High Longitudinal Relaxivity Research Articles

Construction of New MRI Contrast Agents for Spatiotemporal Visualization of Nitric Oxide in Ischemia/Reperfusion Organs.

Noninvasive and real-time nitric oxide (NO) visualization in vivo is still a challenge. Herein, we constructed a series of NO-responsive magnetic resonance imaging (MRI) contrast agents Gd1b-e by modifying Gd-DO3A using a bis-pyridyl-ethylamine side chain as a signal-amplifying moiety and o-phenylenediamine as a NO-responsive linker. It was found that Gd1b, d, and e can form macromolecular ternary complexes (Gd-Zn2+-HSA) with high longitudinal relaxivity (r1) (12.2-16.2 mM-1 s-1). Once reacting with NO, the o-phenylenediamine linker was hydrolyzed to produce a small molecular Gd complex with sharply decreased r1 (4.7-6.3 mM-1 s-1). Among them, Gd1d with a desirable pharmacokinetic profile (t1/2 = 5.91 h) could clearly distinguish the ischemia-reperfusion (IR) liver with excessive NO in rats. Meanwhile, the temporarily reduced amount of NO in the IR liver and brain by the NO scavenger 2-phenyl-4,4,5,5-tetramethylimidazoline-3-oxide-1-oxyl could enhance the signal of Gd1d, suggesting anticipated NO-responsive property. This research offers a new avenue for insight into the NO spatiotemporal property in multiple IR organs.

Employing antagonistic C-X-C motif chemokine receptor 4 antagonistic peptide functionalized NaGdF4 nanodots for magnetic resonance imaging-guided biotherapy of breast cancer

C-X-C motif chemokine receptor 4 (CXCR4) is a promising therapeutic target of breast cancer because it is overexpressed on cell surface of all molecular subtypes of breast cancer including triplenegative breast cancer (TNBC). Herein, CXCR4 antagonistic peptide-NaGdF4 nanodot conjugates (termed as anti-CXCR4-NaGdF4 NDs) have been constructed for magnetic resonance imaging (MRI)-guided biotherapy of TNBC through conjugation of the C-X-C Motif Chemokine 12 (CXCL12)-derived cyclic peptide with tryptone coated NaGdF4 nanodots (5 ± 0.5 nm in diameter, termed as Try-NaGdF4 NDs). The as-prepared anti-CXCR4-NaGdF4 NDs exhibits high longitudinal relaxivity (r1) value (21.87 mM−1S−1), reasonable biocompatibility and good tumor accumulation ability. The features of anti-CXCR4-NaGdF4 NDs improve the tumor-MRI sensitivity and facilitate tumor biotherapy after injection in mouse-bearing MDA-MB-231 tumor model in vivo. MRI-guided biotherapy using anti-CXCR4-NaGdF4 NDs enables to suppress 46% tumor growth. In addition, about 47% injection dose of anti-CXCR4-NaGdF4 NDs is found in the mouse urine at 24 h post-injection. These findings demonstrate that anti-CXCR4-NaGdF4 NDs enable to be used as renal clearable nanomedicine for biotherapy and MRI of breast cancer.

Catalase catalyzed tannic acid-Fe3+ network coating: A theranostic strategy for intestinal barrier restoration

Epithelial barrier impairment of intestinal inflammation leads to the leakage of bacteria, antigens and consequent persistent immune imbalance. Restoring the barrier function holds promise for management of intestinal inflammation, while the theragnostic strategies are limited. In this study, we developed a novel coating by catalase (CAT)-catalyzed polymerization of tannic acid (TA) and combined chelation network with Fe3+. TA-Fe3+ coating was self-polymerized in situ along the small intestinal mucosa, demonstrating persistent adhesion properties and protective function. In enteritis models, sequential administration of TA-Fe3+ complex solution effectively restored the barrier function and alleviated the intestinal inflammation. Overexpressed CAT in inflammatory lesion is more favorable for the in situ targeting growth of TA-Fe3+ coating onto the defective barrier. Based on the high longitudinal relaxivity of Fe3+, the pathologically catalyzed coating facilitated the visualization of intestinal barrier impairment through MRI. In conclusion, the novel TA-Fe3+ delivery coating proposed an alternative approach to promote theranostic intervention for intestinal diseases.

Folate Receptor Targeting Mn(II) Complex Encapsulated Porous Silica Nanoparticle as an MRI Contrast Agent for Early-State Detection of Cancer.

Cancer is recognized as one of the major causes of mortality, however, early-stage detection can increase the survival chance greatly. It is recognized that folate receptors are gradually overexpressed in the cellular membrane with the progress of cancer from stage 1 to stage 4. Utilizing the fact, herein, developed a porous silica nanoparticle system C1@SiO2-FA-NP; A) impregnated with thermodynamically stable Mn(II) complex (1) molecules within the core of the nanoparticle, and B) surface functionalized with folate units. It exhibited a high longitudinal relaxivity value r1 = 21.45 mM-1s-1 that substantially increased to r1 = 40.97 mM-1s-1 in the presence of 0.67mM concentration of BSA under the physiological condition. The in vitro fluorescent images after surface conjugation of C1@SiO2-FA-NP with FITC (fluorescein isothiocyanate) buttressed the inclusion of the nanoparticle exclusively within the cancerous HeLa cells than that of healthy HEK293 cells. The importance of the surface-bound folate unit in the nanoparticle is further established by comparing the fluorescent images of HeLa cells in the absence of the group. Finally, the applicability of C1@SiO2-FA-NP as the T1-weighted MRI contrast agent for early-stage cancer diagnosis is established within C57BL/6 mice after infecting the mice with HeLa cells.

A Hexanuclear Gadolinium(III)-Based Nanoprobe for Magnetic Resonance Imaging of Tumor Apoptosis.

Magnetic resonance imaging (MRI) is instrumental in the noninvasive evaluation of tumor tissues in patients subjected to chemotherapy, thereby yielding essential diagnostic data crucial for the prognosis of tumors and the formulation of therapeutic strategies. Currently, commercially available MRI contrast agents (CAs) predominantly consist of mononuclear gadolinium(III) complexes. Because there is only one Gd(III) atom per molecule, these CAs often require administration in high doses to achieve the desired contrast quality, which inevitably leads to some adverse events. Herein, we develop a six-nuclei, apoptosis-targeting T1 CA, Gd6-ZnDPA nanoprobe, which consists of a hexanuclear gadolinium nanocluster (Gd6) with an apoptosis-targeting group (ZnDPA). The amplification of Gd(III) by the hexanuclear structure generates its high longitudinal relaxivity (44.67 mM-1 s-1, 1T) and low r1/r2 ratio (0.68, 1T). Based on the Solomon-Bloembergen-Morgan (SBM) theory, this notable improvement is primarily ascribed to a long correlation tumbling time (τR). More importantly, the Gd6-ZnDPA nanoprobe shows excellent tumor apoptosis properties with an enhanced MR signal ratio (∼74%) and a long MRI imaging acquisition time window (∼48 h) in 4T1 tumor-bearing mice. This study introduces an experimental gadolinium-based CA for the potential imaging of tumor apoptosis in the context of MRI.

Decoration of 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) with N-oxides increases the T1 relaxivity of Gd-complexes.

High complex stability and longitudinal relaxivity of Gd-based contrast agents are important requirements for magnetic resonance imaging (MRI) because they ensure patient safety and contribute to measurement sensitivity. Charged and zwitterionic Gd3+-complexes of the well-known chelator 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) provide an excellent basis for the development of safe and sensitive contrast agents. In this report, we describe the synthesis of DOTA-NOx, a DOTA derivative with four N-oxide functionalities via "click" functionalization of the tetraazide DOTAZA. The resulting complexes Gd-DOTA-NOx and Eu-DOTA-NOx are stable compounds in aqueous solution. NMR-spectroscopic characterization revealed a high excess of the twisted square antiprismatic (TSAP) coordination geometry over square antiprismatic (SAP). The longitudinal relaxivity of Gd-DOTA-NOx was found to be r1=7.7 mm-1 s-1 (1.41 T, 37 °C), an unusually high value for DOTA complexes of comparable weight. We attribute this high relaxivity to the steric influence and an ordering effect on outer sphere water molecules surrounding the complex generated by the strongly hydrated N-oxide groups. Moreover, Gd-DOTA-NOx was found to be stable against transchelation with high excess of EDTA (200 eq) over a period of 36 h, and it has a similar in vitro cell toxicity as clinically used DOTA-based GBCAs.

Multi-functional GdEuxTb1-xO3 (x = 0 to 1) nanoparticles: colour tuning optical properties, water proton spin relaxivities, and X-ray attenuation properties.

Multi-functional nanoparticles are useful for various applications, such as biomedical imaging, detection, and display technologies. Colour-tunable GdEuxTb1-xO3 nanoparticles were synthesized with emission colour ranging from green (545 nm) to red (616 nm) by varying x (x = 0, 0.1, 0.3, 0.5, 0.7, 0.9, and 1). These nanoparticles were surface-grafted with polyacrylic acid and a small quantity of 2,6-pyridinedicarboxylic acid. This modification aimed to ensure long-term colloidal stability (>1 year without precipitation) and high quantum yields (>30%) in aqueous media. Additionally, they exhibited long emission lifetimes (∼1 ms), high longitudinal water proton spin relaxivities (>30 s-1mM-1), and high X-ray attenuation efficiencies (∼10 HU mM-1). These multiple exceptional properties within a single nanoparticle make them highly valuable for applications in biomedical imaging, noise-free signal detection, and colour display.

Preparation, Characterization, and Magnetic Resonance Imaging of Mn@SiO2 Nanowires.

The deposition time was controlled to prepare Mn nanowires of different lengths and diameters on templates of anodic aluminum oxide (AAO) with different pore sizes. The surface of as-prepared Mn nanowires was modified with SiO2 using the sol-gel method to improve their dispersion in aqueous solution. The effects of the diameter and length of the as-prepared Mn nanowires coated with SiO2 on the relaxivity were investigated. It was found that the Mn@SiO2 nanowires have smaller diameters and a higher longitudinal relaxivity (r1) with an increased length. Mn3@SiO2 nanowires had the highest r1 value of 5.8 mM-1 s-1 among the Mn@SiO2 nanowires (Mn3 nanowires have a diameter of about 30 nm and a length of about 0.5 μm length). Additionally, the biocompatibility and in vivo imaging ability of the Mn3@SiO2 nanowires were evaluated. The Mn3@SiO2 nanowires had good cytotoxicity and biocompatibility, and the kidney of SD rats showed a positive enhancement effect during small animal imaging at 1.5 T. This study showed that the Mn3@SiO2 nanowires could potentially become contrast agents (CAs) of longitudinal relaxation time (T1).

Bioinspired theranostic quantum dots: Paving the road to a new paradigm for cancer diagnosis and therapeutics

Despite extensive research, a complete cure remains lacking for most types of cancer. Nanotechnology-based carriers, such as liposomes, nanoparticles (NPs), dendrimers, nanoemulsions, and other nanocarriers, can target cancer cells, but their in vivo fate is unpredictable. Bioinspired quantum dots (BQDs) offer enhanced aqueous solubility, exceptionally low toxicity, biocompatibility, easy biofunctionalization, and selective cancer targeting. Due to their photoluminescence, high longitudinal relaxation value, photothermal effect upon laser irradiation, generation of singlet oxygen, and production of H2S for gas therapy, BQDs are excellent cancer theranostic agents. In this review, we highlight the theranostic application of, and existing challenges relating to BQDs.

Biotin‐Conjugated Poly(Acrylic Acid)‐Grafted Ultrasmall Gadolinium Oxide Nanoparticles for Enhanced Tumor Imaging

AbstractHerein, biotin (Bio)‐conjugated poly(acrylic acid) (PAA)‐grafted ultrasmall gadolinium oxide nanoparticles (Bio‐PAA‐Gd2O3 NPs) were synthesized for enhanced tumor imaging using Bio as a tumor‐targeting ligand. The average particle diameter of Gd2O3 NPs was 2.1 nm. The Bio‐PAA‐Gd2O3 NPs exhibited excellent colloidal stability (i. e., no precipitation) and a high longitudinal water proton spin relaxivity (r1) of 23.8 s−1 mM−1 (r2/r1=1.6 and r2=transverse water proton spin relaxivity), which was ∼6 times higher than those of commercial Gd‐chelated magnetic resonance imaging (MRI) contrast agents. Cytotoxicity tests using two cell lines showed that the Bio‐PAA‐Gd2O3 NPs were almost non‐toxic up to the measured concentration of 500 μM Gd. The enhanced tumor imaging of the Bio‐PAA‐Gd2O3 NPs was demonstrated through their higher positive contrasts and longer contrast retention at the tumor after intravenous injection in T1 MR images, compared with those of the control PAA‐Gd2O3 NPs.

High temperature flow synthesis of iron oxide nanoparticles: Size tuning via reactor engineering

Batch thermal decomposition syntheses of iron oxide nanoparticles (IONPs) provide precise control of particle properties, but their scalability and reproducibility is challenging. This is addressed in this work via a versatile high temperature flow reactor with adjustable temperature profiles through three individual stages operated between 180 °C and 280 °C. The tuneable temperature profiles in combination with self-seeded growth methods made it possible to synthesise IONPs between 2 and 17 nm (a size increase that corresponds to a >600 fold particle volume increase) at production rates of several gIONP per day. The precursor solutions contained only iron(III) acetylacetonate in a polyol solvent and no nucleation or growth inhibitors, oxidation or reducing agents, ligands or any other additives . This broad size range covers most biomedical applications and is of special interest for T1 MRI contrast agents (2–5 nm), as well as for magnetic hyperthermia cancer therapy (>10 nm). The potential of the IONPs produced was demonstrated by their high longitudinal relaxivity >16 mM−1s−1 at a transversal/longitudinal relaxivity ratio <2.5 (small IONPs) and specific absorption rates increasing with the IONP size up to180 W/gFe. In addition, the polyol method employed allowed for simple ligand exchange with biocompatible sodium tripolyphosphate to make the IONPs stable in water, thus rendering them suitable for biomedical applications. The continuous high temperature process presented shows how to control the particle size not via the chemistry (e.g., chemical additives affecting the particle size through the surface chemistry), but engineering parameters, i.e., reactor temperature profiles, reagent addition sequences and seeded growth strategies.

Magnetic Resonance Diagnosis of Early Triple-Negative Breast Cancer Based on the Ionic Covalent Organic Framework with High Relaxivity and Long Retention Time.

Patients with triple-negative breast cancer (TNBC) have dismal prognoses due to the lack of therapeutic targets and susceptibility to lymph node (LN) metastasis. Therefore, it is essential to develop more effective approaches to identify early TNBC tissues and LNs. In this work, a magnetic resonance imaging (MRI) contrast agent (Mn-iCOF) was constructed based on the Mn(II)-chelated ionic covalent organic framework (iCOF). Because of the porous structure and hydrophilicity, the Mn-iCOF has a high longitudinal relaxivity (r1) of 8.02 mM-1 s-1 at 3.0 T. For the tumor-bearing mice, a lower dose (0.02 mmol [Mn]/kg) of Mn-iCOF demonstrated a higher signal-to-noise ratio (SNR) value (1.8) and longer retention time (2 h) compared to a 10-fold dose of commercial Gd-DOTA (0.2 mmol [Gd]/kg). Moreover, the Mn-iCOF can provide continuous and significant MR contrast for the popliteal LNs within 24 h, allowing for accurate evaluation and dissection of LNs. These excellent MRI properties of the Mn-iCOF may open new avenues for designing more biocompatible MRI contrast agents with higher resolutions, particularly in the diagnosis of TNBC.

Water-Soluble Gd(III)-Porphyrin Complexes Capable of Both Photosensitization and Relaxation Enhancement.

With the aim of developing more stable Gd(III)-porphyrin complexes, two types of ligands 1 and 2 with carboxylic acid anchors were synthesized. Due to the N-substituted pyridyl cation attached to the porphyrin core, these porphyrin ligands were highly water-soluble and formed the corresponding Gd(III) chelates, Gd-1 and Gd-2. Gd-1 was sufficiently stable in neutral buffer, presumably due to the preferred conformation of the carboxylate-terminated anchors connected to nitrogen in the meta position of the pyridyl group helping to stabilize Gd(III) complexation by the porphyrin center. 1H NMRD (nuclear magnetic relaxation dispersion) measurements on Gd-1 revealed high longitudinal water proton relaxivity (r1 = 21.2 mM-1 s-1 at 60 MHz and 25 °C), which originates from slow rotational motion resulting from aggregation in aqueous solution. Under visible light irradiation, Gd-1 showed extensive photoinduced DNA cleavage in line with efficient photoinduced singlet oxygen generation. Cell-based assays revealed no significant dark cytotoxicity of Gd-1, while it showed sufficient photocytotoxicity on cancer cell lines under visible light irradiation. These results indicate the potential of this Gd(III)-porphyrin complex (Gd-1) as a core for the development of bifunctional systems acting as an efficient photodynamic therapy photosensitizer (PDT-PS) with magnetic resonance imaging (MRI) detection capabilities.

Fe3+@PDOPA‑b‑PSar Nanoparticles for Magnetic Resonance Imaging and Cancer Chemotherapy.

Chemotherapy treatments for cancer are always accompanied by a low concentration of drug delivered in the tumor area and severe side effects including systemic toxicity. Improving the concentration, biocompatibility, and biodegradability of regional chemotherapy drugs is a pressing challenge in the field of materials. N-Phenyloxycarbonyl-amino acids (NPCs) which exhibit significant tolerance to nucleophiles, such as water and hydroxyl-containing compounds, are promising monomers for the synthesis of polypeptides and polypeptoids. Cell line and mouse models were used to comprehensively explore how to enhance the tumor MRI signal and evaluate the therapeutic effect of Fe@POS-DOX nanoparticles. In this study, poly(3,4-dihydroxy-L-phenylalanine)-b-polysarcosine (PDOPA-b-PSar, simplified as POS) was synthesized by the block copolymerization of DOPA-NPC with Sar-NPC. Fe@POS-DOX nanoparticles were prepared in order to utilize the strong chelation of catechol ligands to iron (III) cations and the hydrophobic interaction between DOX and DOPA block to deliver chemotherapeutics to tumor tissue. The Fe@POS-DOX nanoparticles exhibit high longitudinal relaxivity (r 1 = 7.06 mM-1·s-1) and act as T 1-weighted magnetic resonance (MR) imaging contrast agents. Further, the main focus was improving tumor site-specific bioavailability and achieving therapeutic effects through the biocompatibility and biodegradability of Fe@POS-DOX NPs. The Fe@POS-DOX treatment exhibited excellent antitumor effects. Upon intravenous injection, Fe@POS-DOX delivers DOX specifically to the tumor tissues, as revealed by MR, and leads to the inhibition of tumor growth without overt toxicity to normal tissues, thus displaying considerable potential for use in clinical applications.

Metal-Assembled Collagen Peptide Microflorettes as Magnetic Resonance Imaging Agents

Magnetic resonance imaging (MRI) is a medical imaging technique that provides detailed information on tissues and organs. However, the low sensitivity of the technique requires the use of contrast agents, usually ones that are based on the chelates of gadolinium ions. In an effort to improve MRI signal intensity, we developed two strategies whereby the ligand DOTA and Gd(III) ions are contained within Zn(II)-promoted collagen peptide (NCoH) supramolecular assemblies. The DOTA moiety was included in the assembly either via a collagen peptide sidechain (NHdota) or through metal-ligand interactions with a His-tagged DOTA conjugate (DOTA-His6). SEM verified that the morphology of the NCoH assembly was maintained in the presence of the DOTA-containing peptides (microflorettes), and EDX and ICP-MS confirmed that Gd(III) ions were incorporated within the microflorettes. The Gd(III)-loaded DOTA florettes demonstrated higher intensities for the T1-weighted MRI signal and higher longitudinal relaxivity (r1) values, as compared to the clinically used contrast agent Magnevist. Additionally, no appreciable cellular toxicity was observed with the collagen microflorettes loaded with Gd(III). Overall, two peptide-based materials were generated that have potential as MRI contrast agents.

Engineered Graphene Quantum Dots as a Magnetic Resonance Signal Amplifier for Biomedical Imaging.

The application of magnetic resonance imaging (MRI) nano-contrast agents (nano-CAs) has increasingly attracted scholarly interest owing to their size, surface chemistry, and stability. Herein, a novel T1 nano-CA (Gd(DTPA)-GQDs) was successfully prepared through the functionalization of graphene quantum dots with poly(ethylene glycol) bis(amine) and their subsequent incorporation into Gd-DTPA. Remarkably, the resultant as-prepared nano-CA displayed an exceptionally high longitudinal proton relaxivity (r1) of 10.90 mM-1 s-1 (R2 = 0.998), which was significantly higher than that of commercial Gd-DTPA (4.18 mM-1 s-1, R2 = 0.996). The cytotoxicity studies indicated that the Gd(DTPA)-GQDs were not cytotoxic by themselves. The results of the hemolysis assay and the in vivo safety evaluation demonstrate the outstanding biocompatibility of Gd(DTPA)-GQDs. The in vivo MRI study provides evidence that Gd(DTPA)-GQDs exhibit exceptional performance as T1-CAs. This research constitutes a viable approach for the development of multiple potential nano-CAs with high-performance MR imaging capabilities.

High-stability spherical lanthanide nanoclusters for magnetic resonance imaging.

High-nuclear lanthanide clusters have shown great potential for the administration of high-dose mononuclear gadolinium chelates in magnetic resonance imaging (MRI). The development of high-nuclear lanthanide clusters with excellent solubility and high stability in water or solution has been challenging and is very important for expanding the performance of MRI. We used N-methylbenzimidazole-2-methanol (HL) and LnCl3·6H2O to synthesize two spherical lanthanide clusters, Ln32 (Ln = Ho, Ho32; and Ln = Gd, Gd32), which are highly stable in solution. The 24 ligands L- are all distributed on the periphery of Ln32 and tightly wrap the cluster core, ensuring that the cluster is stable. Notably, Ho32 can remain highly stable when bombarded with different ion source energies in HRESI-MS or immersed in an aqueous solution of different pH values for 24 h. The possible formation mechanism of Ho32 was proposed to be Ho(III), (L)- and H2O → Ho3(L)3/Ho3(L)4 → Ho4(L)4/Ho4(L)5 → Ho6(L)6/Ho6(L)7 → Ho16(L)19 → Ho28(L)15 → Ho32(L)24/Ho32(L)21/Ho32(L)23. To the best of our knowledge, this is the first study of the assembly mechanism of spherical high-nuclear lanthanide clusters. Spherical cluster Gd32, a form of highly aggregated Gd(III), exhibits a high longitudinal relaxation rate (1 T, r1 = 265.87 mM-1·s-1). More notably, compared with the clinically used commercial material Gd-DTPA, Gd32 has a clearer and higher-contrast T1-weighted MRI effect in mice bearing 4T1 tumors. This is the first time that high-nuclear lanthanide clusters with high water stability have been utilized for MRI. High-nuclear Gd clusters containing highly aggregated Gd(III) at the molecular level have higher imaging contrast than traditional Gd chelates; thus, using large doses of traditional gadolinium contrast agents can be avoided.

Smart Nanosensitizers for Activatable Sono‐Photodynamic Immunotherapy of Tumors by Redox‐Controlled Disassembly

AbstractTumor‐targeted and stimuli‐activatable nanosensitizers are highly desirable for cancer theranostics. However, designing smart nanosensitizers with multiple imaging signals and synergistic therapeutic activities switched on is challenging. Herein, we report tumor‐targeted and redox‐activatable nanosensitizers (1‐NPs) for sono‐photodynamic immunotherapy of tumors by molecular co‐assembly and redox‐controlled disassembly. 1‐NPs show a high longitudinal relaxivity (r1=18.7±0.3 mM−1 s−1), but “off” dual fluorescence (FL) emission (at 547 and 672 nm), “off” sono‐photodynamic therapy and indoleamine 2,3‐dioxygenase 1 (IDO1) inhibition activities. Upon reduction by glutathione (GSH), 1‐NPs rapidly disassemble and remotely release small molecules 2‐Gd, Zn‐PPA‐SH and NLG919, concurrently switching on (1) dual FL emission, (2) sono‐photodynamic therapy and (3) IDO1 inhibition activities. After systemic injection, 1‐NPs are effective for bimodal FL and magnetic resonance (MR) imaging‐guided sono‐photodynamic immunotherapy of orthotropic breast and brain tumors in mice under combined ultrasound (US) and 671‐nm laser irradiation.

Smart Nanosensitizers for Activatable Sono-Photodynamic Immunotherapy of Tumors by Redox-Controlled Disassembly.

Tumor-targeted and stimuli-activatable nanosensitizers are highly desirable for cancer theranostics. However, designing smart nanosensitizers with multiple imaging signals and synergistic therapeutic activities switched on is challenging. Herein, we report tumor-targeted and redox-activatable nanosensitizers (1-NPs) for sono-photodynamic immunotherapy of tumors by molecular co-assembly and redox-controlled disassembly. 1-NPs show a high longitudinal relaxivity (r1 =18.7±0.3 mM-1 s-1 ), but "off" dual fluorescence (FL) emission (at 547 and 672 nm), "off" sono-photodynamic therapy and indoleamine 2,3-dioxygenase 1 (IDO1) inhibition activities. Upon reduction by glutathione (GSH), 1-NPs rapidly disassemble and remotely release small molecules 2-Gd, Zn-PPA-SH and NLG919, concurrently switching on (1) dual FL emission, (2) sono-photodynamic therapy and (3) IDO1 inhibition activities. After systemic injection, 1-NPs are effective for bimodal FL and magnetic resonance (MR) imaging-guided sono-photodynamic immunotherapy of orthotropic breast and brain tumors in mice under combined ultrasound (US) and 671-nm laser irradiation.

A trade-off between ligand coating and crystallinity of Gd-doped ultrasmall CeO2 for improving relaxivity.

A Gd-doped ultrasmall CeO2 contrast agent was prepared with high longitudinal relaxivity (r1 = 10.1 mM-1 s-1, 7.0 T) through rationally regulating the crystallinity and surface coatings, providing a new paradigm for optimizing MRI performance. Moreover, responsive photoacoustic imaging (PAI) was established via tumor microenvironment-triggered oxidation, affording dual-modal imaging.