Nanoprobes For Molecular Imaging Research Articles

Molecular imaging of tumour-associated pathological biomarkers with smart nanoprobe: From "Seeing" to "Measuring".

Although the extraordinary progress has been made in molecular biology, the prevention of cancer remains arduous. Most solid tumours exhibit both spatial and temporal heterogeneity, which is difficult to be mimicked in vitro. Additionally, the complex biochemical and immune features of tumour microenvironment significantly affect the tumour development. Molecular imaging aims at the exploitation of tumour-associated molecules as specific targets of customized molecular probe, thereby generating image contrast of tumour markers, and offering opportunities to non-invasively evaluate the pathological characteristics of tumours in vivo. Particularly, there are no "standard markers" as control in clinical imaging diagnosis of individuals, so the tumour pathological characteristics-responsive nanoprobe-based quantitative molecular imaging, which is able to visualizeand determine the accurate content values of heterogeneous distribution of pathological molecules in solid tumours, can provide criteria for cancer diagnosis. In this context, a variety of "smart" quantitative molecular imaging nanoprobes have been designed, in order to provide feasible approaches to quantitatively visualize the tumour-associated pathological molecules in vivo. This review summarizes the recent achievements in the designs of these nanoprobes, and highlights the state-of-the-art technologies in quantitative imaging of tumour-associated pathological molecules.

Near-infrared absorbing semiconducting polymer nanomedicines for cancer therapy.

As a new type of organic optical nanomaterials, semiconducting polymer nanoparticles (SPNs) have the advantages of good optical characteristics and photostability, low toxicity concerns, and relatively simple preparation processes. Particularly, near-infrared (NIR) absorbing SPNs have shown a great promise in biomedicine. In addition to acting as nanoprobes for molecular imaging, these SPNs can produce local heat and reactive oxygen species with the stimulation of NIR light, allowing photothermal therapy (PTT) and photodynamic therapy (PDT), respectively. Herein, we summarize the recent development of SPN-based nanomedicines for cancer therapy. The rational designs of SPNs for enhanced PTT, PDT, or combinational PTT/PDT to achieve effective ablation of tumor tissues are highlighted. Via loading/conjugating SPNs with other therapeutic elements (such as chemotherapeutic drugs and immunotherapeutic agents), phototherapy-combined chemotherapy or immunotherapy can be realized, which is then discussed. In especial, the constructions of SPN-based nanomedicines for NIR photoactivatable chemotherapy and immunotherapy are introduced with representative examples. Finally, we discuss the current challenges and key concerns of SPNs for their biomedical applications and give an outlook for their future clinical translation. This article is categorized under: Therapeutic Approaches and Drug Discovery > Nanomedicine for Oncologic Disease.

In vivo immunotoxicity of Gd2 O3 :Eu3+ nanoparticles and the associated molecular mechanism.

The in vivo toxicity of Gd2 O3 :Eu3+ nanoparticles (NPs) used as dual-modal nanoprobes for molecular imaging has not been studied, and the corresponding molecular mechanism of immunotoxicity remains unknown. In this study, we investigated the cytotoxicity, in vitro apoptosis, and in vivo immunotoxicity of Gd2 O3 :Eu3+ NPs. The NPs showed little immunotoxicity to BALB/c mice. We explored the possible role of the phosphoinositide 3-kinase (PI3K) signaling pathway and found that reactive oxygen species could act as secondary messengers in cellular signaling, inhibiting PI3K expression in the liver. The immune suppression caused by PI3K inhibition helped the mice adapt to stress. The immunotoxicities caused by Gd2 O3 :Eu3+ and gadodiamide, a commonly used contrast agent, were not significantly different, and the mice were able to tolerate the immunotoxicity caused Gd2 O3 :Eu3+ NPs in vitro and in vivo experiments. The results suggest that Gd2 O3 :Eu3+ NPs are sufficiently biocompatible to be used safely in preclinical applications and show promise as bio-imaging agents. Moreover, the in vivo molecular mechanism of immunotoxicity caused by the Gd2 O3 :Eu3+ NPs provides a platform for further research on the immunotoxicity of nano-sized biomaterials.

A literature review on multimodality molecular imaging nanoprobes for cancer detection

Abstract Molecular imaging techniques using nanoparticles have significant potential to be widely used for the detection of various types of cancers. Nowadays, there has been an increased focus on developing novel nanoprobes as molecular imaging contrast enhancement agents in nanobiomedicine. The purpose of this review article is to summarize the use of a variety of nanoprobes and their current achievements in accurate cancer imaging and effective treatment. Nanoprobes are rapidly becoming potential tools for cancer diagnosis by using novel molecular imaging modalities such as Ultrasound (US) imaging, Computerized Tomography (CT), Single Photon Emission Tomography (SPECT) and Positron Emission Tomography (PET), Magnetic Resonance Imaging (MRI), and Optical Imaging. These imaging modalities may facilitate earlier and more accurate diagnosis and staging the most of cancers.

"Smart" Nanoprobes for Visualization of Tumor Microenvironments.

Physiological parameters in tumor microenvironments, including hypoxia, low extracellular pH, enzymes, reducing conditions, and so on, are closely associated with the proliferation, angiogenesis, invasion, and metastasis of cancer, and impact the therapeutic administrations. Therefore, monitoring the tumor microenvironment is significant for diagnosing tumors, predicting the invasion potential, evaluating therapeutic efficacy, planning the treatment, and cancer prognostics. Noninvasive molecular imaging technologies combined with novel "smart" nanoparticle-based activatable probes provide a feasible approach to visualize tumor-associated microenvironment factors. This review summarizes recent achievements in the designs of "smart" molecular imaging nanoprobes responding to the tumor microenvironment-related features, and highlights the state of the art in tumor heterogeneity imaging.

Development of optical nanoprobes for molecular imaging of reactive oxygen and nitrogen species

Reactive oxygen and nitrogen species (RONS) play important roles in cell signal transduction. However, overproduction of RONS is associated with a series of pathological processes and may disrupt cellular homeostasis, causing oxidative and nitrosative stress. Accurate methods to selectively and specifically monitor RONS in living systems are required to further elucidate the biological functions of these species. Optical imaging possesses high sensitivity, high spatiotemporal resolution, and real-time imaging capability. These qualities are advantageous for the detection of RONS in living systems. This review summarizes the development of optical nanoprobes with near-infrared (NIR) fluorescent, upconversion luminescent, chemiluminescent, or photoacoustic signals for molecular imaging of RONS in living systems. In this review, we discuss the design principles and advantages of RONS-responsive activatable nanoprobes, as well as applications of these optical imaging modalities in different disease models.

Dopamine coating technology transforming nanoparticles into nanoprobes for molecular imaging

Dopamine coating technology transforming nanoparticles into nanoprobes for molecular imaging

Intracellular Self‐Assembly of Nanoprobes for Molecular Imaging

AbstractMolecular imaging can be roughly defined as the characterization and measurement of biological processes at the molecular and cellular level. Nanoprobes (NPs) are advantageous over small molecular probes for molecular imaging in the amount of signaling molecule as well as signal intensity. Compared with ex situ self‐assembling strategies for NP fabrication, those intracellular intelligent self‐assembling strategies that use small molecules to prepare NPs in situ with amplified signals and longer retention time are more efficient and attractive. This review summarizes recent advances of intracellular self‐assembly of NPs for molecular imaging in five modalities (magnetic resonance imaging, computed tomography, radionuclide imaging, optical imaging, and photoacoustic imaging). Moreover, using intracellular self‐assembly strategies to fabricate NPs in situ for multimodality imaging in the future is outlooked in this review.

Peptide-based nanoprobes for molecular imaging and disease diagnostics.

Pathological changes in a diseased site are often accompanied by abnormal activities of various biomolecules in and around the involved cells. Identifying the location and expression levels of these biomolecules could enable early-stage diagnosis of the related disease, the design of an appropriate treatment strategy, and the accurate assessment of the treatment outcomes. Over the past two decades, a great diversity of peptide-based nanoprobes (PBNs) have been developed, aiming to improve the in vitro and in vivo performances of water-soluble molecular probes through engineering of their primary chemical structures as well as the physicochemical properties of their resultant assemblies. In this review, we introduce strategies and approaches adopted for the identification of functional peptides in the context of molecular imaging and disease diagnostics, and then focus our discussion on the design and construction of PBNs capable of navigating through physiological barriers for targeted delivery and improved specificity and sensitivity in recognizing target biomolecules. We highlight the biological and structural roles that low-molecular-weight peptides play in PBN design and provide our perspectives on the future development of PBNs for clinical translation.

Applications, opportunities and challenges of molecular probes in the diagnosis and treatment of major diseases

Minimally invasive treatment of cancer can significantly reduce surgery risks due to many advantages, such as no laparotomy, small wound and early recovery and so on. Especially, it is suitable for patients who cannot be operated on due to tumor distant metastasis, oldness, weakness, and major organ dysfunction. According to clinical statistics, more than 60% of patients with mid-advanced cancer can be cured by employing minimally invasive surgery. Malignant tumors often show invasive growth and unclear boundary, resulting in partial removal of healthy tissue during surgery, hence postoperative sequelae and dysfunction. In order to carry out minimally invasive surgery and targeted elimination of tumor, the size and location of the tumors must be accurately identified before therapy, which requires the imaging guidance. By using optical molecular imaging, we can find a small tumor less than ~1mm. Therefore, the molecular imaging navigation provides a great opportunity for the development of minimally invasive interventional therapy for cancer. Especially, the cancer specific probes are emerging as one of the key technologies of molecular imaging. Compared with small molecular probes, nanoprobes show longer imaging time, remarkable signal multiplication and drug loading capacity. There, specific nanoprobes become the development direction of the molecular imaging navigation technology. Aiming at accuracy, high efficacy and minimal invasiveness of cancer treatments, we need solve two key scientific issues including identification of tumor boundary and predictability of lymph node metastases, and develop three key technologies including: high accumulation of nanoprobes at tumor sites, high sensitivity of nanoprobes to cancer cells, high precision imaging methods based on nanoprobes. This project will design and construct a variety of safe and efficient nanoprobes and related nanomaterials with independent intellectual property rights. For example, ultra pH (or enzyme)-sensitive fluorescent nanoprobes will be fabricated for the imaging of a broad range of tumours by nonlinear amplification of microenvironment signals. Multifunctional nanoprobes will be developed for simultaneous molecular imaging and interventional therapy of cancer. Fluorescent/ultrasound nanoprobes will be prepared to achieve a bimodal imaging with excellent signal sensitivity and high spatial resolution. Theranostic nanoprobes will be produced for both targeted imaging (diagnosis) and interventional therapy (laser, ultrasound, microwave, radiofrequency or combination etc.). In addition, we will establish a practical and feasible technology platform for large-scale production of nanoprobes, and in vivo and in vitro evaluation systems for the clinical applications of nanoprobes. It is of crucial importance to investigate the biological influence of nanoprobes on cell division, proliferation, apoptosis and signal transduction pathways, assess in vivo transport mechanism across biological barriers, and evaluate biosafety of nanoprobes, such as acute toxicity, long-term toxicity, nervous system toxicity and immunogenicity. Moreover, fluorescence confocal microendoscope and minimally invasive therapeutic devices will be developed based on nanoprobes. Finally, we will assess invasion depth and lymph node metastasis in early gastric cancer, as well as retroperitoneal lymph node metastasis of ovarian cancer by using nanoprobes in combination of fluorescence confocal microendoscope and molecular imaging navigation system. The sensitivity and specificity of molecular imaging nanoprobes are evaluated by using pathology as the gold standard. The precise interventional therapy (photodynamic, photothermal and sonodynamic etc.) will be implemented by irradiating the tumor tissue using laser or ultrasound under the guidance of nanoprobe-enhanced molecular imaging. It is essential to investigate the evaluation methods of therapeutic efficacy. We will explore the synergistic, anti-metastatic and overcoming drug resistance effects of interventional therapy combined with chemotherapy. In conclusion, molecular imaging nanoprobes can be used not only for imaging and diagnosis, but also for the minimally invasive interventional treatments. In particular, the research and application of nanoprobes will promote the development and application of fluorescence confocal microendoscope, molecular imaging navigation systems and minimally invasive interventional therapy systems. This will accelerate the breakthrough in the key technology of major medical equipment. Undoubtedly, the accomplishment of the project would enhance the innovation capability and international competitiveness of China in nanobiomedicine and medical equipment.

Contrast agents based on switchable near-infrared fluorescent nanoprobes for highly sensitive optical imaging

We have synthesized and characterized photophysical properties of a novel contrast agent based on switchable near-infrared (NIR) fluorescent nanoprobes that enables optical imaging with a higher sensitivity than conventional contrast agents allow. The high sensitivity was a result not only of the intrinsically high signal-to-background ratio that could be obtained in the NIR spectral region, but also from the increased signal intensity that was provided by using activatable nanoprobes. The NIR fluorescent nanoprobes were synthesized by encapsulating indocyanine green (ICG) into pH-responsive polymer nanoparticles. The intensity of the NIR fluorescence signal from the nanoparticles increased about 11-fold in acidic solution, due to the release of ICG molecules from the nanoparticles. The efficacy of fluorescence recovery from the quenched state to the de-quenched state could be modulated by controlling the relative concentrations between pH-responsive polymer and ICG. The fluorescence recovery properties of switchable NIR nanoprobes were also evaluated by cellular uptake experiments. Our experimental results support the use of pH-responsive nanoparticles with incorporated contrast agents as activatable molecular imaging nanoprobes.

Construction and in vitro characterization of dual-modality single-photon emission computed tomography - MRI nanoprobes targeting HAb18G/CD147 in breast tumors

Objective: To prepare dual-modality single-photon emission computed tomography (SPECT)-MRI molecular nanoprobes targeting HAb18G/CD147 expressed on breast cancer cell membranes and investigate the physicochemical and biological properties in vitro. Methods: Superparamagnetic iron oxide nanoparticles (SPIOs) were prepared by one-pot reaction method as described. The single-chain antibody fragments HAbF18(ab') 2 were conjugated to SPIOs via chemical method and then labeled with 125I using Iodogen method. The final 125I-SPIO-HAbF18(ab') 2 nanoprobes were purified. SPIOs or 125I-HAbF18(ab') 2 were used as control. We carried preliminary evaluation on their physicochemical properties and biological characteristics in vitro: transmission electron microscope (TEM) and dynamic light scattering (DLS) were used to measure these nanoparticle sizes and the hydrodynamic diameters. The MRI T 2 transverse relaxation efficiency of these nanoprobes at different Fe2+ concentrations were measured with 1.5 T clinical MR scanner. The 125I-SPIO-HAbF18(ab') 2 and 125I-HAbF18(ab') 2 radiochemical purity were measured by thin layer chromatography and the radio chemical yield was calculated. We also conducted stability tests in vitro and octanol/water partition coefficient experiments. Two breast tumor cell lines, MDA-MB-231 (HAb18G-overexpressing cells,experimental group) and MDA-MB-468 (control), were used for assessment of cells viability at different Fe2+ concentrations (1, 5, 10, 20, 40 μg/ml) by methyl thiazolyl tetrazolium assay. Specific binding experiments in vitro included two parts:magnetic resonance imaging and radionuclide tests, the above-mentioned breast cancer cell lines were incubated with 125I-SPIO-HAbF18(ab') 2 nanoprobes respectively and took MDA-MB-231 cells which were not treated as blank group. First comparing the MR signal intensity differences among experimental group, the control group and blank group, then calculated the rate of MRI signal changes; Two breast tumor cell lines, MDA-MB-231 and MDA-MB-468 were incubated with 125I-SPIO-HAbF18(ab') 2 nanoprobes too, then measured radioactivity counting by γ counter at different time and calculated the cell binding rates, and did statistical analysis by using one-way ANOVA. Results: The SPIOs were fairly homogeneous with an average core size of (10.32±1.30) nm;the SPIO and 125I-SPIO-HAbF18(ab') 2 hydrodynamic diameter of 44.80 and 52.64 nm, and MRI scanning showed that the transverse relaxation efficiency of SPIO and 125I-SPIO-HAbF18(ab') 2 were 38.79 and 106.73 mM-1 · s-1, respectively. The radio chemical yield of 125I-SPIO-HAbF18(ab') 2 and 125I-HAbF18(ab') 2 were 41.90% and 85.50%, respectively. The radio chemical yield of the two groups were >95%, suggesting well stability in vitro. The lipo-hydro partition coefficient values were -0.99 ± 0.03 and-1.49 ± 0.08, respectively, which demonstrated that they were both water-soluble substances. Different Fe2+ concentrations (1,5,10,20,40μg/ml) of 125I-SPIO-HAbF18(ab') 2 on breast cancer cell lines MDA-MB-231 and MDA-MB-468 showed no significant inhibition of cell proliferation (F values were 0.78, 0.66; P values were 0.58, 0.66). The cell-specific binding experiment showed: MRI signal intensity values on experimental group, the control group and the blank group were (1 670 ± 5), (1 930 ± 8), (2 349 ± 14), respectively, significant differences existed among these groups (F=4 408.48, P=0.000), the rate of signal intensity change of experimental group and the control group were 28.87%, 17.78%. SPECT:MDA-MB-231 could uptake 125I-SPIO-HAbF18(ab') 2 , the cell binding rates were (6.52 ± 0.60)% and (10.52 ± 2.04)% in 20 min and 4 h, respectively. Conclusions: Our results suggested that the dual-modality SPECT-MRI nanoprobes 125I-SPIO-HAbF18(ab') 2 were prepared successfully with good physicochemical properties and biological characteristics in vitro. These dual-modality molecular imaging nano-probes may have potential to improvearly detection and diagnosis of HAb18G/CD147-expressing cancers and to facilitate the development of HAb18G/CD147-directed interventions.

Progress of the nano probes for molecular imaging

Current imaging techniques, such as Computed tomography (CT) imaging, ultrasound, magnetic resonance imaging (MRI), has been unable to meet more high demand for disease diagnosis. However, Molecular imaging enables the visualization of cellular functions, physiological and pathological changes and the follow-up of molecular process in living organisms with intravital, real-time, non-invasive, dynamic three-dimensional imaging. The development of new and efficient imaging probes is the key to molecular imaging in addition to developing imaging equipments. But the current conventional contrast agents and molecular probes can not meet the requirements for their shortcomings such as low signal to noise ratio, no targeting effect. While nano probes based on nanomaterials have attracted intense attentions and showed good imaging effect. This paper reviews current nano probes, their application and development in optical imaging, MRI, CT, positron emission tomography (PET), Single-Photon-Emission Computed Tomography(SPECT), photoacoustic (PA) imaging, multimodality imaging and so on.

Anchored Proteinase‐Targetable Optomagnetic Nanoprobes for Molecular Imaging of Invasive Cancer Cells

Aktivierbare Nanosonde: Eine neu entwickelte Nanosonde zeigt Membran-Typ-1-Matrixmetalloproteinase(MT1-MMP)-Aktivität durch einen Anstieg der Signalintensitäten in Fluoreszenzbildgebung (FI) und Kernspintomographie (MRI) an. MNCs=magnetische Nanokristalle, Q=Löscheinheit, F=Fluoreszenzfarbstoff. Detailed facts of importance to specialist readers are published as ”Supporting Information”. Such documents are peer-reviewed, but not copy-edited or typeset. They are made available as submitted by the authors. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.

Anchored Proteinase‐Targetable Optomagnetic Nanoprobes for Molecular Imaging of Invasive Cancer Cells

Herein, we describe the development of a bimodalimaging probe enabling precise recognition of the expressionof MT1-MMP anchored on invasive cancer cells and itsprotease activity simultaneously. MT1-MMP may be atargetable biomarker for a specific delivery and possessesproteolytic activity for certain substrates.

Near-infrared fluorescent nanoprobes for cancer molecular imaging: status and challenges

Near-infrared fluorescence (NIRF) imaging promises to improve cancer imaging and management; advances in nanomaterials allow scientists to combine new nanoparticles with NIRF imaging techniques, thereby fulfilling this promise. Here, we present a synopsis of current developments in NIRF nanoprobes, their use in imaging small living subjects, their pharmacokinetics and toxicity, and finally their integration into multimodal imaging strategies. We also discuss challenges impeding the clinical translation of NIRF nanoprobes for molecular imaging of cancer. Whereas utilization of most NIRF nanoprobes remains at a proof-of-principle stage, optimizing the impact of nanomedicine in cancer patient diagnosis and management will probably be realized through persistent interdisciplinary amalgamation of diverse research fields.

Artificially engineered magnetic nanoparticles for ultra-sensitive molecular imaging

Successful development of ultra-sensitive molecular imaging nanoprobes for the detection of targeted biological objects is a challenging task. Although magnetic nanoprobes have the potential to perform such a role, the results from probes that are currently available have been far from optimal. Here we used artificial engineering approaches to develop innovative magnetic nanoprobes, through a process that involved the systematic evaluation of the magnetic spin, size and type of spinel metal ferrites. These magnetism-engineered iron oxide (MEIO) nanoprobes, when conjugated with antibodies, showed enhanced magnetic resonance imaging (MRI) sensitivity for the detection of cancer markers compared with probes currently available. Also, we successfully visualized small tumors implanted in a mouse. Such high-performance, nanotechnology-based molecular probes could enhance the ability to visualize other biological events critical to diagnostics and therapeutics.

Immobilization of histidine-tagged proteins by magnetic nanoparticles encapsulated with nitrilotriacetic acid (NTA)-phospholipids micelle

We described the development of functionalized magnetic nanoparticles (MNPs) with PEG-modification, a phospholipids micelle coating, and their use in manipulating histidine-tagged proteins. Highly monodisperse MNPs were synthesized in an organic solvent and could be phase-transferred into an aqueous solution by encapsulating the nanoparticles with a phospholipids micelle. The phospholipids micelle coating rendered the nanoparticles highly water-soluble, and the functional groups of the phospholipids coating allowed for the bioconjugation of various moieties, such as fluorescent molecules and engineered proteins. Functionalized phospholipids, such as nitrilotriacetic acid (NTA)-phospholipids, caused the MNPs to bind and allowed for manipulation of histidine-tagged proteins. Due to their high surface/volume ratio, the MNPs showed better performance (about 100 times higher) in immobilizing engineered proteins than conventional micrometer-sized beads. This demonstrates that MNPs coated with phospholipids micelle can be a versatile platform for the effective manipulation of various kinds of engineered proteins, which is very important in the field of proteomics. It is expected that a combination of MNPs with optical fluorescent molecules can find applications in bimodal (magnetic and optical) molecular imaging nanoprobes.