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.

A Molecular Imaging Primer: Modalities, Imaging Agents, and Applications

Advances in nanoparticle synthesis and engineering have produced nanoscale agents affording both therapeutic and diagnostic functions that are often referred to by the portmanteau 'nanotheranostics'. The field is associated with many applications in the clinic, especially in cancer management. These include patient stratification, drug-release monitoring, imaging-guided focal therapy and post-treatment response monitoring. Recent advances in nanotheranostics have expanded this notion and enabled the characterization of individual tumours, the prediction of nanoparticle-tumour interactions, and the creation of tailor-designed nanomedicines for individualized treatment. Some of these applications require breaking the dogma that a nanotheranostic must combine both therapeutic and diagnostic agents within a single, physical entity; instead, it can be a general approach in which diagnosis and therapy are interwoven to solve clinical issues and improve treatment outcomes. In this Review, we describe the evolution and state of the art of cancer nanotheranostics, with an emphasis on clinical impact and translation.

Rethinking cancer nanotheranostics.

A first-in-human clinical trial of ultrasmall inorganic hybrid nanoparticles, “C dots” (Cornell dots), in patients with metastatic melanoma is described for the imaging of cancer. These renally excreted silica particles were labeled with 124I for positron emission tomography (PET) imaging and modified with cRGDY peptides for molecular targeting. 124I-cRGDY–PEG–C dot particles are inherently fluorescent, containing the dye, Cy5, so they may be used as hybrid PET-optical imaging agents for lesion detection, cancer staging, and treatment management in humans. However, the clinical translation of nanoparticle probes, including quantum dots, has not kept pace with the accelerated growth in minimally invasive surgical tools that rely on optical imaging agents. The safety, pharmacokinetics, clearance properties, and radiation dosimetry of 124I-cRGDY–PEG–C dots were assessed by serial PET and computerized tomography after intravenous administration in patients. Metabolic profiles and laboratory tests of blood and urine specimens, obtained before and after particle injection, were monitored over a 2-week interval. Findings are consistent with a well-tolerated inorganic particle tracer exhibiting in vivo stability and distinct, reproducible pharmacokinetic signatures defined by renal excretion. No toxic or adverse events attributable to the particles were observed. Coupled with preferential uptake and localization of the probe at sites of disease, these first-in-human results suggest safe use of these particles in human cancer diagnostics.

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Clinical translation of an ultrasmall inorganic optical-PET imaging nanoparticle probe

Owing to their unique physical and chemical properties, magnetic iron oxide nanoparticles have become a powerful platform in many diverse aspects of biomedicine, including magnetic resonance imaging, drug and gene delivery, biological sensing, and hyperthermia. However, the biomedical applications of magnetic iron oxide nanoparticles arouse serious concerns about their pharmacokinetics, metabolism, and toxicity. In this review, the updated research on the biomedical applications and potential toxicity of magnetic iron oxide nanoparticles is summarized. Much more effort is required to develop magnetic iron oxide nanoparticles with improved biocompatible surface engineering to achieve minimal toxicity, for various applications in biomedicine.

Applications and Potential Toxicity of Magnetic Iron Oxide Nanoparticles

Integrins are key regulators of communication between cells and with their microenvironment. Eight members of the integrin superfamily recognize the tripeptide motif Arg-Gly-Asp (RGD) within extracelluar matrix (ECM) proteins. These integrins constitute an important subfamily and play a major role in cancer progression and metastasis via their tumor biological functions. Such transmembrane adhesion and signaling receptors are thus recognized as promising and well accessible targets for novel diagnostic and therapeutic applications for directly attacking cancer cells and their fatal microenvironment. Recently, specific small peptidic and peptidomimetic ligands as well as antibodies binding to distinct integrin subtypes have been developed and synthesized as new drug candidates for cancer treatment. Understanding the distinct functions and interplay of integrin subtypes is a prerequisite for selective intervention in integrin-mediated diseases. Integrin subtype-specific ligands labelled with radioisotopes or fluorescent molecules allows the characterization of the integrin patterns in vivo and later the medical intervention via subtype specific drugs. The coating of nanoparticles, larger proteins, or encapsulating agents by integrin ligands are being explored to guide cytotoxic reagents directly to the cancer cell surface. These ligands are currently under investigation in clinical studies for their efficacy in interference with tumor cell adhesion, migration/invasion, proliferation, signaling, and survival, opening new treatment approaches in personalized medicine.

Exploring the Role of RGD-Recognizing Integrins in Cancer.

The radiopharmaceutical agent 18F-FPPRGD2 has desirable pharmacokinetic and biodistribution properties, with the latter favoring PET applications in the head, neck, thorax, and extremities.

Pilot pharmacokinetic and dosimetric studies of (18)F-FPPRGD2: a PET radiopharmaceutical agent for imaging α(v)β(3) integrin levels.

First in man studies of [18F]FPPRGD2: A novel PET radiopharmaceutical for imaging {alpha}v{beta}3 integrin levels

1433 Objectives Angiogenesis is essential for tumor growth. The expression of αvβ3 on capillary cells has a key role in this process. We have developed a novel 18F-based PET radiopharmaceutical, [18F]FPPRGD2 (FDA eIND 104150), based on the dimeric RGD peptide sequence, which targets the αvβ3 integrin. We present data on the first people imaged with this tracer. Methods Five healthy volunteers (mean age: 42) were recruited. Three PET and 1 PET/CT scans were obtained up to 3 hours post-injection (dose: 9.5 ± 3.4 mCi; specific activity: 1200 ± 714 mCi/umol) using a GE Discovery LS PET/CT scanner. During this time, vitals, EKGs, and blood samples were obtained at regular intervals. The blood was used to calculate time activity curves and to ensure stability of the tracer and lab values. The imaging data was used to evaluate biodistribution, as well as for dosimetry calculations using OLINDA. Results The radiopharmaceutical was well tolerated with no alterations in vitals, EKGs, or lab values noted. There was stable distribution in all patients with primary clearance through the kidneys, as well as the liver, spleen, and bowel. Only minimal uptake was seen elsewhere. Time activity curves showed rapid clearance from the vasculature within 30 minutes, with most of the activity in the plasma. Dosimetry (units are rem/mCi) showed the principal organs to be the urinary bladder (0.863) (bladder voiding model), lower large intestine (0.529), kidneys (0.360), and spleen (0.250). Conclusions [18F]FPPRGD2 is safe, with desirable pharmacokinetic and biodistribution characteristics for imaging angiogenesis (αvβ3-integrin expression), especially in the head, neck, thorax and extremities. Testing of [18F]FPPRGD2 in patients with cancers is planned. Based on these results, this radiopharmaceutical would be optimal for brain, lung, and breast cancers, but may also be useful for other regions and non-imaging applications

First in man studies of [18F]FPPRGD2: A novel PET radiopharmaceutical for imaging αvβ3 integrin levels

Erik Mittra , S. MD , PhD Michael Goris ,L. MD , PhD Andrei H. Iagaru , MD Arash Kardan , MD Lindee Burton , BS Rhona Berganos , BS Edwin Chang , PhD Shuanglong Liu , PhD Bin Shen , PhD Frederick Chin ,. PhD T Xiaoyuan Chen , PhD Sanjiv GambhirS. MD , , PhD Purpose:

Arash Kardan

Papers

Pilot pharmacokinetic and dosimetric studies of (18)F-FPPRGD2: a PET radiopharmaceutical agent for imaging α(v)β(3) integrin levels.

First in man studies of [18F]FPPRGD2: A novel PET radiopharmaceutical for imaging {alpha}v{beta}3 integrin levels

First in man studies of [18F]FPPRGD2: A novel PET radiopharmaceutical for imaging αvβ3 integrin levels

Radiopharmaceutical Agent for Imaging a v b 3 Integrin Levels 1