Longitudinal Relaxivity Research Articles

Albumin-constrained large-scale synthesis of renal clearable ferrous sulfide quantum dots for T1-Weighted MR imaging and phototheranostics of tumors

Ultrasmall-sized iron-based nanoparticles are showing increasing potentials to be alternatives as T1-weighted magnetic resonance imaging (MRI) contrast agents to the currently-used gadolinium-based compounds. However, their synthesis particularly in a large-scale and green fashion is still a big challenge. Herein, we report an albumin-constrained strategy to synthesize tiny and highly dispersible ferrous sulfide (termed FeS@BSA) quantum dots (QDs) at ambient conditions. FeS@BSA QDs exhibit ultrasmall size of ca. 3.0 nm with an ultralow magnetization, affording them an appealing longitudinal relaxivity for T1-weighted MRI. The design principle leverages on albumin-mediated biomimetic synthesis and spatial isolation of the protein interface prevents bulk aggregation of the particles. Albumin was found to play crucial roles in the synthesis process: a constrained-microenvironment reactor for particle growth, a water-soluble layer for colloidal stability and a carrier for multi-functionality. This synthetic strategy was found facile, green and particularly large-scalable to 10 L. Mice experiments show good T1-weighted MRI capability of FeS@BSA QDs, significantly lighting the whole body organs, blood vessels and tumors. And interestingly, these QDs can be further used to conduct phototheranostic of tumor benefited from their intense absorption at near-infrared region. In particular, they can be cleared via glomerular filtration into bladder after treatment. Given this approach is biomimetic, scalable and does not require any complicated chemical synthesis or modifications, the method demonstrated here will find great potentials for clinical translation in T1-weighted MRI of diseases and inspire other functional tiny nanoprobes for biomedical applications.

Enhancing the Efficacy of Metal-Free MRI Contrast Agents via Conjugating Nitroxides onto PEGylated Cross-Linked Poly(Carboxylate Ester).

Herein, two water‐soluble PROXYL‐based magnetic resonance imaging (MRI) macromolecular organic contrast agents (mORCAs) are designed and synthesized: linear and cross‐linked PCE‐mPEG‐Ppa‐PROXYL. They are prepared by conjugating linear and cross‐linked poly(carboxylate ester) (PCE) with poly(ethylene glycol) (mPEG2000)‐modified nitroxides (PROXYL), respectively. Both mORCAs form self‐assembled aggregates in an aqueous phase and PROXYL is protected inside a hydrophobic core to achieve great resistance to reduction in the physiological environment, and they have low toxicity. Since cross‐linked PCE‐mPEG‐Ppa‐PROXYL possess a branched architecture, its self‐assembled aggregate is more stable and compact with a greater particle size. Cross‐linked PCE‐mPEG‐Ppa‐PROXYL outperform the linear one in the following aspects: 1) its longitudinal relaxivity (r 1 = 0.79 mm −1 s−1) is higher than that of the linear one (r 1 = 0.64 mm −1 s−1) and both excel the best mORCA reported so far (r 1 = 0.42 mm −1 s−1); 2) its blood retention time (≈48 h) is longer than that of its linear counterpart (≈10 h); 3) cross‐linked PCE‐mPEG‐Ppa‐PROXYL provided better MR imaging contrast resolution in normal organs (liver and kidney) and tumor of mice than the linear one. Overall, cross‐linked PCE‐mPEG‐Ppa‐PROXYL may have great potential to be a novel metal‐free macromolecular contrast agent for MR imaging.

Ellagic acid–Fe nanoscale coordination polymer with higher longitudinal relaxivity for dual-modality T1-weighted magnetic resonance and photoacoustic tumor imaging

Dual-modality contrast agents for T1-weighted magnetic resonance imaging (MRI) and photoacoustic imaging have attracted substantial attention as they combine the advantages of unlimited penetration depth and high sensitivity. However, most of the reported agents are Gd-based materials that exhibit nephrotoxicity, and few studies have focused on Fe-based materials owing to their lower relaxivity. This work describes the development of an ellagic acid (EA)–Fe nanoscale coordination polymer with high longitudinal relaxivity and strong near-infrared absorption for dual-modality T1-weighted MRI and photoacoustic imaging. The longitudinal relaxivity (r1) of the prepared EA-Fe@BSA nanoparticles was 2.54 mM−1 s−1, an increase of 185% compared with previously reported gallic acid-Fe nanoparticles. Furthermore, in vitro and in vivo experiments demonstrate that the EA-Fe@BSA NPs are an excellent T1-weighted MRI and photoacoustic dual-modality contrast agent with the advantages of convenient synthesis and low toxicity, exhibiting great potential for clinical use in tumor imaging.

Gd(DOTA)-grafted submicronic polysaccharide-based particles functionalized with fucoidan as potential MR contrast agent able to target human activated platelets

Early detection of thrombotic events remains a big medical challenge. Dextran-based submicronic particles bearing Gd(DOTA) groups and functionalized with fucoidan have been produced via a simple and green water-in-oil emulsification/co-crosslinking process. Their capacity to bind to human activated platelets was evidenced in vitro as well as their cytocompatibility with human endothelial cells. The presence of Gd(DOTA) moieties was confirmed by elemental analysis and total reflection X-ray fluorescence (TRXF) spectrometry. Detailed characterization of particles was performed in terms of size distribution, morphology, and relaxation rates. In particular, longitudinal and transversal proton relaxivities were respectively 1.7 and 5.0 times higher than those of DOTAREM. This study highlights their potential as an MRI diagnostic platform for atherothrombosis.

Molecular Magnetic Resonance Imaging of Nitric Oxide in Biological Systems.

Detection of nitric oxide (NO) in biological systems is challenging due to both physicochemical properties of NO and limitations of current imaging modalities and probes. Magnetic resonance imaging (MRI) could be applied for studying NO in living tissue with high spatiotemporal resolution, but there is still a need for chemical agents that effectively sensitize MRI to biological NO production. To develop a suitable probe, we studied the interactions between NO and a library of manganese complexes with various oxidation states and molecular structures. Among this set, the manganese(III) complex with N,N'-(1,2-phenylene)bis(5-fluoro-2-hydroxybenzamide) showed favorable changes in longitudinal relaxivity upon addition of NO-releasing chemicals in vitro while also maintaining selectivity against other biologically relevant reactive nitrogen and oxygen species, making it a suitable NO-responsive contrast agent for T1-weighted MRI. When loaded with this compound, cells ectopically expressing nitric oxide synthase (NOS) isoforms showed MRI signal decreases of over 20% compared to control cells and were also responsive to NOS inhibition or calcium-dependent activation. The sensor could also detect endogenous NOS activity in antigen-stimulated macrophages and in a rat model of neuroinflammation in vivo. Given the key role of NO and associated reactive nitrogen species in numerous physiological and pathological processes, MRI approaches based on the new probe could be broadly beneficial for studies of NO-related signaling in living subjects.

Facile synthesis of metal-polyphenol-formaldehyde coordination polymer colloidal nanoparticles with sub-50 nm for T1-weighted magnetic resonance imaging

Plant polyphenol-based coordination polymers (CPs) with ultra-small particle size and tailorable compositions are highly desired in biomedical applications, but their synthesis is still challenging due to the sophisticated coordination assembly process and unavoidable self-oxidation polymerization of polyphenol. Herein, a general ligand covalent-modification mediated coordination assembly strategy is proposed for the synthesis of water-dispersible CPs with tunable metal species (e.g., Gd, Cu, Ni, Zn, Fe) and ultra-small diameter (8.6–37.8 nm) using nontoxic plant polyphenol (e.g., tannic acid, gallic acid) as a polymerizable ligand. Polyphenol molecules react with formaldehyde firstly, which can effectively retard the oxidation induced self-polymerization of polyphenol and lead to the formation of metal ions containing CPs colloidal nanoparticles. These ultrafine nanoparticles with stably chelated metal ions are highly water dispersible and thus advantageous for bioimaging. As an example, ultra-small Gd contained CPs exhibit higher longitudinal relaxivity (r1 = 25.5 L mmol−1 s−1) value with low r2/r1 (1.19) than clinically used Magnevist (Gd-DTPA, r1 = 3.7 L mmol−1 s−1). Due to the enhanced permeability and retention effect, they can be further used as a positive contrast agent for T1-weighted MR imaging of tumour.

Persistent Luminescence Nanoplatform with Fenton-like Catalytic Activity for Tumor Multimodal Imaging and Photoenhanced Combination Therapy.

Reactive oxygen species-mediated tumor chemodynamic therapy and photodynamic therapy have captured extensive attention in practical cancer combination therapies. However, the severe treatment conditions and the hypoxic microenvironment of solid tumors significantly limit the efficacy of these therapies. This work demonstrates the design and fabrication of a multifunctional persistent luminescence nanoplatform (PHFI, refers to PLNP-HSA-Fe3+-IR780) for cancer multimodal imaging and effective photoenhanced combination therapy. The near-infrared-emitted persistent luminescence nanoparticles (PLNP) was modified with human serum albumin (HSA) combined with an IR780 probe and Fe3+. The synthesized PHFI possesses high longitudinal relaxivity, obvious photoacoustic contrast signals, and long-lasting persistent luminescence, indicating that PHFI can be used for cancer magnetic resonance imaging, photoacoustic imaging, and persistent luminescence multimodal imaging. PHFI shows intrinsic photoenhanced Fenton-like catalytic activities as well as photodynamic and photothermal effects and thereby can effectively overcome severe treatment conditions for killing tumor cells. It is worth noting that PHFI serving as a rechargeable internal light source for photoenhanced combination therapy was first disclosed. We believe that our work shows the great potential of PHFI for cancer theranostics and will advance the development of PLNP-based nanoplatforms in tumor catalytic therapy.

In vivo Monitoring of Oxygen Levels in Human Brain Tumor Between Fractionated Radiotherapy Using Oxygen-enhanced MR Imaging.

It was known that the response of tumor cells to radiation is closely related to tissue oxygen level and fractionated radiotherapy allows reoxygenation of hypoxic tumor cells. Non-invasive mapping of tissue oxygen level may hold great importance in clinic. The aim of this study is to evaluate the role of oxygen-enhanced MR imaging in the detection of tissue oxygen levels between fractionated radiotherapy. A cohort of 10 patients with brain metastasis was recruited. Quantitative oxygen enhanced MR imaging was performed prior to, 30 minutes and 22 hours after first fractionated radiotherapy. The ΔR1 (the difference of longitudinal relaxivity between 100% oxygen breathing and air breathing) increased in the ipsilateral tumor site and normal tissue by 242% and 152%, respectively, 30 minutes after first fractionated radiation compared to pre-radiation levels. Significant recovery of ΔR1 in the contralateral normal tissue (p < 0.05) was observed 22 hours compared to 30 minutes after radiation levels. R1-based oxygen-enhanced MR imaging may provide a sensitive endogenous marker for oxygen changes in the brain tissue between fractionated radiotherapy.

Characterization and Water-Proton Longitudinal Relaxivities of Liposome-Type Radical Nanoparticles Prepared via a Supramolecular Approach.

For the construction of metal-free magnetic resonance imaging (MRI) contrast agents, radical-based nanoparticles (RNPs) are promising materials because they allow the water-proton longitudinal relaxivity (r1) to be enhanced not only by paramagnetic resonance effects but also by prolonging the rotational correlation times (τR). However, the τR effect is limited because the radical units are often located within the central hydrophobic core of oil-in-water (o/w) emulsions, resulting in a lack of water molecules surrounding the radical units. In this study, to construct supramolecular RNPs that have high r1 values, we designed a liposome-type RNP in which the radical units are located at positions with sufficient surrounding water molecules. Using this strategy, PRO1 with a PROXYL framework was prepared by introducing hydrophilic groups on both sides of the radical unit. The RNP composed of PRO1 formed spherical nanoparticles approximately 100 nm in size and yielded a higher r1 value (0.26 mM-1 s-1) compared to those of small radical species and similar supramolecular o/w emulsion-type nanoparticles (0.17 mM-1 s-1 in PRO2).

Enhancing the magnetic relaxivity of MRI contrast agents via the localized superacid microenvironment of graphene quantum dots

The design of contrast agents (CAs) with high magnetic relaxivities is a key issue in the field of magnetic resonance imaging (MRI). The traditional strategy employed is aimed at optimizing the structural design of the magnetic atoms in the CA. However, it is difficult to obtain an agent with magnetic relaxivity over 100 mM−1 s−1 using this approach. In this work, we demonstrate that modulation of the localized superacid microenvironment of certain CAs (Gd3+ loaded polyethylene glycol modified graphene oxide quantum dots or ‘GPG’ for short) can effectively enhance the longitudinal magnetic relaxivities (r1) by accelerating proton exchange. r1 values of a series of GPGs are significantly increased by 20–30 folds compared to commercially available CAs over a wide range of static magnetic field strengths (e.g. 210.9 mM−1 s−1vs. 12.3 mM−1 s−1 at 114 μT, 127.0 mM−1 s−1vs. 4.9 mM−1 s−1 at 7.0 T). GPG aided MRI images is then acquired both in vitro and in vivo with low biotoxicities. Furthermore, folic-acid-modified GPG is demonstrated suitable for MRI-fluorescence dual-modal tumor targeting imaging in animals with more than 98.3% specific cellular uptake rate.

Effect of Gd and Dy Concentrations in Layered Double Hydroxides on Contrast in Magnetic Resonance Imaging

In this work, we explore the synthesis of layered double hydroxide (LDH) particles containing different molar ratios of Gd3+ and Dy3+ cations. A single crystalline phase was obtained for Zn2.0Al0.75Gd0.125Dy0.125-LDH and Zn2.0Al0.5Gd0.25Dy0.25-LDH, and their efficiency as contrast agents was evaluated by T1- and T2-weighted magnetic resonance imaging (MRI). Both GdDy-LDHs exhibited longitudinal relaxivity (r1) higher than a commercial reference. The highest contrast in the T1 mode was achieved with the Zn2.0Al0.75Gd0.125Dy0.125-LDH, which contained the lowest concentration of lanthanides; this efficiency is related to the lowest amount of carbonate anions complexing the lanthanide sites. On the contrary, the best contrast in the T2 mode was achieved with Zn2.0Al0.5Gd0.25Dy0.25-LDH. Zn2.0Al0.75Gd0.125Dy0.125-LDH and Zn2.0Al0.5Gd0.25Dy0.25-LDH presented r2/r1 ratios of 7.9 and 22.5, respectively, indicating that the inclusion of gadolinium and dysprosium into layered structures is a promising approach to the development of efficient bimodal (T1/T2) MRI contrast agents.

MnO Nanoparticles Embedded in Functional Polymers as T1 Contrast Agents for Magnetic Resonance Imaging

The design and development of contrast agents (CAs) for magnetic resonance imaging (MRI) in clinical analysis is expected to improve the image spatial resolution and to increase the detection sensitivity, especially regarding neurological disorders and cancer disease. In particular, advanced CAs for T1-weighted images are investigated to achieve the sensitive detection of early-stage primary tumors or brain metastases. In this study, we present a strategy toward diagnostic T1 CAs for MRI, based on polymer-modified MnO nanoparticles (NPs). Two different nanosystems were synthesized, consisting of (1) colloidal MnO nanocrystals wrapped by a multidentate amphiphilic polymer and (2) MnO nanocrystals embedded within poly(lactic-co-glycolic acid) (PLGA) NPs. These nanosystems were compared in terms of their MRI contrast power and biological safety. The latter system combines the excellent biocompatibility of PLGA with the unique magnetic properties of MnO NPs and allows sustained contrast enhancement over time. Longitudinal relaxivities of both MnO composite nanomaterials proved to be higher than those of commercial Gd-based CAs and Teslascan, both in phosphate-buffered saline and in plasma, also exhibiting low cytotoxicity. The high relaxation rates achieved with these contrast enhancers are promising toward future application in in vivo imaging.

Magnetic core\u2013shell nanowires as MRI contrast agents for cell tracking

BackgroundIdentifying the precise location of cells and their migration dynamics is of utmost importance for achieving the therapeutic potential of cells after implantation into a host. Magnetic resonance imaging is a suitable, non-invasive technique for cell monitoring when used in combination with contrast agents.ResultsThis work shows that nanowires with an iron core and an iron oxide shell are excellent materials for this application, due to their customizable magnetic properties and biocompatibility. The longitudinal and transverse magnetic relaxivities of the core–shell nanowires were evaluated at 1.5 T, revealing a high performance as T2 contrast agents. Different levels of oxidation and various surface coatings were tested at 7 T. Their effects on the T2 contrast were reflected in the tailored transverse relaxivities. Finally, the detection of nanowire-labeled breast cancer cells was demonstrated in T2-weighted images of cells implanted in both, in vitro in tissue-mimicking phantoms and in vivo in mouse brain. Labeling the cells with a nanowire concentration of 0.8 μg of Fe/mL allowed the detection of 25 cells/µL in vitro, diminishing the possibility of side effects. This performance enabled an efficient labelling for high-resolution cell detection after in vivo implantation (~ 10 nanowire-labeled cells) over a minimum of 40 days.ConclusionsIron-iron oxide core–shell nanowires enabled the efficient and longitudinal cellular detection through magnetic resonance imaging acting as T2 contrast agents. Combined with the possibility of magnetic guidance as well as triggering of cellular responses, for instance by the recently discovered strong photothermal response, opens the door to new horizons in cell therapy and make iron-iron oxide core–shell nanowires a promising theranostic platform.

CT/MR Dual-Modality Imaging Tracking of Mesenchymal Stem Cells Labeled with a Au/GdNC@SiO2 Nanotracer in Pulmonary Fibrosis.

Mesenchymal stem cells (MSCs) have shown potential as an innovative treatment for pulmonary fibrosis (PF), due to their capability to ameliorate the inflammation and moderate the deterioration of PF. The fate of the stem cells transplanted into the lung, including survival, migration, homing, and functions, however, has not been fully understood yet. In this paper, we report the development of a computed tomography/magnetic resonance (CT/MR) dual-modal nanotracer, gold/gadolinium nanoclusters overcoated with a silica shell (Au/GdNC@SiO2), for noninvasive labeling and tracking of the transplanted human MSCs (hMSCs) in a PF model. The Au/GdNC@SiO2 nanotracer exhibits good colloidal and chemical stability, high biocompatibility, enhanced longitudinal MR relaxivity, and superior X-ray attenuation property. The hMSCs can be effectively labeled with Au/GdNC@SiO2, resulting in a significantly increased cellular CT/MR imaging contrast, without any obvious adverse effect on the function, including proliferation and differentiation of the labeled stem cells. Moreover, by using the Au/GdNC@SiO2 nanotracer, the hMSCs transplanted in the lung can be tracked for 7 d via in vivo CT/MR dual-modality imaging. This work may provide an insight into the role the transplanted hMSCs play in PF therapy, thus promoting the stem cell-based regenerative medicine.

PH-Dependent Hydration Change in a Gd-Based MRI Contrast Agent with a Phosphonated Ligand.

The heptadentate ligand L was shown to form an extremely stable Gd complex at neutral pH with a pGd value of 18.4 at pH 7.4. The X-ray crystal structures of the complexes formed with Gd and Tb displayed two very different coordination behaviors being, respectively, octa- and nonacoordinated. The relaxometric properties of the Gd complex were studied by field-dependent relaxivity measurements at various temperatures and by 17 O NMR spectroscopy. The pH-dependence of the longitudinal relaxivity profile indicated large changes around neutral pH leading to a very large value of 10.1 mm-1 ⋅s-1 (60 MHz, 298 K) at pH 4.7. The changes were attributed to an increase of the hydration number from one water molecule in basic conditions to two at acidic pH. A similar trend was observed for the luminescence of the Eu complex, confirming the change in hydration state. DOSY experiments were performed on the Lu analogue, pointing to the absence of dimers in solution in the considered pH range. A breathing mode of the complex was postulated, which was further supported by 1 H and 31 P NMR spectroscopy of the Yb complex at varying pH and was finally modeled by DFT calculations.

Structure, mechanical, optical, and imaging contrast features of Yb3+ , Dy3+ , Tb3+ , Gd3+ , Eu3+ , and Nd3+ substituted Y2 O3 -Ln2 O3 solid solution.

Bulk ceramic that possess the combined features of structural stability at elevated temperatures, appropriate mechanical stability, luminescence features, magnetic resonance (MR) and computed tomography (CT) imaging capacity in a single platform is considered an exciting prospect in biomedical applications. In this study, six different lanthanides (Ln3+ :Yb3+ , Dy3+ , Tb3+ , Gd3+ , Eu3+ , and Nd3+ ) were combined together to yield a Y2 O3 :Ln2 O3 solid solution and subsequently tested for the proposed application. Three different Y2 O3 :Ln2 O3 solid solutions were formed by varying the concentrations of Ln3+ precursors. A unique cubic crystal structure with Ia-3 (206) space setting is retained until 1500 °C and moreover an expanded lattice is accomplished with the gradual inclusion of six different Ln3+ . Optical analysis inferred the characteristic electronic transitions of all the Ln3+ and moreover up-conversion and down-conversion emission behavior were also attributed by the material during excitation at 795 and 350 nm. Nanoindentation studies exercised on the material envisaged reasonably enhanced hardness and Young's modulus values. Further, the enhanced CT imaging potential alongside in vitro MRI study deliberating the longitudinal (T1 ) and transverse (T2 ) relaxivity ability of the material is also established.

In Vivo Positive Magnetic Resonance Imaging Applications of Poly(methyl vinyl ether-alt-maleic acid)-coated Ultra-small Paramagnetic Gadolinium Oxide Nanoparticles.

The study of ultra-small paramagnetic gadolinium oxide (Gd2O3) nanoparticles (NPs) as in vivo positive (T1) magnetic resonance imaging (MRI) contrast agents is one of the most attractive fields in nanomedicine. The performance of the Gd2O3 NP imaging agents depends on the surface-coating materials. In this study, poly(methyl vinyl ether-alt-maleic acid) (PMVEMA) was used as a surface-coating polymer. The PMVEMA-coated paramagnetic ultra-small Gd2O3 NPs with an average particle diameter of 1.9 nm were synthesized using the one-pot polyol method. They exhibited excellent colloidal stability in water and good biocompatibility. They also showed a very high longitudinal water proton spin relaxivity (r1) value of 36.2 s−1mM−1 (r2/r1 = 2.0; r2 = transverse water proton spin relaxivity) under a 3.0 tesla MR field which is approximately 10 times higher than the r1 values of commercial molecular contrast agents. High positive contrast enhancements were observed in in vivo T1 MR images after intravenous administration of the NP solution sample, demonstrating its potential as a T1 MRI contrast agent.

Characterization of the Nuclear Magnetic Resonance Relaxivity of Gadolinium Functionalized Magnetic Nanoparticles

The need to develop specific magnetic nanostructures for resonance imaging becomes more evident by the day. In this study, iron oxide magnetic nanoparticles stabilized with ethylenediaminetetraacetic acid (EDTA), followed by a gadolinium (Gd) ion chelation reaction Gd-EDTA-MNPs were synthesized and evaluated as a potential magnetic resonance imaging contrast agent. The contrast agent has been developed by a facile and universal coordination chemistry method. The compositions, structures, as well as the physicochemical characterization techniques, are reported. Fourier-transform infrared spectroscopy and X-ray photoelectron spectroscopy demonstrate the success of gadolinium complexation by the carboxyl group of EDTA coated iron oxide nanoparticles. Cytotoxicity measurements have been performed using a cell culture of normal human keratinocytes (HaCaT cell line) and human malignant melanoma (A375). Our results show a significant increase in the transverse relaxivity induced by the complexation with gadolinium, 540 mM−1 s−1 for Gd-EDTA-MNPs. The longitudinal relaxation dispersion curves show one order of magnitude enhancement of the longitudinal relaxivity from 2.2 mM−1 s−1 (EDTA-MNPs) to 29.6 mM−1 s−1 (Gd-EDTA-MNPs) at a 20 MHz resonance frequency. The results suggest that Gd complexation may represent a viable approach in obtaining contrast agents able to reduce both T1 and T2 nuclear relaxation times.

Synergistic regulation of longitudinal and transverse relaxivity of extremely small iron oxide nanoparticles (ESIONPs) using pH-responsive nanoassemblies.

Extremely small iron oxide nanoparticles (ESIONPs), as a kind of the special T1 magnetic resonance imaging (MRI) contrast agent that can provide T1 contrasting enhancement since their magnetically disordered shells are dominant compared to their magnetic cores and have powerful potential for constructing stimuli-responsive contrast agents (CAs) to realize precise the tumor diagnosis with high specificity and sensitivity. The stimuli-responsive function of ESIONPs-based CAs can be directly endowed through the synergistic regulation of the longitudinal and transverse relaxivity (r1 and r2) of ESIONPs. However, the systematical investigation for the synergistic regulation of r1 and r2 of ESIONPs is quite lacking. Herein, based on the relaxivity theories, three kinds of ESIONPs-based nanoassemblies with pH-responsiveness were designed and constructed to explore the possibility of various synergistic regulations on r1 and r2. When three kinds of ESIONPs-based nanoassemblies were converted to dissociated ones under a weak acid environment, ESIONPs micelle could realize a synergistic regulation of the single r2 decrease along with the stable r1, while gold nanoparticles-ESIONPs (AuNPs-ESIONPs) vesicle could provide a synergistic regulation comprising the single r1 increase along with the stable r2, and ESIONPs vesicle could offer a synergistic regulation involving the r2 decrease together with the r1 increase. Moreover, all the synergistic regulations on r1 and r2 were efficient strategies to fabricate ESIONPs-based CAs with the stimuli-responsive function. These systematic and feasible synergistic regulations of r1 and r2 may guide and promote the development of ESIONPs-based stimuli-responsive CAs for the highly sensitive and specific tumor diagnosis.

Renal-clearable hyaluronic acid functionalized NaGdF4 nanodots with enhanced tumor accumulation.

Integration of high tumor-targeting capacity, controlling in vivo transport and low normal tissue retention into one engineered nanoparticle is a critical issue for future clinically translatable anti-cancer nanomedicines. Herein, hyaluronic acid functionalized 3.8 nm NaGdF4 nanodots (named NaGdF4 ND@HAs) have been prepared through conjugation of tryptone capped NaGdF4 nanodots (NaGdF4 ND@tryptone) with hyaluronic acid (HA, a naturally occurring glycosaminoglycan), which can recognize the overexpressed CD44 on cancer cell membranes. The as-prepared NaGdF4 ND@HAs have good paramagnetic properties (longitudinal relaxivity (r1) = 7.57 × 10−3 M S−1) and low cytotoxicity. The in vivo experimental results demonstrate that the NaGdF4 ND@HAs can not only efficiently accumulate in mouse-bearing MDA-MB-231 tumors (ca. 5.3% injection dosage (ID) g−1 at 2 h post-injection), but also have an excellent renal clearance efficiency (ca. 75% injection dosage (ID) at 24 h post-injection). The as-prepared NaGdF4 ND@HAs have good paramagnetic properties with enhanced tumor-targeting capacity, which provides a useful strategy for the preparation of renal clearable magnetic resonance imaging (MRI) contrast agents for tumors.