From a technical aspect, high-speed magnetic resonance imaging (MRI) technologies such as multichannel technology, sparse sampling, and synthetic MRI are the latest and most notable developments in MRI systems. Based on high-speed MRI technologies, a resting-state functional MRI method was developed and applied to obtain objective diagnoses for psychiatric disorders. First, I summarize the recent technical progress in MRI systems. Next, “hyperpolarization technology”, which can increase the signal-to-noise ratio by more than a thousand times (a hundred thousand times ideally) in MRI is introduced. Recently, hyperpolarized 13-C pyruvate was applied to human phase-I trials in the United States. I summarize the advantages and potential issues of this method. Finally, I describe our recent progress in responsive nano-contrast agents such as calcium phosphate nano-micelle with manganese contrast agent and thermo-activatable liposome, and theranostic applications using drug delivery systems.

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The studies to apply imaging with nanoparticles to an elucidation of a mechanism of cancer or a development of diagnostic technology of cancer have received a lot of attention in recent years. We created novel nanoperticles which possess fluorescence or X-ray absorption and then combined such technology with own of optical system and image analysis system for development of quantitative nano-bio-imaging, in order to visualize disease state of cancer. In this review paper, we introduce three topics of cancer studies using the nano-bio-imaging. The first topic is analysis of mechanisms of cancer metastasis. We have developed a method for in vivo imaging with very high spatial accuracy（～9nm） using quantum dots and succeeded in tracking the membrane protein during metastasis in living mice. The second topic is development of a cancer detection method. We created gold nanoparticles conjugated with polyethylene glycol chains as a new contrast agent and succeeded in imaging millimeter-sized microtumors with X-ray computed tomography by injecting the nanoparticles into tumor-bearing mice. The third topic is development of technology to predict drug efficacy in chemotherapy given before surgery of human breast cancer. We created organic fluorophore assembly-conjugated nanoparticles suitable for immunohistochemistry and applied the nanoparticles to categorize the response to molecular target-based drug therapy in breast cancer patients. We hope that these topics are useful to the reader.

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Ultrasound imaging and ultrasound therapy using high intensity focused ultrasound are applied in clinic. Ultrasound is a promising candidate for developing theranostics system because of its safety, non-invasiveness, relatively cheap equipment and imaging in real time. Ultrasound contrast agents (Microbubble) have been developed to visualize tissues clearly. Recently, the combination of microbubbles and ultrasound is not only applied for imaging but also therapy like enhanced drug delivery. Ultrasound can induce microbubble oscillation, stable cavitation and inertial cavitation depending on the ultrasound intensity. These phenomena are used for imaging and therapy. Although several microbubbles have been developed in the world and applied for ultrasound diagnostics, it is not approved for therapy. Therefore, in order to establish ultrasound theranostics, we have tried to develop novel bubbles which are suitable for diagnostics and therapeutics. In this review, we describe our studies and introduce recent studies for establishing ultrasound theranostics.

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In development of many oxidative disease, change of redox reaction and generation of free radicals have been reported to be involved. Here, for detection of redox status and free radical reaction (especially, lipid-derived radicals), we focus on nitroxide compounds having stable unpaired electrons in the molecule. Since this molecule can react with redox compounds or bind with carbon-centered radicals, we can use a detection probe for these molecules in experimental animal models. In this paper, we show that lipid-derived radicals are generated during induction of chemical carcinogenesis and light-induced retinal damages in animal models using this probes, and this information will provide the timing of inhibitor injection to the animals. In other words, we will explain the study of theranostics through detection and inhibition of lipid-derived radicals.

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Positron emission tomography （PET） visualizes radiolabeled compounds in the living body with a high sensitivity, quantitative performance, and considerably high spatial and temporal resolution. This technique is useful for pharmacokinetic analysis and drug efficacy evaluation in preclinical and clinical studies. PET enables the investigation of drug concentrations in human tissues, which was impossible by conventional evaluation technologies. In addition, we can use PET probes to visualize the expression and function of disease-related molecules as surrogate endpoints in clinical trials. In this review, we will exemplify our collaborative preclinical and clinical studies on pharmacokinetics, DDS, and theranostics with a variety of academic and industrial collaboraters. First, we developed a series of PET probes to study transporters （organic anion transporting polypeptides, multidrug resistance-associated protein 2, etc.） such as ［¹¹C］Dehydropravastatin. Because substantial species differences in expression and function of transporters have been reported, these probes are especially useful to examine drug-drug interactions in human beings. Secondly, we established a PET-based system to visualize translocation of intranasally administered drugs and analyze pharmacokinetics on nasal drug absorption using 2-deoxy-2-［¹⁸F］fluoroglucose in rats. As far as we know, this is the first study that demonstrated the visualization of nasal absorption process and detailed pharmacokinetic analysis. Thirdly, HER2-positive breast cancer and its metastasis were successfully delineated in a ⁶⁴Cu-trastuzumab clinical PET study, which indicates immuno-PET probes are potential companion diagnostics for molecular target medicines and will become alternatives to biopsy. PET imaging strongly connects drug efficacy with pharmacokinetics, which could accelerate drug development during overall process.

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“Theranostics” represents a ground-breaking concept of medical modality featuring a hybrid of therapeutic and diagnostic systems. We have recently fabricated a 27 kDa single chain variable fragment （scFv）, which is essentially a humanized and shortened variant of IgG to establish clinically-applicable PET imaging and theranostics in cancer medicine. A target molecule is mesothelin, a 40 kDa-tumor differentiation-related cell surface glycoprotein antigen, that is frequently expressed by malignant tumors. The theranostics system which comprises of a novel ⁸⁹Zr-labeled drug delivery system （DDS）, derived from novel biodegradable polymeric micelle, “Lactosome”, conjugated with specific scFv, aims to successfully deliver therapeutically effective molecules, such as, apoptosis-inducing small interfering RNA （siRNA）, into targeted cells and to offer simultaneous visualization of targets via PET imaging. In particular, the combination of photodynamic therapy （PDT） with 5-aminolevulinic acid （ALA） and photo-controlled intracellular siRNA delivery system further offers a promising theranostic-based system, ideally via its targeted apoptosis-inducing feature.

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Near infrared wavelength region is known to have the most transparency of live body for electromagnetic wave with wavelength around the visible wavelength. Namely, the near infrared with a wavelength longer than 1000 nm (OTN-NIR) shows more transparency than that with shorter wavelength. The observation depth can be several centimeters with the OTN-NIR fluorescence, while that is limited to be only several millimeters with visible fluorescence. As OTN-NIR fluorescent agents, dyes, quantum dots, carbon nanotubes and rare-earth doped ceramic nanoparticles (RED-CNP) are known. A special feature of the RED-CNP is to show infrared-to-visible upconversion to emit visible light with a near infrared excitation, simultaneously with the OTN-NIR fluorescence. As a theranostic approach, nanomaterials for achieving photodynamic therapy with the near infrared excitation are introduced. Another special feature of the RED-CNP is the potential use for fluorescence nanothermometry. A scheme for ratiometric fluorescence nanothermometry with the OTN-NIR fluorescence is described. By using a RED-CNP with holomium and erbium co-doping, ratiometric fluorescence nanothermometry was successfully demonstrated. As shown with the case of photodynamic therapy with near infrared excitation, by applying an upconversion excitation scheme, visible light emission for photochemical reaction is possible with a near infrared excitation with high transparency in a live body. By constructing these multiple functions on the RED-CNP, various theranostic approach can be achieved. The size and bio distribution controls are important issues for applications of the RED-CNP for medical applications.

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