancement. In vitro experiments show that monodispersed HR-ESIONPs could effectively aggregate in the mimical hypoxic environment of tumors and switch from a T1 to T2 contrast agent. Moreover, in vivo experiments further confirm that HR-ESIONPs could effectively accumulate and realize the MRI signal switch from T1 to T2 contrast enhancement in tumors originating from the aggregation of HR-ESIONPs induced by the hypoxic environment, which promotes the diagnostic precision of tumors. Additionally, with the confirmation of favorable biosafety on cells and mice, hypoxia-responsive HR-ESIONPs are potential platforms to improve the diagnostic accuracy and sensitivity of MRI for tumors.

Tumor microenvironment-responsive histidine modified-hyaluronic acid-based MnO2 as in vivo MRI contrast agent

Tumor microenvironment (TME)-responsive manganese dioxide (MnO2) nanoparticles as a good T1 contrast agent could reduce unwanted toxicity and improve the accuracy of cancer detection. Despite these distinct advantages of MnO2-based nanoparticles, their synthesis involves multi-step processes with relatively long synthesis times. In this study, we synthesized histidine-modified hyaluronic acid (HA-His), and the prepared HA-His conjugates quickly reduce permanganate to MnO2, leading to facile production of HA-His/MnO2 nanoparticles with good water-dispersibility and stability under biological conditions. The synthesized HA-His/MnO2 nanoparticles readily responded to the TME (low pH, high H2O2, and high glutathione), and they were internalized into SCC7 cells with high CD44 expression. Moreover, the systemically administered HA-His/MnO2 nanoparticles with biocompatibility were specifically accumulated in tumor tissues, thereby efficiently enhancing T1 contrast in MRI. Therefore, the HA-His/MnO2 nanoparticles synthesized herein can be used as a promising T1 contrast agent for tumor MR imaging.

Engineered Protein-Driven Synthesis of Tunable Iron Oxide Nanoparticles as T1 and T2 Magnetic Resonance Imaging Contrast Agents.

Iron oxide nanoparticles (IONPs) have become one of the most promising nanomaterials for biomedical applications because of their biocompatibility and physicochemical properties. This study demonstrates the use of protein engineering as a novel approach to design scaffolds for the tunable synthesis of ultrasmall IONPs. Rationally designed proteins, containing different number of metal-coordination sites, were evaluated to control the size and the physicochemical and magnetic properties of a set of protein-stabilized IONPs (Prot-IONPs). Prot-IONPs, synthesized through an optimized coprecipitation approach, presented good T1 and T2 relaxivity values, stability, and biocompatibility, showing potential for magnetic resonance imaging (MRI) applications.

Synthesis and Characterization of Gold-Shell Magnetic Nanowires for Theranostic Applications

Increasing interest has been given in recent years to alternative physical therapies for cancer, with a special focus on magneto-mechanical actuation of magnetic nanoparticles. The reported findings underline the need for highly biocompatible nanostructures, along with suitable mechanical and magnetic properties for different configurations of alternating magnetic fields. Here, we show how the biocompatibility of magnetic nanowires (MNWs), especially CoFe, can be increased by gold coating, which can be used both in cancer therapy and magnetic resonance imaging (MRI). This study provides a new approach in the field of theranostic applications, demonstrating the capabilities of core–shell nanowires to be used both to increase the cancer detection limit (as T2 contrast agents) and for its treatment (through magneto-mechanical actuation). The MNWs were electrodeposited in alumina templates, whereas the gold layer was electroless-plated by galvanic replacement. The gold-coated CoFe nanowires were biocompatible until they induced high cellular death to human osteosarcoma cells via magneto-mechanical actuation. These same MNWs displayed increased relaxivities (r1, r2). Our results show that the gold-coated CoFe nanowires turned out to be highly efficient in tumor cell destruction, and, at the same time, suitable for MRI applications.

PH-Responsive chitosan-modified gadolinium oxide nanoparticles delivering 5-aminolevulinic acid: A dual cellular and metabolic T1-T2* contrast agent for glioblastoma brain tumors detection

Diagnosis of glioblastoma multiforme (GBM) with high sensitivity and specificity requires cellular and metabolic imaging. In this study, we aimed to endow gadolinium oxide nanoparticles (Gd2O3 NPs) as an interesting T1 contrast agent with T2* contrast ability through intracellular iron assistance induced by 5-aminolevulinic acid (5-ALA) with ferric ammonium citrate (FAC). Chitosan (CS)-loaded Gd2O3 NPs were loaded with 5-aminolevulinic acid (Gd2O3/CS-TPP@5-ALA NPs), and then evaluated as a pH-responsive dual cellular and metabolic T1 and T2* contrast agent for GBM diagnosis. The target NPs with an average size of 138 nm revealed concentration-dependent toxicity against glioblastoma C6 cells. The relaxation rate (R1) of the C6 cells treated with Gd2O3/CS-TPP@5-ALA NPs plus FAC was remarkably higher than the controls including Gd2O3/CS-TPP NPs, Gd2O3/CS-TPP@5-ALA NPs, and FAC (17.2 ± 2.4 vs. 8 ± 1.5, 8.4 ± 1.2, and 2.3 ± 0.5, respectively). Interestingly, the transverse relaxation rate (R2*) of the C6 cells treated with Gd2O3/CS-TPP@5-ALA NPs + FAC was significantly higher than the controls including Gd2O3/CS-TPP NPs, Gd2O3/CS-TPP@5-ALA NPs, and FAC (96 ± 8 vs. 25 ± 4, 27 ± 5, and 19 ± 2.6, respectively). We believe that Gd2O3/CS-TPP@5-ALA NPs + FAC could be introduced as promising dual cellular and metabolic T1-T2* contrast agents for GBM diagnosis in MRI.

High spin Fe(III)-doped nanostructures as T1 MR imaging probes.

Magnetic Resonance Imaging (MRI) T1 contrast agents based on Fe(III) as an alternative to Gd-based compounds have been under intense scrutiny in the last 6-8 years and a number of nanostructures have been designed and proposed for in vivo diagnostic and theranostic applications. Excluding the large family of superparamagnetic iron oxides widely used as T2 -MR imaging agents that will not be covered by this review, a considerable number and type of nanoparticles (NPs) have been employed, ranging from amphiphilic polymer-based NPs, NPs containing polyphenolic binding units such as melanin-like or polycatechols, mixed metals such as Fe/Gd or Fe/Au NPs and perfluorocarbon nanoemulsions. Iron(III) exhibits several favorable magnetic properties, high biocompatibility and improved toxicity profile that place it as the paramagnetic ion of choice for the next generation of nanosized MRI and theranostic contrast agents. An analysis of the examples reported in the last decade will show the opportunities for relaxivity and MR-contrast enhancement optimization that could bring Fe(III)-doped NPs to really compete with Gd(III)-based nanosystems. This article is categorized under: Diagnostic Tools > In Vivo Nanodiagnostics and Imaging Diagnostic Tools > Diagnostic Nanodevices Therapeutic Approaches and Drug Discovery > Nanomedicine for Oncologic Disease.

Fibrin-Targeted Nanoparticles for Finding, Visualizing and Characterizing Blood Clots in Acute Ischemic Stroke.

Recanalization of the occluded artery is the gold standard treatment for acute ischemic stroke, which includes enzymatic fibrinolytic treatment with the use of recombinant tissue plasminogen activators (rtPAs) to disrupt the occluding clot, the use of mechanical thrombectomy to physically remove the clot, or a combination of both. Fibrin is one of the main components of blood clots causing ischemic stroke and is the target of rtPA upon activation of plasminogen in the clot. In addition, fibrin content also influences the efficacy of mechanical thrombectomy. Current imaging methods can successfully identify occlusions in large vessels; however, there is still a need for contrast agents capable of visualizing small thrombi in ischemic stroke patients. In this work, we describe the synthesis and the in vitro characterization of a new diagnostic nanoparticle, as well as the in vivo evaluation in an animal model of thromboembolic stroke. Gd-labeled KCREKA peptides were synthesized and attached onto the surface of PEGylated superparamagnetic nanoparticles. Magnetic resonance imaging (MRI) of blood clots was performed in vitro and in vivo in animal models of thromboembolic stroke. KCREKA-NPs were synthesized by attaching the peptide to the amino (N) termini of the PEG-NPs. The sizes of the nanoparticles, measured via DLS, were similar for both KCREKA-NPs and PEG-NPs (23 ± 4 nm, PDI = 0.11 and 25 ± 8 nm, PDI = 0.24, respectively). In the same line, r2 relaxivities were also similar for the nanoparticles (149 ± 2 mM Fe s−1 and 151 ± 5 mM Fe s−1), whereas the r1 relaxivity was higher for KCREKA-NPs (1.68 ± 0.29 mM Fe s−1 vs. 0.69 ± 0.3 mM Fe s−1). In vitro studies showed that blood clots with low coagulation times were disrupted by rtPA, whereas aged clots were almost insensitive to the presence of rtPA. MRI in vitro studies showed a sharp decrease in the T1 × T2 signals measured for aged clots incubated with KCREKA-NPs compared with fresh clots (47% [22, 80] to 26% [15, 51]). Furthermore, the control blood showed a higher value of the T1 × T2 signal (39% [20, 61]), being the blood clots with low coagulation times the samples with the lowest values measured by MRI. In vivo studies showed a significant T1 × T2 signal loss in the clot region of 24% after i.v. injection of KCREKA-NPs. The thrombus age (2.5% ± 6.1% vs. 81.3% ± 19.8%, p < 0.01) confirmed our ability to identify in vivo fresh blood clots. In this study, we developed and tested a dual MRI nanoparticle, acting as T1 and T2 contrast agents in MRI analyses. The developed KCREKA-NPs showed affinity for the fibrin content of blood clots, and the MRI signals provided by the nanoparticles showed significant differences depending on the clot age. The developed KCREKA-NPs could be used as a tool to predict the efficacy of a recanalization treatment and improve the triage of ischemic stroke patients.

Green synthesis of biocompatible superparamagnetic iron oxide-gold composite nanoparticles for magnetic resonance imaging, hyperthermia and photothermal therapeutic applications

Magnetic nanocomposites are extensively used for biomedical applications such as drug delivery, diagnosis, and therapeutics, etc. Here we report a green synthesis of biocompatible, superparamagnetic, and near-infrared absorbing, iron oxide-gold composite nanoparticles (IO–Au NPs) using aqueous leaf extract of a medicinal plant Pimenta dioica for biomedical applications. The MTT (3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assay was performed to assess the cytotoxicity of the IO-Au NPs in-vitro. Results of the MTT assay show that the green synthesized IO-Au NPs are safe for cells up to a high concentration of 500 μg/ml. The IO-AuNPs exhibit a superparamagnetic behavior with a large magnetization of 65 emu/g. These IO-Au NPs exhibit a high relaxivities ratio (r2/r1) of 13.20 (r1 = 10.67 s−1 mM−1 and r2 = 140.87 s−1 mM−1 respectively), indicating the potential of these IO-Au NPs as a T2 contrast agent. Magnetic resonance imaging of chicken tissue and poultry heart has been done to confirm the contrast enhancement performance of these nanoparticles. Moreover, the magnetic heating efficacy of the green synthesized IO-Au NPs has been evaluated in an external magnetic field. Owing to their excellent optical property, these green synthesized IO-Au NPs have great potential for NIR photothermal applications. The results of this study suggest that these IO-Au NPs could be used as theranostic agents for in-vivo biomedical imaging and therapeutics.

Extremely Small Iron Oxide Nanoparticles with pH-Dependent Solubility Transition as T1/T2 Switchable Contrast Agents for MRI

Extremely small iron oxide nanoparticles (ESIONPs), which have a switchable contrast signal and a favorable biocompatibility, are gaining considerable attention as smart magnetic resonance imaging (MRI) contrast agents (CAs). Adaptive MRI CAs could improve the accuracy of tumor diagnosis because they realize rapid imaging signal conversion under an endogenous stimulus. Herein, based on the hydrophilic to hydrophobic transition of polymers, we propose a pH-responsive T1/T2 switchable ESIONP contrast agent. ESIONPs are functionalized at the surface with adamantane groups through a polyethylene glycol (PEG) chain, and subsequently, a stimuli-responsive polymer (PSDM) with pH-dependent solubility is introduced through the host–guest interaction between adamantane and β-cyclodextrin (β-CD). The obtained ESIONPs-PEG-PSDM is equipped with remarkable pH responsiveness, which triggers the aggregation of ESIONPs under the tumor acid condition, leading to the switch from a T1 to a T2 contrast agent. In vivo MRI experiments show that the T2 contrast signal is selectively enhanced at the tumor location after injection of ESIONPs-PEG-PSDM. Therefore, ESIONPs-PEG-PSDM with pH-induced hydrophilic to hydrophobic transition is a potential smart MRI contrast agent for precise tumor diagnosis.

White matter microstructure and longitudinal relaxation time anisotropy in human brain at 3 and 7 T.

A high degree of structural order by white matter (WM) fibre tracts creates a physicochemical environment where water relaxations are rendered anisotropic. Recently, angularly dependent longitudinal relaxation has been reported in human WM. We have characterised interrelationships between T1 relaxation and diffusion MRI microstructural indices at 3 and 7 T. Eleven volunteers consented to participate in the study. Multishell diffusion MR images were acquired with b-values of 0/1500/3000 and 0/1000/2000 s/mm2 at 1.5 and 1.05 mm3 isotropic resolutions at 3 and 7 T, respectively. DTIFIT was used to compute DTI indices; the fibre-to-field angle (θFB ) maps were obtained using the principal eigenvector images. The orientations and volume fractions of multiple fibre populations were estimated using BedpostX in FSL, and the orientation dispersion index (ODI) was estimated using the NODDI protocol. MP2RAGE was used to acquire images for T1 maps at 1.0 and 0.9 mm3 isotropic resolutions at 3 and 7 T, respectively. At 3 T, T1 as a function of θFB in WM with high fractional anisotropy and one-fibre orientation volume fraction or low ODI shows a broad peak centred at 50o , but a flat baseline at 0o and 90o . The broad peak amounted up to 7% of the mean T1. At 7 T, the broad peak appeared at 40o and T1 in fibres running parallel to B0 was longer by up to 75 ms (8.3% of the mean T1) than in those perpendicular to the field. The peak at 40o was approximately 5% of mean T1 (i.e., proportionally smaller than that at 54o at 3 T). The data demonstrate T1 anisotropy in WM with high microstructural order at both fields. The angular patterns are indicative of the B0-dependency of T1 anisotropy. Thus myelinated WM fibres influence T1 contrast both by acting as a T1 contrast agent and rendering T1 dependent on fibre orientation with B0.

Water‐dispersible Gadolinium Oxide Nanoplates as an Effective Positive Magnetic Resonance Imaging Contrast Agent

AbstractGadolinium oxide (Gd2O3) nanoplates have been successfully synthesized by thermal decomposition method in the presence of oleic acid and oleylamine as surfactants. As a result, the nanoplates have average edge length and thickness around 10 nm and 1.1 nm, respectively. The hydrophobic OA/OM capped Gd2O3 nanoplates were encapsulated with amphiphilic poly (maleic anhydride‐alt‐1‐octadecene) polymer (PMAO) for phase transfer into aqueous media. The obtained Gd2O3@PMAO showed a hydrodynamic size of 32 nm with good dispersion in water solvent and stable in wide range of pH (pH=2÷11) and at electrolyte concentrations as high as NaCl 380 mM. In addition, the in vitro toxicity tests confirmed the biocompatibility of Gd2O3@PMAO nanoplates. The magnetic resonance imaging (MRI) result exhibited the r1 of Gd2O3@PMAO nanoplates (16.95 mM−1s−1) is four times higher than that of clinically used Gd‐DTPA. These results suggest that the PMAO coated ‐Gd2O3 nanoplates are potential T1 contrast agents for in vivo MRI application.

Theranostic Applications of an Ultra-Sensitive T1 and T2 Magnetic Resonance Contrast Agent Based on Cobalt Ferrite Spinel Nanoparticles.

Simple SummaryMagnetic nanoparticles (MNPs) represent an important class of nanomaterials that has been actively employed in multiple technological applications. The MNPs and their based composites have been intensively developed for magnetic resonance imaging, targeted drug delivery, magnetic hyperthermia, and other applications. Magnetic Resonance Imaging (MRI) has a prominent position among clinical imaging modalities as it allows for high spatial resolution and tissue specificity without harmful ionizing radiation. The aim of the study was the demonstration of the potential use of magnetic nanoparticles based on cobalt ferrite spinel as advanced MRI contrast agents that are capable of both T1-weighted positive and T2-weighted negative contrast enhancements in vitro and in vivo. Furthermore, in the present study, we combined novel physical, chemical, and biomedical approaches to develop a multifunctional MRI-detectable drug delivery system that was an efficient T1- and T2-weighted MRI contrast agent and a nanocarrier for targeted drug delivery in vivo.Nano-dimensional materials have become a focus of multiple clinical applications due to their unique physicochemical properties. Magnetic nanoparticles represent an important class of nanomaterials that are widely studied for use as magnetic resonance (MR) contrast and drug delivery agents, especially as they can be detected and manipulated remotely. Using magnetic cobalt ferrite spinel (MCFS) nanoparticles, this study was aimed at developing a multifunctional drug delivery platform with MRI capability for use in cancer treatment. We found that MCFS nanoparticles demonstrated outstanding properties for contrast MRI (r1 = 22.1 s–1mM–1 and r2 = 499 s–1mM–1) that enabled high-resolution T1- and T2-weighted MRI-based signal detection. Furthermore, MCFS nanoparticles were used for the development of a multifunctional targeted drug delivery platform for cancer treatment that is concurrently empowered with the MR contrast properties. Their therapeutic effect in systemic chemotherapy and unique MRI double-contrast properties were confirmed in vivo using a breast cancer mouse tumor model. Our study thus provides an empirical basis for the development of a novel multimodal composite drug delivery system for anticancer therapy combined with noninvasive MRI capability.

Biodegradable and biocompatible exceedingly small magnetic iron oxide nanoparticles for T1-weighted magnetic resonance imaging of tumors

Magnetic resonance imaging (MRI) has been widely using in clinical diagnosis, and contrast agents (CAs) can improve the sensitivity MRI. To overcome the problems of commercial Gd chelates-based T1 CAs, commercial magnetic iron oxide nanoparticles (MIONs)-based T2 CAs, and reported exceedingly small MIONs (ES-MIONs)-based T1 CAs, in this study, a facile co-precipitation method was developed to synthesize biodegradable and biocompatible ES-MIONs with excellent water-dispersibility using poly (aspartic acid) (PASP) as a stabilizer for T1-weighted MRI of tumors. After optimization of the synthesis conditions, the final obtained ES-MION9 with 3.7 nm of diameter has a high r1 value (7.0 ± 0.4 mM−1 s−1) and a low r2/r1 ratio (4.9 ± 0.6) at 3.0 T. The ES-MION9 has excellent water dispersibility because of the excessive –COOH from the stabilizer PASP. The pharmacokinetics and biodistribution of ES-MION9 in vivo demonstrate the better tumor targetability and MRI time window of ES-MION9 than commercial Gd chelates. T1-weighted MR images of aqueous solutions, cells and tumor-bearing mice at 3.0 T or 7.0 T demonstrate that our ES-MION9 has a stronger capability of enhancing the MRI contrast comparing with the commercial Gd chelates. The MTT assay, live/dead staining of cells, and H&E-staining indicate the non-toxicity and biosafety of our ES-MION9. Consequently, the biodegradable and biocompatible ES-MION9 with excellent water-dispersibility is an ideal T1-weighted CAs with promising translational possibility to compete with the commercial Gd chelates.

Magneto-fluorescent contrast agents based on carbon Dots@Ferrite nanoparticles for tumor imaging

Bimodal magnetic-fluorescent materials for diagnostic imaging needs surface-engineered nanoparticles with great biosafety, pronounced colloidal stability, high magnetic moments, and strong photoluminescence (PL) emission. This work presents polymer-coated nanoparticles (PCNPs) based on manganese ferrites covered with a thin shell of nitrogen-doped carbon dots for magnetic-resonance and fluorescent dual mode imaging of cancerous tumors in vivo. An in situ thermolysis of metal oxalates and phenylenediamine in diphenyl ether allows for the facile synthesis of hybrid magneto-fluorescent nanoparticles. They possess an average size of 55 ± 5 nm with strong and excitation-independent PL emission at about 600 nm with a saturation magnetization of ∼ 19 emu/g. In vivo dispersion and biosafety of the hybrid nanoparticles are improved by a polymer-coating strategy with the aid of Tween polysorbate. In vitro studies for SK-OV-3 cells reveal that PCNPs are not toxic up to a high concentration of 125 µg/mL. H&E-stained sections of vital organs of animals treated with dosages of 5 mg/kg fail to present any histopathological changes after 24 h post-injection. The fluorescence intensity in the tumor tissue region appears to increases over time and the tumor becomes clearly visible after 60 min. Magnetic resonance imaging (MRI) of phantoms and animal cases also indicates the high efficiency of PCNPs as an T2 contrast agent in clinical diagnosis. Therefore, the developed PCNPs offer great potential for dual mode imaging of malignant tumors.

Multimodal Magnetic Resonance and Photoacoustic Imaging of Tumor-Specific Enzyme-Responsive Hybrid Nanoparticles for Oxygen Modulation.

Multimodal imaging contrast agents for cancer that can not only perform diagnostic functions but also serve as tumor microenvironment-responsive biomaterials are encouraging. In this study, we report the design and fabrication of a novel enzyme-responsive T1 magnetic resonance imaging (MRI) contrast agent that can modulate oxygen in the tumor microenvironment via the catalytic conversion of H2O2 to O2. The T1 contrast agent is a core-shell nanoparticle that consists of manganese oxide and hyaluronic acid (HA)-conjugated mesoporous silica nanoparticle (HA-MnO@MSN). The salient features of the nanoparticle developed in this study are as follows: 1) HA serves as a targeting ligand for CD44-expressing cancer cells; 2) HA allows controlled access of water molecules to the MnO core via the digestion of enzyme hyaluronidase; 3) the generation of O2 bubbles in the tumor by consuming H2O2; and 4) the capability to increase the oxygen tension in the tumor. The r 1 relaxivity of HA-MnO@MSN was measured to be 1.29 mM-1s-1 at a magnetic field strength of 9.4 T. In vitro results demonstrated the ability of continuous oxygen evolution by HA-MnO@MSN. After intratumoral administration of HA-MnO@MSN to an HCT116 xenograft mouse model, T1 weighted MRI contrast was observed after 5h postinjection and retained up to 48h. In addition, in vivo photoacoustic imaging of HA-MnO@MSN demonstrated an increase in the tumor oxygen saturation over time after i. t. administration. Thus, the core-shell nanoparticles developed in this study could be helpful in tumor-targeted T1 MR imaging and oxygen modulation.