Molecular imaging is revolutionizing the way we study the inner workings of the human body, diagnose diseases, approach drug design, and assess therapies. The field as a whole is making possible the ...visualization of complex biochemical processes involved in normal physiology and disease states, in real time, in living cells, tissues, and intact subjects. In this review, we focus specifically on molecular imaging of intact living subjects. We provide a basic primer for those who are new to molecular imaging, and a resource for those involved in the field. We begin by describing classical molecular imaging techniques together with their key strengths and limitations, after which we introduce some of the latest emerging imaging modalities. We provide an overview of the main classes of molecular imaging agents (i.e., small molecules, peptides, aptamers, engineered proteins, and nanoparticles) and cite examples of how molecular imaging is being applied in oncology, neuroscience, cardiology, gene therapy, cell tracking, and theranostics (therapy combined with diagnostics). A step-by-step guide to answering biological and/or clinical questions using the tools of molecular imaging is also provided. We conclude by discussing the grand challenges of the field, its future directions, and enormous potential for further impacting how we approach research and medicine.
Molecular imaging agents for ultrasound Zlitni, Aimen; Gambhir, Sanjiv S
Current opinion in chemical biology,
08/2018, Letnik:
45, Številka:
C
Journal Article
Recenzirano
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Schematic representation of molecular US imaging using nano-sized ultrasound contrast agents (nUCAs). (a) Molecular US imaging using echogenic nanobubbles (NBs) which extravasate to target ...extravascular markers. (b) Molecular US imaging using phase-change droplets (PCDs) which retain their nano-size to extravasate and transform to echogenic micron-particles upon heat activation. (c) Molecular US imaging using gas-generating nanoparticles (GGNPs) which extravasate to the tumor microenvironment and undergo reactions producing echogenic gas bubbles. ▪
•First in human trials show promise in the utility of molecular US imaging in identifying malignant from benign lesions.•Nanometer sized bubbles which can extravasate have been reported but require further evaluation.•Phase-change nanodroplets provide a unique strategy to utilize nanoparticles as US contrast agents.•Gas-generating nanoparticles have great potential as theranostic US imaging agents.
Ultrasound (US) imaging is a safe, sensitive and affordable imaging modality with a wide usage in the clinic. US signal can be further enhanced by using echogenic contrast agents (UCAs) which amplify the US signal. Developments in UCAs which are targeted to sites of disease allow the use of US imaging to provide molecular information. Unfortunately, traditional UCAs are too large to leave the vascular space limiting the application of molecular US to intravascular markers. In this mini review, we highlight the most recent reports on the application of molecular US imaging in the clinic and summarize the latest nanoparticle platforms used to develop nUCAs. We believe that the highlighted technologies will have a great impact on the evolution of the US imaging field.
Therapeutic checkpoint inhibitors on tumor-infiltrating lymphocytes (TIL) are being increasingly utilized in the clinic. The T-cell immunoreceptor with Ig and ITIM domains (TIGIT) is an inhibitory ...receptor expressed on T and natural killer cells. The TIGIT signaling pathway is an alternative target for checkpoint blockade to current PD-1/CTLA-4 strategies. Elevated TIGIT expression in the tumor microenvironment correlates with better therapeutic responses to anti-TIGIT therapies in preclinical models. Therefore, quantifying TIGIT expression in tumors is necessary for determining whether a patient may respond to anti-TIGIT therapy. PET imaging of TIGIT expression on TILs can therefore aid diagnosis and in monitoring therapeutic responses.
Antibody-based TIGIT imaging radiotracers were developed with the PET radionuclides copper-64 (
Cu) and zirconium-89 (
Zr).
characterization of the imaging probes was followed by
evaluation in both xenografts and syngeneic tumor models in mouse.
Two anti-TIGIT probes were developed and exhibited immunoreactivity of >72%, serum stability of >95%, and specificity for TIGIT with both mouse TIGIT-expressing HeLa cells and
-activated primary splenocytes.
, the
Zr-labeled probe demonstrated superior contrast than the
Cu probe due to
Zr's longer half-life matching the TIGIT antibody's pharmacokinetics. The
Zr probe was used to quantify TIGIT expression on TILs in B16 melanoma in immunocompetent mice and confirmed by
flow cytometry.
This study develops and validates novel TIGIT-specific
Cu and
Zr PET probes for quantifying TIGIT expression on TILs for diagnosis of patient selection for anti-TIGIT therapies.
Photoacoustic imaging holds great promise for the visualization of physiology and pathology at the molecular level with deep tissue penetration and fine spatial resolution. To fully utilize this ...potential, photoacoustic molecular imaging probes have to be developed. Here, we introduce near-infrared light absorbing semiconducting polymer nanoparticles as a new class of contrast agents for photoacoustic molecular imaging. These nanoparticles can produce a stronger signal than the commonly used single-walled carbon nanotubes and gold nanorods on a per mass basis, permitting whole-body lymph-node photoacoustic mapping in living mice at a low systemic injection mass. Furthermore, the semiconducting polymer nanoparticles possess high structural flexibility, narrow photoacoustic spectral profiles and strong resistance to photodegradation and oxidation, enabling the development of the first near-infrared ratiometric photoacoustic probe for in vivo real-time imaging of reactive oxygen species--vital chemical mediators of many diseases. These results demonstrate semiconducting polymer nanoparticles to be an ideal nanoplatform for developing photoacoustic molecular probes.
Radiotheranostics: a roadmap for future development Herrmann, Ken; Schwaiger, Markus; Lewis, Jason S ...
Lancet oncology/Lancet. Oncology,
March 2020, 2020-03-00, 20200301, Letnik:
21, Številka:
3
Journal Article
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Odprti dostop
Radiotheranostics, injectable radiopharmaceuticals with antitumour effects, have seen rapid development over the past decade. Although some formulations are already approved for human use, more ...radiopharmaceuticals will enter clinical practice in the next 5 years, potentially introducing new therapeutic choices for patients. Despite these advances, several challenges remain, including logistics, supply chain, regulatory issues, and education and training. By highlighting active developments in the field, this Review aims to alert practitioners to the value of radiotheranostics and to outline a roadmap for future development. Multidisciplinary approaches in clinical trial design and therapeutic administration will become essential to the continued progress of this evolving therapeutic approach.
Nanoparticles (NPs) offer diagnostic and therapeutic capabilities not available with small molecules or microscale tools. As the field of molecular imaging has emerged from the blending of molecular ...biology with medical imaging, NP imaging is increasingly common for both therapeutic and diagnostic applications. The term theranostic describes technology with concurrent and complementary diagnostic and therapeutic capabilities. Although NPs have been FDA-approved for clinical use as transport vehicles for nearly 15 years, full translation of their theranostic potential is incomplete. However, NPs have shown remarkable success in the areas of drug delivery and magnetic resonance imaging. Emerging applications include image-guided resection, optical/photoacoustic imaging in vivo, contrast-enhanced ultrasound, and thermoablative therapy. Diagnosis with NPs in molecular imaging involves the correlation of the signal with a phenotype. The location and intensity of NP signals emanating from a living subject indicate the disease area’s size, stage, and biochemical signature. Therapy with NPs uses the image for resection or delivery of a small molecule or RNA therapeutic. Ablation of the affected area is also possible via heat or radioactivity. The ideal theranostic NP includes several features: (1) it selectively and rapidly accumulates in diseased tissue; (2) it reports biochemical and morphological characteristics of the area; (3) it delivers an effective therapeutic; and (4) it is safe and biodegrades with nontoxic byproducts. Such a system contains a central imaging core surrounded by small molecule therapeutics. The system targets via ligands such as IgG and is protected from immune scavengers by a cloak of protective polymer. Although no NP has achieved all of the above criteria, many NPs possess one or more of these features. While the most clinically translatable NPs have been used in the field of magnetic resonance imaging, other types in development are quickly becoming more biocompatible through methods that modify their toxicity and biodistribution profiles. In this Account, we describe diagnostic imaging and therapeutic uses of NPs. We propose and offer examples of five primary types of nanoparticles with concurrent diagnostic and therapeutic uses.
Most clinical blood biomarkers lack the necessary sensitivity and specificity to reliably detect cancer at an early stage, when it is best treatable. It is not yet clear how early a clinical blood ...assay can be used to detect cancer or how biomarker-based strategies can be improved to enable earlier detection of smaller tumors. To address these issues, we developed a mathematical model describing dynamic plasma biomarker kinetics in relation to the growth of a tumor, beginning with a single cancer cell. To exemplify a realistic scenario in which biomarker is shed by both cancerous and noncancerous cells, we primed the model on ovarian tumor growth and CA125 shedding data, for which tumor growth parameters and shedding rates are readily available in published literature. We found that a tumor could grow unnoticed for more than 10.1 years and reach a volume of about π/6(25.36 mm)(3), corresponding to a spherical diameter of about 25.36 mm, before becoming detectable by current clinical blood assays. Model parameters were perturbed over log orders of magnitude to quantify ideal shedding rates and identify other blood-based strategies required for early submillimeter tumor detectability. The detection times we estimated are consistent with recently published tumor progression time lines based on clinical genomic sequencing data for several cancers. Here, we rigorously showed that shedding rates of current clinical blood biomarkers are likely 10(4)-fold too low to enable detection of a developing tumor within the first decade of tumor growth. The model presented here can be extended to virtually any solid cancer and associated biomarkers.
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