Injectable Hydrogels Including Magnetic Nanosheets for Multidisciplinary Treatment of Hepatocellular Carcinoma via Magnetic Hyperthermia.

Relapse and unresectability have become the main obstacle for further improving hepatocellular carcinoma (HCC) treatment effect. Currently, single therapy for HCC in clinical practice is limited by postoperative recurrence, intraoperative blood loss and poor patient outcomes. Multidisciplinary therapy has been recognized as the key to improving the long-term survival rate for HCC. However, the clinical application of HCC synthetic therapy is restricted by single functional biomaterials. In this study, a magnetic nanocomposite hydrogel (CG-IM) with iron oxide nanoparticle-loaded mica nanosheets (Iron oxide nanoparticles@Mica, IM) is reported. This biocompatible magnetic hydrogel integrated high injectability, magnetocaloric property, mechanical robustness, wet adhesion, and hemostasis, leading to efficient HCC multidisciplinary therapies including postoperative tumor margin treatment and percutaneous locoregional ablation. After minimally invasive hepatectomy of HCC, the CG-IM hydrogel can facilely seal the bleeding hepatic margin, followed by magnetic hyperthermia ablation to effectively prevent recurrence. In addition, CG-IM hydrogel can inhibit unresectable HCC by magnetic hyperthermia through the percutaneous intervention under ultrasound guidance.

In situ Thermal-Responsive Magnetic Hydrogel for Multidisciplinary Therapy of Hepatocellular Carcinoma.

Current surgical single modality treatments for hepatocellular carcinoma (HCC) were restricted by recurrence, blood loss, significant trauma, and poor prognostic. Although multidisciplinary strategies for HCC treatment have been highly recommended by the clinical guidelines, there was limited choice of materials and treatments. Herein, we reported an in situ formed magnetic hydrogel with promising bioapplicable thermal-responsiveness, strong adhesion in wet conditions, high magnetic hyperthermia, and biocompatibility, leading to efficient HCC multidisciplinary treatment including postoperative treatment and transarterial embolization therapy. In vivo results indicated that this hydrogel could reduce the postoperative recurrence rate. The hemostatic ability of the thermal-responsive hydrogel was further demonstrated in both the liver scratch model and liver tumor resection. Computed tomography imaging suggested that the hydrogel could completely embolize the arterial vessels of rabbit liver tumor by vascular intervention operation, which could serve as multidisciplinary responsive materials to external magnetic field and body temperature for HCC treatment.

Effects of iron oxide nanoparticles as T2-MRI contrast agents on reproductive system in male mice.

Iron oxide nanoparticles (IONPs)-based contrast agents are widely used for T2-weighted magnetic resonance imaging (MRI) in clinical diagnosis, highlighting the necessity and importance to evaluate their potential systematic toxicities. Although a few previous studies have documented the toxicity concerns of IONPs to major organs, limited data are available on the potential reproductive toxicity caused by IONPs, especially when administrated via intravenous injection to mimic clinical use of MRI contrast agents. Our study aimed to determine whether exposure to IONPs would affect male reproductive system and cause other related health concerns in ICR mice. The mice were intravenously injected with different concentrations IONPs once followed by routine toxicity tests of major organs and a series of reproductive function-related analyses at different timepoints. As a result, most of the contrast agents were captured by reticuloendothelial system (RES) organs such as liver and spleen, while IONPs have not presented adverse effects on the normal function of these major organs. In contrast, although IONPs were not able to enter testis through the blood testicular barrier (BTB), and they have not obviously impaired the overall testicular function or altered the serum sex hormones levels, IONPs exposure could damage Sertoli cells in BTB especially at a relative high concentration. Moreover, IONPs administration led to a short-term reduction in the quantity and quality of sperms in a dose-dependent manner, which might be attributed to the increase of oxidative stress and apoptotic activity in epididymis. However, the semen parameters have gradually returned to the normal range within 14 days after the initial injection of IONPs. Collectively, these results demonstrated that IONPs could cause reversible damage to the reproductive system of male mice without affecting the main organs, providing new guidance for the clinical application of IONPs as T2-MRI contrast agents.

Injectable magnetic montmorillonite colloidal gel for the postoperative treatment of hepatocellular carcinoma.

Bioactive materials have been extensively developed for the adjuvant therapy of cancer. However, few materials can meet the requirements for the postoperative resection of hepatocellular carcinoma (HCC) due to massive bleeding and high recurrence. In particular, combination therapy for HCC has been highly recommended in clinical practice, including surgical resection, interventional therapy, ablation therapy and chemotherapy. Herein, an injectable magnetic colloidal gel (MCG) was developed by controllable electrostatic attraction between clinically available magnetic montmorillonites and amphoteric gelatin nanoparticles. The optimized MCG exhibited an effective magnetic heating effect, remarkable rheological properties, and high gel network stability, realizing the synergistic treatment of postoperative HCC by stimuli-responsive drug delivery, hemostasis and magnetic hyperthermia. Furthermore, a minimal invasive MCG-induced interventional magnetic hyperthermia therapy (MHT) under ultrasound guidance was realized on hepatic tumor rabbits, providing an alternative therapeutics to treat the postoperative recurrence. Overall, MCG is a clinically available injectable formulation for adjuvant therapy after HCC surgical resection.

Parkin overexpression reduces inflammation-mediated cardiomyocyte apoptosis through activating Nrf2/ARE signaling pathway.

Inflammation has been acknowledged as one of the pathological alterations in various cardiovascular disorders. Parkin has been found to be associated with mitochondrial protection. In the present study, we explored the influence of Parkin overexpression on cardiomyocyte induced by LPS-mediated inflammation response. Our results demonstrated that cardiomyocyte viability was reduced and apoptotic rate was increased upon LPS treatment, an effect that may be caused by cardiomyocyte oxidative stress. At the molecular levels, LPS treatment promoted ROS production, a result that was followed by a drop in the levels of anti-oxidants. Interestingly, Parkin overexpression significantly promoted cardiomyocyte survival and this cardioprotective was attributable to the anti-oxidative property. Parkin overexpression enhanced the expression of anti-oxidative factors such as GSH, SOD and GPX, resulting into depressed ROS production. Further, we found that Parkin modulated cellular anti-oxidative capacity through the Nrf2/ARE signaling pathway. This finding demonstrates that oxidative stress could be considered as the core of inflammation response. Further, therapeutic approaches targeting Parkin would improve cardiomyocyte anti-oxidative capacity through activating Nrf2/ARE signaling pathway.

In Situ Fabrication of Electrospun Magnetic Film Under Laparoscopic Guidance for Preventing Postoperative Recurrence of Hepatocellular Carcinoma.

Despite laparoscopic-guided minimally invasive hepatectomy emerging as the primary approach for resecting hepatocellular carcinoma (HCC), there's still a significant gap in suitable biomaterials that seamlessly integrate with these techniques to achieve effective hemostasis and suppress residual tumors at the surgical margin. Electrospun films are increasingly used for wound closure, yet the employment of prefabricated electrospun films for hemostasis during minimally invasive HCC resection is hindered by prolonged operation times, complexity in implementation, limited visibility during surgery, and inadequate postoperative prevention of HCC recurrence. In this study, we integrated montmorillonite-iron oxide sheets into the PVP polymer framework, enhancing the resulting electrospun polyvinylpyrrolidone (PVP) /montmorillonite-iron oxide (MI) film (abbreviated as PMI) with robustness, hemostatic capability, and magnetocaloric properties. In contrast to the in vitro prefabricated electrospun films, the electrospun PMI film is designed to be formed in situ on liver wounds under laparoscopic guidance during hepatectomy. This design affords superior wound adaptability, facilitating meticulous wound closure and expeditious hemostasis, thereby simplifying the operative process and ultimately alleviating the workload of healthcare professionals. Moreover, when exposed to an alternating magnetic field, the film can efficiently ablate residual tumors, significantly augmenting the treatment efficacy of HCC. This article is protected by copyright. All rights reserved.

Minimally Invasive Delivery of Percutaneous Ablation Agent via Magnetic Colloidal Hydrogel Injection for Treatment of Hepatocellular Carcinoma.

Percutaneous thermotherapy, a minimally invasive operational procedure, is employed in the ablation of deep tumor lesions by means of target-delivering heat. Conventional thermal ablation methods, such as radiofrequency or microwave ablation, to a certain extent, are subjected to extended ablation time as well as biosafety risks of unwanted overheating. Given its effectiveness and safety, percutaneous thermotherapy gains a fresh perspective, thanks to magnetic hyperthermia. In this respect, an injectable- and magnetic-hydrogel-construct-based thermal ablation agent is likely to be a candidate for the aforementioned clinical translation. Adopting a simple and environment-friendly strategy, a magnetic colloidal hydrogel injection is introduced by a binary system comprising super-paramagnetic Fe3O4 nanoparticles and gelatin nanoparticles. The colloidal hydrogel constructs, unlike conventional bulk hydrogel, can be easily extruded through a percutaneous needle and then self-heal in a reversible manner owing to the unique electrostatic cross-linking. The introduction of magnetic building blocks is exhibited with a rapid magnetothermal response to an alternating magnetic field. Such hydrogel injection is capable of generating heat without limitation of deep penetration. The materials achieve outstanding therapeutic results in mouse and rabbit models. These findings constitute a new class of locoregional interventional thermal therapies with minimal collateral damages.

PEGylated upconverting luminescent hollow nanospheres for drug delivery and in vivo imaging.

Upconversion luminescent hollow Y2 O3 :Yb(3+) /Er(3+) nanospheres can be synthesized by an etching-free process, which hold promising potential for applications such as drug delivery, angiography, and high-contrast cellular as well as tissue imaging, with no damage from radiation or toxicity.

Predictive value of radiomics analysis of enhanced CT for three-tiered microvascular invasion grading in hepatocellular carcinoma.

BACKGROUND: Microvascular invasion (MVI) is a major risk factor, for recurrence and metastasis of hepatocellular carcinoma (HCC) after radical surgery and liver transplantation. However, its diagnosis depends on the pathological examination of the resected specimen after surgery; therefore, predicting MVI before surgery is necessary to provide reference value for clinical treatment. Meanwhile, predicting only the existence of MVI is not enough, as it ignores the degree, quantity, and distribution of MVI and may lead to MVI-positive patients suffering due to inappropriate treatment. Although some studies have involved M2 (high risk of MVI), majority have adopted the binary classification method or have not included radiomics. PURPOSE: To develop three-class classification models for predicting the grade of MVI of HCC by combining enhanced computed tomography radiomics features with clinical risk factors. METHODS: The data of 166 patients with HCC confirmed by surgery and pathology were analyzed retrospectively. The patients were divided into the training (116 cases) and test (50 cases) groups at a ratio of 7:3. Of them, 69 cases were MVI positive in the training group, including 45 cases in the low-risk group (M1) and 24 cases in the high-risk group (M2), and 47 cases were MVI negative (M0). In the training group, the optimal subset features were obtained through feature selection, and the arterial phase radiomics model, portal venous phase radiomics model, delayed phase radiomics model, three-phase radiomics model, clinical imaging model, and combined model were developed using Linear Support Vector Classification. The test group was used for validation, and the efficacy of each model was evaluated through the receiver operating characteristic curve (ROC). RESULTS: The clinical imaging features of MVI included alpha-fetoprotein, tumor size, tumor margin, peritumoral enhancement, intratumoral artery, and low-density halo. The area under the curve (AUC) of the ROC values of the clinical imaging model for M0, M1, and M2 were 0.831, 0.701, and 0.847, respectively, in the training group and 0.782, 0.534, and 0.785, respectively, in the test group. After combined radiomics analyis, the AUC values for M0, M1, and M2 in the test group were 0.818, 0.688, and 0.867, respectively. The difference between the clinical imaging model and the combined model was statistically significant (p = 0.029). CONCLUSION: The clinical imaging model and radiomics model developed in this study had a specific predictive value for HCC MVI grading, which can provide precise reference value for preoperative clinical diagnosis and treatment. The combined application of the two models had a high predictive efficacy.

Self-assembling ferrimagnetic fluorescent micelles for bioimaging guided efficient magnetic hyperthermia therapy.

Multifunctional magnet-fluorescent nanocomposites are widely applied in biomedical applications. Incorporating biocompatible quantum dots with highly ferrimagnetic magnetic nanoparticles into one nanoplatform for achieving efficient magnetic hyperthermia therapy (MHT) is very important. Herein, we reported an amphiphilic block copolymer with a flowable hydrophobic chain to encapsulate highly ferrimagnetic magnetic nanoparticles and ZnS/InP quantum dots via a facile self-assembly method. The obtained ferrimagnetic fluorescent micelle (FMFM) exhibited a uniform diameter of about 180 nm. In stark contrast, larger aggregation (400 nm in diameter) inevitably occurred using common poly(D,L-lactide) (PLA)-based amphiphilic block copolymer with a rigid hydrophobic chain, which was readily cleared by the reticuloendothelial system (RES). The flowable FMFM exhibited long-term colloidal stability within one month and desired fluorescent stability within 84 h. Benefiting from the high ferrimagnetism, the FMFM revealed excellent magnetic heating effect and magnetic resonance imaging capability. With accurate manipulation under an external magnetic field, FMFM realized in vitro enhanced fluorescence imaging sensitivity and accumulation efficiency at the tumor region, achieving in vitro and vivo improved MHT efficacy.

Highly hydrated paramagnetic amorphous calcium carbonate nanoclusters as an MRI contrast agent.

Amorphous calcium carbonate plays a key role as transient precursor in the early stages of biogenic calcium carbonate formation in nature. However, due to its instability in aqueous solution, there is still rare success to utilize amorphous calcium carbonate in biomedicine. Here, we report the mutual effect between paramagnetic gadolinium ions and amorphous calcium carbonate, resulting in ultrafine paramagnetic amorphous carbonate nanoclusters in the presence of both gadolinium occluded highly hydrated carbonate-like environment and poly(acrylic acid). Gadolinium is confirmed to enhance the water content in amorphous calcium carbonate, and the high water content of amorphous carbonate nanoclusters contributes to the much enhanced magnetic resonance imaging contrast efficiency compared with commercially available gadolinium-based contrast agents. Furthermore, the enhanced T1 weighted magnetic resonance imaging performance and biocompatibility of amorphous carbonate nanoclusters are further evaluated in various animals including rat, rabbit and beagle dog, in combination with promising safety in vivo. Overall, exceptionally facile mass-productive amorphous carbonate nanoclusters exhibit superb imaging performance and impressive stability, which provides a promising strategy to design magnetic resonance contrast agent.

Injectable ferrimagnetic silk fibroin hydrogel for magnetic hyperthermia ablation of deep tumor.

Due to the well-recognized biocompatibility, silk fibroin hydrogels have been developed for biomedical applications including bone regeneration, drug delivery and cancer therapy. For the treatment of cancer, silk-based photothermal agents exhibit the high photothermal conversion efficiency, but the limited light penetration depth of photothermal therapy restricts the treatment of some tumors in deep positions, such as liver tumor and glioma. To provide an alternative strategy, here we developed an injectable magnetic hydrogel based on silk fibroin and iron oxide nanocubes (IONCs). The as-prepared ferrimagnetic silk fibroin hydrogel could be easily injected through a syringe into tumor, especially rabbit hepatocellular carcinoma in deeper positions using ultrasound-guided interventional treatment. Compared with photothermal agents, the embedded IONCs endowed the ferrimagnetic silk fibroin hydrogel with remote hyperthermia performance under an alternating magnetic field, resulting in the effective magnetic hyperthermia of deep tumors including subcutaneously implanted tumor model in Balb/c mouse after the coverage of a fresh pork tissue and orthotopic transplantation liver tumor in rabbit. Furthermore, due to the confinement of IONCs in silk fibroin hydrogel, the undesired thermal damage toward normal tissue could be avoided compared with directly administrating monodispersed magnetic nanoparticles.

Ferrimagnetic mPEG-b-PHEP copolymer micelles loaded with iron oxide nanocubes and emodin for enhanced magnetic hyperthermia-chemotherapy.

As a non-invasive therapeutic method without penetration-depth limitation, magnetic hyperthermia therapy (MHT) under alternating magnetic field (AMF) is a clinically promising thermal therapy. However, the poor heating conversion efficiency and lack of stimulus-response obstruct the clinical application of magnetofluid-mediated MHT. Here, we develop a ferrimagnetic polyethylene glycol-poly(2-hexoxy-2-oxo-1,3,2-dioxaphospholane) (mPEG-b-PHEP) copolymer micelle loaded with hydrophobic iron oxide nanocubes and emodin (denoted as EMM). Besides an enhanced magnetic resonance (MR) contrast ability (r 2 = 271 mM-1 s-1) due to the high magnetization, the specific absorption rate (2518 W/g at 35 kA/m) and intrinsic loss power (6.5 nHm2/kg) of EMM are dozens of times higher than the clinically available iron oxide nanoagents (Feridex and Resovist), indicating the high heating conversion efficiency. Furthermore, this composite micelle with a flowable core exhibits a rapid response to magnetic hyperthermia, leading to an AMF-activated supersensitive drug release. With the high magnetic response, thermal sensitivity and magnetic targeting, this supersensitive ferrimagnetic nanocomposite realizes an above 70% tumor cell killing effect at an extremely low dosage (10 µg Fe/mL), and the tumors on mice are completely eliminated after the combined MHT-chemotherapy.

PEGylated rhenium nanoclusters: a degradable metal photothermal nanoagent for cancer therapy.

A common issue of functional nanoagents for potential clinical translation is whether they are biodegradable or renal clearable. Previous studies have widely explored noble metal nanoparticles (Au and Pd) as the first generation of photothermal nanoagents for cancer therapy, but all of the reported noble metal nanoparticles are non-degradable. On the other hand, rhenium (Re), one of the noble and precious metals with a high atomic number (Z = 75), has been mainly utilized as a jet superalloy or chemical catalyst, but the biological characteristics and activity of Re nanoparticles have never been evaluated until now. To address these issues, here we report a simple and scalable liquid-reduction strategy to synthesize PEGylated Re nanoclusters, which exhibit intrinsically high photothermal conversion efficacy (33.0%) and high X-ray attenuation (21.2 HU mL mg-1), resulting in excellent photothermal ablation (100% tumor elimination) and higher CT enhancement (15.9 HU mL mg-1 for commercial iopromide in clinics). Impressively, biocompatible Re nanoclusters can degrade into renal clearable ReO4 - ions after exposure to H2O2, and thus achieve much higher renal clearance efficiency than conventional gold nanoparticles. This work reveals the potential of theranostic application of metallic Re nanoclusters with both biodegradation and renal clearance properties and provides insights into the design of degradable metallic platforms with high clinical prospects.

Magnetic liposomal emodin composite with enhanced killing efficiency against breast cancer.

As an active natural ingredient extracted from the plant Rheum palmatum, emodin exhibits various pharmacological activities, especially the inhibition of tumor growth and migration. However, the anticancer activity of emodin is limited mainly due to its poor solubility and the lack of specific targeting. Herein, we employed liposome to load emodin into the lipid bilayer, and high-performance ferromagnetic iron oxide nanocubes were simultaneously encapsulated in the hydrophilic bilayer. The optimized magnetic liposomal emodin nanocomposite (MLE) exhibited a 24.1% increase in the efficiency of killing MCF-7 cancer cells at a low concentration of 16 µg mL-1 compared with that of the hydrophobic free emodin. A further 8.67% enhancement of the killing efficiency was obtained by magnetic targeting. Benefitting from the high ferromagnetism, the transverse relaxivity (r2) of MLE was measured to be as high as 392.9 mM-1 s-1. With guidance from the external magnetic field, the effective accumulation of this magnetic liposome in the tumor region of a 4T1 breast tumor bearing mouse was observed by both MR tracking and fluorescence imaging, which should be beneficial for decreasing the required therapeutic dose of emodin. Hemolysis, cytotoxicity and biochemistry assays confirmed the excellent biocompatibility of this magnetic liposomal carrier. The anti-tumor therapeutic effect of MLE was further investigated in vivo, and the tumor in the therapeutic group was almost eliminated, indicating that this magnetic liposomal emodin could serve as a novel magnetically guided theranostic nanoagent.

Fluorine and Nitrogen Co-Doped Carbon Dot Complexation with Fe(III) as a T1 Contrast Agent for Magnetic Resonance Imaging.

Commercial gadolinium-based materials have been widely used as contrast agents for magnetic resonance imaging (MRI), but the high toxicity of leaking free Gd3+ ions still raises biosafety concerns. Here, we develop a novel, safe, and efficient MRI contrast agent based on a stable Fe(III) complex of fluorine and nitrogen co-doped carbon dots (F,N-CDs) that was prepared from glucose and levofloxacin by a simple microwave-assisted thermal decomposition method. The obtained Fe3+@F,N-CD complex exhibits higher longitudinal relaxivity ( r1 = 5.79 mM-1·s-1) than that of the control samples of the Fe3+@CD complex ( r1 = 4.23 mM-1 s-1) and free Fe3+ ( r1 = 1.59 mM-1 s-1) in aqueous solution, as assessed by a 1.5 T NMR analyzer. More importantly, the Fe3+@F,N-CD complex is very stable with a large coordination constant of 1.06 × 107 in aqueous medium. While incubated with HeLa cells, the Fe3+@F,N-CD complex shows clear MR images, demonstrating that it has potential to be an excellent MRI contrast agent. Furthermore, in vivo MRI experiments indicate that the Fe3+@F,N-CD complex provides high-resolution MRI pictures of 4T1 tumor bearing BALB/c mice 15 min after injection and can be completely excreted 2 h after administration. No cytotoxicity was observed with F,N-CDs and Fe concentration up to 0.2 mg/mL and 0.3 mM in 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide cell proliferation assay, respectively. The possible mechanism of the enhanced MRI effect of the Fe3+@F,N-CD complex is therefore proposed. The extremely low toxicity, high r1 relaxivity, strong photoluminescence, and low synthetic cost enable the Fe3+@F,N-CD complex to be a safe and promising T1-weighted MRI contrast agent for clinical applications.

Epitaxial growth of ultrathin layers on the surface of sub-10 nm nanoparticles: the case of ß-NaGdF4:Yb/Er@NaDyF4 nanoparticles.

Upconversion core-shell nanoparticles have attracted a large amount of attention due to their multifunctionality and specific applications. In this work, based on a NaGdF4 sub-10 nm ultrasmall nanocore, a series of core-shell upconversion nanoparticles with uniform size doped with Yb3+, Er3+ and NaDyF4 shells with different thicknesses were synthesized by a facile sequential growth process. NaDyF4 coated upconversion luminescent nanoparticles showed an obvious fluorescence quenching under excitation at 980 nm as a result of energy resonance transfer between Yb3+, Er3+ and Dy3+. NaGdF4:Yb,Er@NaDyF4 core-shell nanoparticles with ultrathin layer shells exhibited a better T 1-weighted MR contrast.

Stable gadolinium based nanoscale lyophilized injection for enhanced MR angiography with efficient renal clearance.

There is a great demand to develop high-relaxivity nanoscale contrast agents for magnetic resonance (MR) angiography with high resolution. However, there should be more focus on stability, ion leakage and excretion pathway of the intravenously injected nanoparticles, which are closely related to their clinic potentials. Herein, uniform ultrasmall-sized NaGdF4 nanocrystal (sub-10 nm) was synthesized using a facile high temperature organic solution method, and the nanocrystals were modified by a ligand-exchange approach using PEG-PAA di-block copolymer. The PEG-PAA modified NaGdF4 nanocrystal (denoted as ppNaGdF4 nanocrystal) exhibited a high r1 relaxivity which was twice of commercially used gadopentetate dimeglumine (Gd-DTPA) injection. MR angiography on rabbit using ppNaGdF4 nanocrystal at a low dose showed enhanced vascular details and long circulation time. Lyophilized powder of ppNaGdF4 nanocrystals have been successfully prepared without aggregation or reduction of MR performance, indicating the stability and an effective way to store this nanoscale contrast agent. No haemolysis was induced by ppNaGdF4 nanocrystal, and an extremely low leakage of gadolinium ions was confirmed. Furthermore, efficient renal excretion was one of the clearance pathways of ppNaGdF4 nanocrystal according to both the time dependent distribution data in blood and tissues and MR images. The in vivo toxicity evaluation further validated the great potential as a clinical agent for blood pool imaging.

Sequential Growth of NaYF4:Yb/Er@NaGdF4 Nanodumbbells for Dual-Modality Fluorescence and Magnetic Resonance Imaging.

Upconversional core-shell nanostructures have gained considerable attention due to their distinct enhanced fluorescence efficiency, multifunctionality, and specific applications. Recently, we have developed a sequential growth process to fabricate unique upconversion core-shell nanoparticles. Time evolution of morphology for the NaYF4:Yb/Er@NaGdF4 nanodumbbells has been extensively investigated. An Ostwald ripening growth mechanism has been proposed to illustrate the formation of NaYF4:Yb/Er@NaGdF4 nanodumbbells. The hydrophilic NaYF4:Yb/Er@NaGdF4 core-shell nanodumbbells exhibited strong upconversion fluorescence and showed higher magnetic resonance longitudinal relaxivity (r1 = 7.81 mM-1 s-1) than commercial contrast agents (Gd-DTPA). NaYF4:Yb/Er@NaGdF4 nanodumbbells can serve as good candidates for high efficiency fluorescence and magnetic resonance imaging.

Sequential growth of CaF2:Yb,Er@CaF2:Gd nanoparticles for efficient magnetic resonance angiography and tumor diagnosis.

It is a significant challenge to develop nanoscale magnetic resonance imaging (MRI) contrast agents with high performance of relaxation. In this work, Gd3+-doped CaF2-based core-shell nanoparticles (CaF2:Yb,Er@CaF2:Gd) of sub-10 nm size were controllably synthesized by a facile sequential growth method. The as-prepared hydrophilic CaF2:Yb,Er@CaF2:Gd nanoparticles modified using PEG-PAA di-block copolymer benefited from the presence of Gd only in the outer CaF2 layer of the nanoparticles, which exhibited r1 as high as 21.86 mM-1 s-1 under 3.0 T, seven times as high as that of commercially used gadopentetate dimeglumine (Gd-DTPA). Low cytotoxicity, no hemolysis phenomenon and no potential gadolinium ion leakage phenomenon of the hydrophilic CaF2:Yb,Er@CaF2:Gd nanoparticles have been observed and confirmed. Clear vascular details can be observed in magnetic resonance angiography and obvious MR signal of 4T1 tumor area could be significantly improved by intravenous injection of the hydrophilic CaF2:Yb,Er@CaF2:Gd nanoparticles at a low dosage in mice. A series of in vivo biological safety evaluations confirmed the good biocompatibility of the hydrophilic CaF2:Yb,Er@CaF2:Gd nanoparticles, which might be employed in clinical blood pool imaging and tumor diagnosis as a safe and efficient MRI probe.