Core–Satellite Polydopamine–Gadolinium‐Metallofullerene Nanotheranostics for Multimodal Imaging Guided Combination Cancer Therapy

Integration of magnetic resonance imaging (MRI) and other imaging modalities is promising to furnish complementary information for accurate cancer diagnosis and imaging‐guided therapy. However, most gadolinium (Gd)–chelator MR contrast agents are limited by their relatively low relaxivity and high risk of released‐Gd‐ions‐associated toxicity. Herein, a radionuclide‐⁶⁴Cu‐labeled doxorubicin‐loaded polydopamine (PDA)–gadolinium‐metallofullerene core–satellite nanotheranostic agent (denoted as CDPGM) is developed for MR/photoacoustic (PA)/positron emission tomography (PET) multimodal imaging‐guided combination cancer therapy. In this system, the near‐infrared (NIR)‐absorbing PDA acts as a platform for the assembly of different moieties; Gd₃N@C₈₀, a kind of gadolinium metallofullerene with three Gd ions in one carbon cage, acts as a satellite anchoring on the surface of PDA. The as‐prepared CDPGM NPs show good biocompatibility, strong NIR absorption, high relaxivity (r ₁ = 14.06 mM^?1 s^?1), low risk of release of Gd ions, and NIR‐triggered drug release. In vivo MR/PA/PET multimodal imaging confirms effective tumor accumulation of the CDPGM NPs. Moreover, upon NIR laser irradiation, the tumor is completely eliminated with combined chemo‐photothermal therapy. These results suggest that the CDPGM NPs hold great promise for cancer theranostics.     

Biodegradable Polysilsesquioxane Nanoparticles as Efficient Contrast Agents for Magnetic Resonance Imaging

Polysilsesquioxane (PSQ) nanoparticles are crosslinked homopolymers formed by condensation of functionalized trialkoxysilanes, and provide an interesting platform for developing biologically and biomedically relevant nanomaterials. In this work, the design and synthesis of biodegradable PSQ particles with extremely high payloads of paramagnetic Gd(III) centers is explored, for use as efficient contrast agents for magnetic resonance imaging (MRI). Two new bis(trialkoxysilyl) derivatives of Gd(III) diethylenetriamine pentaacetate (Gd‐DTPA) containing disulfide linkages are synthesized and used to form biodegradable Gd‐PSQ particles by base‐catalyzed condensation reactions in reverse microemulsions. The Gd‐PSQ particles, PSQ‐ 1 and PSQ‐ 2 , carry 53.8 wt% and 49.3 wt% of Gd‐DTPA derivatives, respectively. In addition, the surface carboxy groups on the PSQ‐ 2 particles can be modified with polyethylene glycol (PEG) and the anisamide (AA) ligand to enhance biocompatibility and cell uptake, respectively. The Gd‐PSQ particles are readily degradable to release the constituent Gd(III) chelates in the presence of endogenous reducing agents such as cysteine and glutathione. The MR relaxivities of the Gd‐PSQ particles are determined using a 3T MR scanner, with r₁ values ranging from 5.9 to 17.8 mMs^?1 on a per‐Gd basis. Finally, the high sensitivity of the Gd‐PSQ particles as T₁‐weighted MR contrast agents is demonstrated with in vitro MR imaging of human lung and pancreatic cancer cells. The enhanced efficiency of the anisamide‐functionalized PSQ‐ 2 particles as a contrast agent is corroborated by both confocal laser scanning microscopy imaging and ICP‐MS analysis of Gd content in vitro.     

Anti‐Biofouling Polymer‐Decorated Lutetium‐Based Nanoparticulate Contrast Agents for In Vivo High‐Resolution Trimodal Imaging

Nanomaterials have gained considerable attention and interest in the development of novel and high‐resolution contrast agents for medical diagnosis and prognosis in clinic. A classical urea‐based homogeneous precipitation route that combines the merits of in situ thermal decomposition and surface modification is introduced to construct polyethylene glycol molecule (PEG)‐decorated hybrid lutetium oxide nanoparticles (PEG–UCNPs). By utilizing the admirable optical and magnetic properties of the yielded PEG–UCNPs, in vivo up‐conversion luminescence and T₁‐enhanced magnetic resonance imaging of small animals are conducted, revealing obvious signals after subcutaneous and intravenous injection, respectively. Due to the strong X‐ray absorption and high atomic number of lanthanide elements, X‐ray computed‐tomography imaging based on PEG–UCNPs is then designed and carried out, achieving excellent imaging outcome in animal experiments. This is the first example of the usage of hybrid lutetium oxide nanoparticles as effective nanoprobes. Furthermore, biodistribution, clearance route, as well as long‐term toxicity are investigated in detail after intravenous injection in a murine model, indicating the overall safety of PEG–UCNPs. Compared with previous lanthanide fluorides, our nanoprobes exhibit more advantages, such as facile construction process and nearly total excretion from the animal body within a month. Taken together, these results promise the use of PEG–UCNPs as a safe and efficient nanoparticulate contrast agent for potential application in multimodal imaging.     

915 nm Light‐Triggered Photodynamic Therapy and MR/CT Dual‐Modal Imaging of Tumor Based on the Nonstoichiometric Na0.52YbF3.52:Er Upconversion Nanoprobes

Lanthanide (Ln³⁺)‐doped upconversion nanoparticles (UCNPs) as a new generation of multimodal bioprobes have attracted great interest for theranostic purpose. Herein, red emitting nonstoichiometric Na_0.52YbF_3.52:Er UCNPs of high luminescence intensity and color purity are synthesized via a facile solvothermal method. The red UC emission from the present nanophosphors is three times more intense than the well‐known green emission from the ≈30 nm sized hexagonal‐phase NaYF₄:Yb,Er UCNPs. By utilizing Na_0.52YbF_3.52:Er@SrF₂ UCNPs as multifunctional nanoplatforms, highly efficient in vitro and in vivo 915 nm light‐triggered photodynamic therapies are realized for the first time, with dramatically diminished overheating yet similar therapeutic effects in comparison to those triggered by 980 nm light. Moreover, by virtue of the high transverse relaxivity (r ₂) and the strong X‐ray attenuation ability of Yb³⁺ ions, these UCNPs also demonstrate good performances as contrast agents for high contrast magnetic resonance and X‐ray computed tomography dual‐modal imaging. Our research shows the great potential of the red emitting Na_0.52YbF_3.52:Er UCNPs for multimodal imaging‐guided photodynamic therapy of tumors.     

Coating Engineering of MnFe2O4 Nanoparticles with Superhigh T2 Relaxivity and Efficient Cellular Uptake for Highly Sensitive Magnetic Resonance Imaging

Superparamagnetic nanoparticles with superhigh T₂ relaxivity and cellular uptake are strongly desired for ultrasensitive magnetic resonance imaging (MRI). Towards this end, highly monodispersed manganese ferrite nanoparticles (MNPs, 6 nm) with mPEG‐g‐PEI and PEG coatings as model system are employed in this study to investigate the coating engineering for simultaneously high T₂ relaxivity and cellular uptake. The quantitative evaluations of the intracellular uptake indicate that mPEG‐g‐PEI modified MNPs possess highly efficient cellular uptake, 2.4‐fold larger than that with mPEG coating. More significantly, this coating simultaneously leads to a remarkably high T₂ relaxivity up to 331.8 mm ⁻¹ s⁻¹, which is 4 times larger than that of the mPEG control and the largest value reported for superparamagnetic iron oxides with similar size. Modeling analysis reveals that the superior relaxivity is mainly attributed to the largely reduced diffusivity of water molecules trapped in the mPEG‐g‐PEI net. Further MRI of MDA‐MB‐231 breast cancer cells loaded MNPs with mPEG‐g‐PEI coating demonstrated the strong MR contrast in vitro effect with a T₂ relaxivity as high as 92.6 mm ⁻¹ s⁻¹, 2.5‐folds larger than reported 10 nm MNPs. This study provides a universal strategy of coating engineering of various magnetic nanoparticles for highly sensitive MRI.     

Application of compatible dual‐echo arteriovenography in stroke: Preliminary observations

Compatible dual‐echo arteriovenography (CODEA) is a recent MRI technique for simultaneous acquisition of an MR angiogram (MRA) and MR venogram (MRV) with image quality comparable to conventional single‐echo acquisitions. The purpose of this study was to evaluate the utility of CODEA in imaging patients with chronic stroke and to test the utility of a new image representation technique (“enhanced maximum intensity projection [MIP]") based on tissue segmentation, intensity inversion, and vessel enhancement filtering) for MRV. Arterial and venous abnormalities associated with stroke were delineated on MRA and MRV acquired simultaneously with the CODEA technique. CODEA MRV displayed with the enhanced MIP technique facilitated the visualization of the overall venous structures in 3D. Reduced venous vascularity was detected in the regions of arterial occlusion compared to the contralateral normal brain regions. The CODEA technique along with the enhanced MIP technique may be valuable, particularly in clinical applications that require efficient MRA/MRV imaging because of limited scan time such as in acute stroke. © 2013 Wiley Periodicals, Inc. Int J Imaging Syst Technol, 23, 152–156, 2013     

Hyperbranched Conjugated Polyelectrolyte for Dual‐modality Fluorescence and Magnetic Resonance Cancer Imaging

Herein is reported the synthesis of gadolinium ion (Gd(III))‐chelated hyperbranched conjugated polyelectrolyte (HCPE‐Gd) and its application in fluorescence and magnetic resonance (MR) dual imaging in live animals. The synthesized HCPE‐Gd forms nanospheres with an average diameter of ～42 nm measured by laser light scattering and a quantum yield of 10% in aqueous solution. The absorption spectrum of HCPE‐Gd has two maxima at 318 and 417 nm, and its photoluminescence maximum centers at 591 nm. Confocal laser scanning microscopy studies indicate that the HCPE‐Gd is internalized in MCF‐7 cancer cell cytoplasm with good photostability and low cytotoxicity. Further fluorescence and MR imaging studies on hepatoma H₂₂ tumor‐bearing mouse model reveal that HCPE‐Gd can serve as an efficient optical/MR dual‐modal imaging nanoprobe for in vivo cancer diagnosis.     

Preoperative Detection and Intraoperative Visualization of Brain Tumors for More Precise Surgery: A New Dual‐Modality MRI and NIR Nanoprobe

In clinical practice, it is difficult to identify tumor margins during brain surgery due to its inherent infiltrative character. Herein, a unique dual‐modality nanoprobe (Gd‐DOTA‐Ag₂S QDs, referred as Gd‐Ag₂S nanoprobe) is reported, which integrates advantages of the deep tissue penetration of enhanced magnetic resonance (MR) imaging of Gd and the high signal‐to‐noise ratio and high spatiotemporal resolution of fluorescence imaging in the second near‐infrared window (NIR‐II) of Ag₂S quantum dots (QDs). Due to the abundant tumor angiogenesis and the enhanced permeability and retention effect in the tumor, a brain tumor (U87MG) in a mouse model is clearly delineated in situ with the help of the Gd assisted T1 MR imaging and the intraoperative resection of the tumor is precisely accomplished under the guidance of NIR‐II fluorescence imaging of Ag₂S QDs after intravenous injection of Gd‐Ag₂S nanoprobe. Additionally, no histologic changes are observed in the main organs of the mouse after administration of Gd‐Ag₂S nanoprobe for 1 month, indicating the high biocompatibility of the nanoprobe. We expect that such a novel “Detection and Operation” strategy based on Gd‐Ag₂S nanoprobe is promising in future clinical applications.     

Dendrimer‐Assisted Formation of Fe3O4/Au Nanocomposite Particles for Targeted Dual Mode CT/MR Imaging of Tumors

A unique dendrimer‐assisted approach is reported to create Fe₃O₄/Au nanocomposite particles (NCPs) for targeted dual mode computed tomography/magnetic resonance (CT/MR) imaging of tumors. In this approach, preformed Fe₃O₄ nanoparticles (NPs) are assembled with multilayers of poly(γ‐glutamic acid) (PGA)/poly(l ‐lysine)/PGA/folic acid (FA)‐modified dendrimer‐entrapped gold nanoparticles via a layer‐by‐layer self‐assembly technique. The interlayers are crosslinked via 1‐ethyl‐3‐(3‐dimethylaminopropyl)carbodiimide chemistry, the assembled Au core NPs are then used as seed particles for subsequent seed‐mediated growth of Au shells via iterative Au salt reduction process, and subsequent acetylation of the remaining amines of dendrimers leads to the formation of Fe₃O₄/Au_n.Ac‐FA NCPs with a tunable molar ratio of Au/Fe₃O₄. It is shown that the Fe₃O₄/Au_n.Ac‐FA NCPs at an optimized Au/Fe₃O₄ molar ratio of 2.02 display a relatively high R₂ relaxivity (92.67 × 10^?3 M^?1 s^?1) and good X‐ray attenuation property, and are cytocompatible and hemocompatible in the given concentration range. Importantly, with the FA‐mediated targeting, the Fe₃O₄/Au_n.Ac‐FA NCPs are able to be specifically uptaken by cancer cells overexpressing FA receptors, and be used as an efficient nanoprobe for targeted dual mode CT/MR imaging of a xenografted tumor model. With the versatile dendrimer chemistry, the developed Fe₃O₄/Au NCPs may be differently functionalized, thereby providing a unique platform for diagnosis and therapy of different biological systems.     

Geometrical confinement of gadolinium-based contrast agents in nanoporous particles enhances T1 contrast

Magnetic resonance imaging contrast agents are currently designed by modifying their structural and physiochemical properties to improve relaxivity and to enhance image contrast. Here, we show a general method for increasing relaxivity by confining contrast agents inside the nanoporous structure of silicon particles. Magnevist, gadofullerenes and gadonanotubes were loaded inside the pores of quasi-hemispherical and discoidal particles. For all combinations of nanoconstructs, a boost in longitudinal proton relaxivity r(1) was observed: Magnevist, r(1) ≈ 14 mM(-1) s(-1)/Gd(3+) ion (～ 8.15 × 10(+7) mM(-1) s(-1)/construct); gadofullerenes, r(1) ≈ 200 mM(-1) s(-1)/Gd(3+) ion (～ 7 × 10(+9) mM(-1) s(-1)/construct); gadonanotubes, r(1) ≈ 150 mM(-1) s(-1)/Gd(3+) ion (～ 2 × 10(+9) mM(-1) s(-1)/construct). These relaxivity values are about 4 to 50 times larger than those of clinically available gadolinium-based agents (～ 4 mM(-1) s(-1)/Gd(3+) ion). The enhancement in contrast is attributed to the geometrical confinement of the agents, which influences the paramagnetic behaviour of the Gd(3+) ions. Thus, nanoscale confinement offers a new and general strategy for enhancing the contrast of gadolinium-based contrast agents.     

Micro‐vascular imaging experiences of time‐of‐flight MRA at 7T for cerebrovascular diseases

Surgical or endovascular approaches have proved effective for large‐vessel diseases over the past decade. However, approaches for small vessel diseases are unlikely to be accomplished by those for large vessels and only few have been applied, because it is hard to access to those small vessels and one could not directly delineate the affected small vessels due to a lack of detection modalities. This study is to examine patients with vascular diseases using ultra‐high field 7T MRI with conventional time‐of‐flight (TOF) sequence, 3D fast low‐angle shot (FLASH) gradient‐echo. We have evaluated several radio‐frequency (RF) coils to find the optimal one for 7T magnetic resonance angiography (MRA), especially for micro‐vascular imaging. We have conducted several comparison studies with vascular disease patients. The results showed that micro‐vessels such as lenticulostriate arteries in the subjects with risk factors like hypertension or stroke patients were significantly less than in the healthy subjects. 7T MRA images in steno‐occlusive patients also showed clearly numerous collateral vessels not visible by 1.5T or 3T MRA. Furthermore, 7T MRA images were comparable to those obtained by digital subtraction angiography (DSA), particularly for micro‐vascular imaging. In this article, we would like to share the clinical experiences on 7T MRA that vascular images of 7T MRA were superior to conventional angiography images including 1.5T and 3T MRA, and even comparable to DSA. We also expect that further technical development and clinical applications of 7T MRA would be a clinically important diagnostic tool, in terms of an early detection of the stroke in a totally non‐invasive manner. © 2014 Wiley Periodicals, Inc. Int J Imaging Syst Technol, 24, 121–128, 2014     

Manganese Doped Fluorescent Paramagnetic Nanocrystals for Dual‐Modal Imaging

In this work, dual‐modal (fluorescence and magnetic resonance) imaging capabilities of water‐soluble, low‐toxicity, monodisperse Mn‐doped ZnSe nanocrystals (NCs) with a size (6.5 nm) below the optimum kidney cutoff limit (10 nm) are reported. Synthesizing Mn‐doped ZnSe NCs with varying Mn²⁺ concentrations, a systematic investigation of the optical properties of these NCs by using photoluminescence (PL) and time resolved fluorescence are demonstrated. The elemental properties of these NCs using X‐ray photoelectron spectroscopy and inductive coupled plasma‐mass spectroscopy confirming Mn²⁺ doping is confined to the core of these NCs are also presented. It is observed that with increasing Mn²⁺ concentration the PL intensity first increases, reaching a maximum at Mn²⁺ concentration of 3.2 at% (achieving a PL quantum yield (QY) of 37%), after which it starts to decrease. Here, this high‐efficiency sample is demonstrated for applications in dual‐modal imaging. These NCs are further made water‐soluble by ligand exchange using 3‐mercaptopropionic acid, preserving their PL QY as high as 18%. At the same time, these NCs exhibit high relaxivity (≈2.95 mM^?1 s^?1) to obtain MR contrast at 25 °C, 3 T. Therefore, the Mn²⁺ doping in these water‐soluble Cd‐free NCs are sufficient to produce contrast for both fluorescence and magnetic resonance imaging techniques.     

A Magnetofluorescent Carbon Dot Assembly as an Acidic H2O2‐Driven Oxygenerator to Regulate Tumor Hypoxia for Simultaneous Bimodal Imaging and Enhanced Photodynamic Therapy

Recent studies indicate that carbon dots (CDs) can efficiently generate singlet oxygen (¹O₂) for photodynamic therapy (PDT) of cancer. However, the hypoxic tumor microenvironment and rapid consumption of oxygen in the PDT process will severely limit therapeutic effects of CDs due to the oxygen‐dependent PDT. Thus, it is becoming particularly important to develop a novel CD as an in situ tumor oxygenerator for overcoming hypoxia and substantially enhancing the PDT efficacy. Herein, for the first time, magnetofluorescent Mn‐CDs are successfully prepared using manganese(II) phthalocyanine as a precursor. After cooperative self‐assembly with DSPE‐PEG, the obtained Mn‐CD assembly can be applied as a smart contrast agent for both near‐infrared fluorescence (FL) (maximum peak at 745 nm) and T₁‐weighted magnetic resonance (MR) (relaxivity value of 6.97 mM^?1 s^?1) imaging. More interestingly, the Mn‐CD assembly can not only effectively produce ¹O₂ (quantum yield of 0.40) but also highly catalyze H₂O₂ to generate oxygen. These collective properties of the Mn‐CD assembly enable it to be utilized as an acidic H₂O₂‐driven oxygenerator to increase the oxygen concentration in hypoxic solid tumors for simultaneous bimodal FL/MR imaging and enhanced PDT. This work explores a new biomedical use of CDs and provides a versatile carbon nanomaterial candidate for multifunctional nanotheranostic applications.     

Nanoagents Based on Poly(ethylene glycol)‐b‐Poly(l‐thyroxine) Block Copolypeptide for Enhanced Dual‐Modality Imaging and Targeted Tumor Radiotherapy

Future healthcare requires development of novel theranostic agents that are capable of not only enhancing diagnosis and monitoring therapeutic responses but also augmenting therapeutic outcomes. Here, a versatile and stable nanoagent is reported based on poly(ethylene glycol)‐b‐poly(l ‐thyroxine) (PEG‐PThy) block copolypeptide for enhanced single photon emission computed tomography/computed tomography (SPECT/CT) dual‐modality imaging and targeted tumor radiotherapy in vivo. PEG‐PThy acquired by polymerization of l ‐thyroxine‐N‐carboxyanhydride (Thy‐NCA) displays a controlled M_n, high iodine content of ≈49.2 wt%, and can spontaneously form 65 nm‐sized nanoparticles (PThyN). In contrast to clinically used contrast agents like iohexol and iodixanol, PThyN reveals iso‐osmolality, low viscosity, and long circulation time. While PThyN exhibits comparable in vitro CT attenuation efficacy to iohexol, it greatly enhances in vivo CT imaging of vascular systems and soft tissues. PThyN allows for surface decoration with the cRGD peptide achieving enhanced CT imaging of subcutaneous B16F10 melanoma and orthotopic A549 lung tumor. Taking advantages of a facile iodine exchange reaction, ¹²⁵I‐labeled PThyN enables SPECT/CT imaging of tumors and monitoring of PThyN biodistribution in vivo. Besides, ¹³¹I‐labeled and cRGD‐functionalized PThyN displays remarkable growth inhibition of the B16F10 tumor in mice (tumor inhibition rate > 89%). These poly(l ‐thyroxine) nanoparticles provide a unique and versatile theranostic platform for varying diseases.     

Multifunctional Magnetic Gd3+‐Based Coordination Polymer Nanoparticles: Combination of Magnetic Resonance and Multispectral Optoacoustic Detections for Tumor‐Targeted Imaging in vivo

To overcome traditional barriers in optical imaging and microscopy, optoacoustic‐imaging has been changed to combine the accuracy of spectroscopy with the depth resolution of ultrasound, achieving a novel modality with powerful in vivo imaging. However, magnetic resonance imaging provides better spatial and anatomical resolution. Thus, a single hybrid nanoprobe that allows for simultaneous multimodal imaging is significant not only for cutting edge research in imaging science, but also for accurate clinical diagnosis. A core‐shell‐structured coordination polymer composite microsphere has been designed for in vivo multimodality imaging. It consists of a Fe₃O₄ nanocluster core, a carbon sandwiched layer, and a carbocyanine‐Gd^III (Cy‐Gd^III) coordination polymer outer shell (Fe₃O₄@C@Cy‐Gd^III). Folic acid‐conjugated poly(ethylene glycol) chains are embedded within the coordination polymer shell to achieve extended circulation and targeted delivery of probe particles in vivo. Control of Fe₃O₄ core grain sizes results in optimal r₂ relaxivity (224.5 × 10^–3 m ⁻¹ s^‐1) for T₂‐weighted magnetic resonance imaging. Cy‐Gd^III coordination polymers are also regulated to obtain a maximum 25.1% of Cy ligands and 5.2% of Gd^III ions for near‐infrared fluorescence and T₁‐weighted magnetic resonance imaging, respectively. The results demonstrate their impressive abilities for targeted, multimodal, and reliable imaging.     

Ten‐Gram‐Scale Facile Synthesis of Organogadolinium Complex Nanoparticles for Tumor Diagnosis

The market of available contrast agents for clinical magnetic resonance imaging (MRI) has been dominated by gadolinium (Gd) chelates based T₁ contrast agents for decades. However, there are growing concerns about their safety because they are retained in the body and are nephrotoxic, which necessitated a warning by the U.S. Food and Drug Administration against the use of such contrast agents. To ameliorate these problems, it is necessary to improve the MRI efficiency of such contrast agents to allow the administration of much reduced dosages. In this study, a ten‐gram‐scale facile method is developed to synthesize organogadolinium complex nanoparticles (i.e., reductive bovine serum albumin stabilized Gd‐salicylate nanoparticles, GdSalNPs‐rBSA) with high r₁ value of 19.51 mm ^?1 s^?1 and very low r₂/r₁ ratio of 1.21 (B₀ = 1.5 T) for high‐contrast T₁‐weighted MRI of tumors. The GdSalNPs‐rBSA nanoparticles possess more advantages including low synthesis cost (≈0.54 USD per g), long in vivo circulation time (t_1/2 = 6.13 h), almost no Gd³⁺ release, and excellent biosafety. Moreover, the GdSalNPs‐rBSA nanoparticles demonstrate excellent in vivo MRI contrast enhancement (signal‐to‐noise ratio (ΔSNR) ≈ 220%) for tumor diagnosis.     

Manganese‐Based Layered Double Hydroxide Nanoparticles as a T1‐MRI Contrast Agent with Ultrasensitive pH Response and High Relaxivity

Recently, Mn(II)‐containing nanoparticles have been explored widely as an attractive alternative to Gd(III)‐based T₁‐weighted magnetic resonance imaging (MRI) contrast agents (CAs) for cancer diagnosis. However, as far as it is known, no Mn‐based MRI CAs have been reported to sensitively respond to a very weakly acidic environment (pH 6.5–7.0, i.e., the pH range in a tumor microenvironment) with satisfactory imaging performance. Here, recently devised pH‐ultrasensitive Mn‐based layered double hydroxide (Mn‐LDH) nanoparticles with superb longitudinal relaxivity (9.48 mm ^?1 s^?1 at pH 5.0 and 6.82 mm ^?1 s^?1 at pH 7.0 vs 1.16 mm ^?1 s^?1 at pH 7.4) are reported, which may result from the unique microstructure of Mn ions in Mn‐LDH, as demonstrated by extended X‐ray absorption fine structure. Further in vivo imaging reveals that Mn‐LDH nanoparticles show clear MR imaging for tumor tissues in mice for 2 d post intravenous injection. Thus, this novel Mn‐doped LDH nanomaterial, together with already demonstrated capacity for drug and gene delivery, is a very potential theranostic agent for cancer diagnosis and treatment.     

Dotted Core–Shell Nanoparticles for T1‐Weighted MRI of Tumors

Gd‐based T ₁‐weighted contrast agents have dominated the magnetic resonance imaging (MRI) contrast agent market for decades. Nevertheless, they are reported to be nephrotoxic and the U.S. Food and Drug Administration has issued a general warning concerning their use. In order to reduce the risk of nephrotoxicity, the MRI performance of the Gd‐based T ₁‐weighted contrast agents needs to be improved to allow a much lower dosage. In this study, novel dotted core–shell nanoparticles (FeGd‐HN3‐RGD2) with superhigh r ₁ value (70.0 mM^?1 s^?1) and very low r ₂/r ₁ ratio (1.98) are developed for high‐contrast T ₁‐weighted MRI of tumors. 3‐(4,5‐Dimethylthiazol‐2‐yl)‐2,5‐diphenyltetrazolium bromide (MTT) assay and histological analyses show good biocompatibility of FeGd‐HN3‐RGD2. Laser scanning confocal microscopy images and flow cytometry demonstrate active targeting to integrin α_vβ₃ positive tumors. MRI of tumors shows high tumor ΔSNR for FeGd‐HN3‐RGD2 (477 ± 44%), which is about 6‐7‐fold higher than that of Magnevist (75 ± 11%). MRI and inductively coupled plasma results further confirm that the accumulation of FeGd‐HN3‐RGD2 in tumors is higher than liver and spleen due to the RGD2 targeting and small hydrodynamic particle size (8.5 nm), and FeGd‐HN3‐RGD2 is readily cleared from the body by renal excretion.     

Gadolinium‐Encapsulated Graphene Carbon Nanotheranostics for Imaging‐Guided Photodynamic Therapy

Photosensitizers (PS) are an essential component of photodynamic therapy (PDT). Conventional PSs are often porphyrin derivatives, which are associated with high hydrophobicity, low quantum yield in aqueous solutions, and suboptimal tumor‐to‐normal‐tissue (T/N) selectivity. There have been extensive efforts to load PSs into nanoparticle carriers to improve pharmacokinetics. The approach, however, is often limited by PS self‐quenching, pre‐mature release, and nanoparticle accumulation in the reticuloendothelial system organs. Herein, a novel, nanoparticle‐based PS made of gadolinium‐encapsulated graphene carbon nanoparticles (Gd@GCNs), which feature a high ¹O₂ quantum yield, is reported. Meanwhile, Gd@GCNs afford strong fluorescence and high T₁ relaxivity (16.0 × 10^?3m ^?1 s^?1, 7 T), making them an intrinsically dual‐modal imaging probe. Having a size of approximately 5 nm, Gd@GCNs can accumulate in tumors through the enhanced permeability and retention effect. The unbound Gd@GCNs cause little toxicity because Gd is safely encapsulated within an inert carbon shell and because the particles are efficiently excreted from the host through renal clearance. Studies with rodent tumor models demonstrate the potential of the Gd@GCNs to mediate image‐guided PDT for cancer treatment. Overall, the present study shows that Gd@GCNs possess unique physical, pharmaceutical, and toxicological properties and are an all‐in‐one nanotheranostic tool with substantial clinical translation potential.     

One‐Step,Room‐Temperature Synthesis of Glutathione‐Capped Iron‐Oxide Nanoparticles and their Application in In Vivo T1‐Weighted Magnetic Resonance Imaging

The room‐temperature, aqueous‐phase synthesis of iron‐oxide nanoparticles (IO NPs) with glutathione (GSH) is reported. The simple, one‐step reduction involves GSH as a capping agent and tetrakis(hydroxymethyl)phosphonium chloride (THPC) as the reducing agent; GSH is an anti‐oxidant that is abundant in the human body while THPC is commonly used in the synthesis of noble‐metal clusters. Due to their low magnetization and good water‐dispersibility, the resulting GSH‐IO NPs, which are 3.72 ± 0.12 nm in diameter, exhibit a low r₂ relaxivity (8.28 mm ^?1s^?1) and r₂/r₁ ratio (2.28)—both of which are critical for T₁ contrast agents. This, together with the excellent biocompatibility, makes these NPs an ideal candidate to be a T₁ contrast agent. Its capability in cellular imaging is illustrated by the high signal intensity in the T₁‐weighted magnetic resonance imaging (MRI) of treated HeLa cells. Surprisingly, the GSH‐IO NPs escape ingestion by the hepatic reticuloendothelial system, enabling strong vascular enhancement at the internal carotid artery and superior sagittal sinus, where detection of the thrombus is critical for diagnosing a stroke. Moreover, serial T₁‐ and T₂‐weighted time‐dependent MR images are resolved for a rat's kidneys, unveiling detailed cortical‐medullary anatomy and renal physiological functions. The newly developed GSH‐IO NPs thus open a new dimension in efforts towards high‐performance, long‐circulating MRI contrast agents that have biotargeting potential.