Nuclear Nanomedicines: Utilization of Radiolabelling Strategies, Drug Formulation, Delivery, and Regulatory Aspects for Disease Management.

Optical Molecular Imaging Approaches in Colorectal Cancer

Molecular imaging agents and a parallel progress in instrumentation ofimaginingtechnology have demonstrated to be effective in improving diagnosis, prognosis, planning, and monitoring of personalized medication. Molecular imaging modalities include positron emission tomography (PET), single photon emission computed tomography (SPECT), magnetic resonance imaging (MRI), computed tomography (CT), ultrasound (US), and optical (Raman, quantum dots, bioluminescence). Among these imaging modalities, PET and SPECT agents could provide target specific information as well as function, pathway activities, and cell migration in the intact organism. Furthermore, the radiotracer could noninvasively assess diseases treatment endpoints which used to rely almost exclusively on biopsies and histopathological assays. New leads on the development of personalized theranostic (image and treat) agents would allow more accuracy in the selection of patients who may respond to treatment. Topics covered in this special issue include advances in biomarkers in preclinical drug discovery, PET/CT and SPECT/CT in disease management, image-guided therapy approach of diseases, imaging technology in drug development, and progress in instrumentation ofimagingtechnology. For instance, upregulation of transporter expressions has often been observed in tumor cells to facilitate their accelerated rates of uptake. Advances in biomarkers in transporter system-based imaging in oncology and neurological diseases such as amino acid (FL. Kong et al.), glucose (YH. Zhang et al.) and dopaminergic (LH. Shen et al.; HF. Hou et al.) transporters were reported. These biomarkers showed that specific uptake in lesions compared to clinic imaging agent. In addition, these biomarkers were capable to be labeled with theranostic isotopes for personalized medication. Most tumors have a considerable proportion of hypoxic cells that are resistant to radio/chemotherapy, with a high propensity to metastasize, and result in worse therapeutic outcome. The contribution by M. Ali et al. and H. Fuji report their newly developed 99mTc-N4-NIM and 125I-IPOS probes for tumor hypoxia. The preclinical findings showed that these biomarkers could image tumor hypoxia by SPECT. The ability to quantify tissue hypoxia would allow the physicians to select patients for additional or alternative treatment regimens that would circumvent the ominous impact of hypoxia. Along this line, L. Jiang and coworkers report the peptide based radiotracer targeting tumor angiogenesis via VEGF integrin alpha(v) beta3. J. Sims-Mourtada and co-workers report 131I-labeled derivatives of the sonic hedgehog (HH) protein for detection of cancer cells via HH receptors. Molecular imaging of cancer stem cell trafficking was reported by T. Xia and co-workers. Hybrid molecular imaging modalities (PET/CT, SPECT/CT) provide high-sensitivity functional and high resolution anatomical imaging, which are important in design personalized treatment. To avoid radiation exposure from multiple slices-CT, K. Tang and co-workers report a reduction of CT tube voltage from 120 kv to 80 kv, the radiation dose could be reduced by 32–42% without losing low-contrast detectability. F. Chao and H. Zhang report the value of using PET/CT in the staging of nonsmall cell lung cancer. Y. Hu and co-workers report the application of PET/CT in assessment of treatment outcome. The application of SPECT/CT in the differential diagnosis of bone metastasis (Y. Zhang et al.) and Parkinson's disease (L. Wang et al.) was reported. Miyake K and co-workers report the application of FDG, MET, and FLT-PET/CT for the management of gliomas. L. Yang and co-workers report the value of using myocardial contrast echocardiography quantitative analysis during adenosine stress over visual analysis before therapy in acute coronary pain. The quantitative analysis correlates well with thrombosis in myocardial infarction. In summary, molecular imaging could integrate metabolomics and chemical biology. Molecular imaging agents could characterize target expressions, understand the disease progression, prediction for drug response and toxicity, staging, grading, and micrometastasis, and support animal studies. This special issue provides a platform of efficacy of personalized medication from molecular imaging technology which may have high impact on drug discovery, delivery, and development. Hong Zhang Mei Tian Enzhong Li Yasuhisa Fujibayashi Lie-Hang Shen David J. Yang

Noninvasive “multimodal” in vivo imaging is not just becoming standard practice in the clinic, but is rapidly changing the evolving field of experimental imaging of genetic expression (“molecular imaging”). The development of multimodality methodology based on nuclear medicine (NM), positron emission tomography (PET) imaging, magnetic resonance imaging (MRI), and optical imaging is the single biggest focus in many imaging and cancer centers worldwide and is bringing together researchers and engineers from the far-ranging fields of molecular pharmacology to nanotechnology engineering. The rapid growth of in vivo multimodality imaging arises from the convergence of established fields of in vivo imaging technologies with molecular and cell biology. The cross-pollination of these disciplines has been accelerated in part by the establishment of the National Institutes of Health NCI P20 and P50 awards, for example, and by the sheer potential of the technology. Multimodality imaging is widely considered to involve the incorporation of two or more imaging modalities, usually within the setting of a single examination using, for example, dual- or triple-labeled optical or nuclear medicine “reporter” agents or by performing ultrasound or optical studies within the MR, single-photon emission computed tomography (SPECT), or x-ray computed tomography (CT) environment. Clinically, the best example of multimodality imaging is seen in the rapid evolution of PET-SPECT and PET-CT scanner hybrids. The PET modality has developed into perhaps the most used “multimodal” imaging method. The incorporation of PET into single, hybrid, and multimodality units to provide functional (typically from injected F-18DG studies) and anatomic information is becoming extremely popular,1–2 so much so that, for example, PET/CT hybrids can be found in outpatient screening centers located in shopping malls. The role of any multimodal imaging …

CN01-02: Incorporating molecular imaging methods in early drug development

Coordinating radiometals of copper, gallium, indium, yttrium, and zirconium for PET and SPECT imaging of disease.

Cardiac computed tomography (CT) and positron emission tomography (PET) are emerging as powerful noninvasive imaging tools for the evaluation of atherosclerosis in patients with known or suspected coronary artery disease (CAD). Unlike invasive coronary angiography, CT coronary angiography (CTA) not only assesses disease within the coronary lumen but can also provide direct qualitative and quantitative information about nonobstructive atherosclerotic plaque burden within the vessel wall. Thus, it is possible that CTA-based patient evaluation may provide more clinically relevant information on which to base risk assessments compared with conventional “lumenography.” On the other hand, PET is rapidly growing as a powerful and efficient alternative to conventional single-photon emission CT (SPECT) imaging to evaluate regional myocardial perfusion and metabolism in patients with CAD. In addition, PET scanners are now being converted to hybrid PET/CT devices, which, in the setting of CAD, offer the potential for a comprehensive noninvasive cardiac evaluation of anatomy and function. This review will discuss current and potential future applications of cardiovascular CT, PET, and hybrid PET/CT, with a particular focus on ischemic heart disease. The information provided by noninvasive imaging generally falls into 1 of 3 categories: myocardial perfusion, left ventricular (LV) function, or coronary artery anatomy. The clinical utility, value, and role of a noninvasive modality are based on 2 test characteristics: What type of information is provided (eg, stress perfusion, stress and/or rest LV function, coronary anatomy), and what is the accuracy of the information provided. For example, SPECT and PET both provide stress and rest perfusion information, but the latter will be a superior clinical tool if the imaging data better represent the actual defect size and are subject to less artifact. The advantage of PET over SPECT will be further enhanced, as will be discussed later, if it provides additional clinically relevant information not …

Noninvasive imaging in the evaluation of a wide variety of cardiovascular diseases has gained an increasing role in the diagnostic strategy in current cardiology practice [1–4]. This holds in particular for patients with myocardial ischaemia due to coronary artery disease (CAD) [5–7]. Of the present imaging modalities, single-photon emission computed tomography (SPECT), positron emission tomography (PET) and cardiac magnetic resonance (CMR) have attained a major position when it comes to myocardial perfusion imaging [8–12]. In the May 2012 issue of the Journal of the American College of Cardiology (JACC), Jaarsma et al. [13] from Maastricht University Medical Center evaluated the diagnostic accuracy of SPECT, PET and CMR for the diagnosis of obstructive CAD. Studies published between 1990 and 2010 identified by PubMed search and citation tracking were examined. A study was included if a perfusion imaging modality was used as a diagnostic test for the detection of obstructive CAD and coronary angiography as the reference standard (50 % diameter luminal stenosis). Out of a total of 3635 studies, 166 articles (including 17,901 patients) met the inclusion criteria: 114 SPECT, 37 CMR, and 15 PET studies. There were insufficient publications on perfusion echocardiography and computed tomography to include these modalities in the study. Patient-based analysis per imaging modality demonstrated pooled sensitivities of 88 % for SPECT, 84 % for PET , and 89 % for CMR; pooled specificities were 61 %, 81 %, and 76 %, respectively. The authors concluded that SPECT, PET, and CMR all yielded high sensitivities, whereas a broad range of specificities were observed. CMR and especially PET showed a significantly higher diagnostic accuracy than SPECT. However, SPECT is more widely available, less expensive, and most extensively validated. In addition, the use of attenuation programs improved the specificity of SPECT. CMR may provide a valid alternative without ionising radiation to the nuclear imaging methods. The authors suggested that referring physicians should consider these findings in the context of local expertise and internal logistics. The authors should be complimented for performing this impressive research. It is the first meta-analysis that has directly compared the three most commonly used techniques for myocardial perfusion imaging, i.e. SPECT, PET, and CMR. The present study emphasises that, from a clinical perspective, each of the studied imaging modalities is in principle suited for detection of abnormalities in myocardial perfusion imaging [14]. As always, selective use is mostly dependent on the institutional availability of the imaging device(s), familiarity with the technique, and the individual expert knowledge of the treating physician [15].

Molecular imaging using nuclear medicine methods, i.e. positron emission tomography (PET) and single photon emission computed tomography (SPECT), is increasingly used in both clinical practice and in research for the investigation of dementias. Dementias are a heterogeneous group of diseases characterized by the loss of cognitive abilities and by behavioral and psychological symptoms, and have an increasing prevalence in our aging population. They represent a urgent issue in global health, given their strong impact not only on patients, but also on caregivers, families and societies. The scientific progresses on dementia biology and the ongoing clinical trials based on disease modifying therapies have heightened the urgency to develop sensitive and reliable markers to diagnose and monitor dementia. Indeed, PET and SPECT imaging are able to assess, non-invasively, neuronal loss and dysfunction, functional compensation strategies as well as the involvement of specific receptors and neurotransmission systems. Thus, they provide biomarkers for disease, particularly helpful as diagnostic tools in the early and preclinical phases of disease. The studies presented in this thesis demonstrate that nuclear medicine imaging of brain glucose metabolism and dopamine transporters, routinely performed in clinical practice, can be effectively combined with a gain in the classification of patients with suspected dementia. These studies also show that specific tracers, allowing the measurement of enzymatic pathways such as cholinesterase activity, are promising markers for the early and differential diagnosis of dementias. Nuclear medicine imaging can also provide important insights on the pathophysiological processes underlying the development and the clinical expression of dementia. An example is the study of the “reserve capacity”: the ability of the brain to compensate for ongoing neurodegenerative processes. The reserve is associated with a high pre-morbid intelligence, educational and occupational attainment and active, stimulating lifestyle. We demonstrated that the activation of brain reserve can be documented by molecular imaging methods already in the early and prodromal phase of Alzheimer's Disease. We also explored the impact of genetic risk factors, such as the Apolipoprotein E genotype, on the expression of reserve, and the association between reserve and the modulation of a specific neurotransmission system, namely the cholinergic system. Finally, new opportunities in this field come from the technological developments integrating nuclear medicine tomographs with other imaging modalities. Given that PET and magnetic resonance imaging (MRI) are the modalities of choice for most indications in neuroimaging, the recently developed hybrid PET/MRI has a tremendous potential for molecular neuroimaging, and preliminary results are described here. The current knowledge provides the bases for future research, exploring an increasing number of molecular biomarkers, such as PET tracers for amyloid plaques, hypoxia and cholinergic receptors, that may ultimately be useful to predict with high levels of accuracy the transition from healthy aging, mild cognitive impairment and clinically overt dementia.

Molecular imaging of metabolism and drug targets in the tumor may well be of additional value in the treatment of cancer patients. It can potentially be used for screening, ((pre) operative) staging, restaging and guiding targeted therapies. Molecular imaging is still in its infancy. It can be performed with various imaging modalities. Tracers used for this purpose can be labeled with either a contrast agent for magnetic resonance imaging (MRI), a fluorescent dye for optical imaging, or a radioactive nuclide for positron emission tomography (PET) and single photon emission computed tomography (SPECT) imaging. We will focus on PET and SPECT imaging given their sensitivity and available results. Most data are gathered on the visualization of general processes such as glucose metabolism and DNA synthesis. The PET-tracer [18F]fluorodeoxyglucose (FDG) is a glucose analogue and is used to visualize glucose metabolism, which is often increased in cancer cells. Increased DNA synthesis can be imaged with the pyrimidine analogue PET-tracer [18F]fluoro-L-thymidine (FLT), where FLT tumor uptake reflects the proliferation rate of cancer cells. With the increasing knowledge of the molecular processes that drive cancer and the introduction of the molecular targeted drugs, interest has been raised to image characteristics of tumor cells such as hormone receptors, growth factors and growth factor receptors. Molecular imaging of these characteristics can provide serial non-invasive information about the status of these characteristics within the tumor and its micro-environment and across lesions in the entire body when whole body imaging is performed. This is of interest as these characteristics can change over time and vary across lesions. Molecular imaging of the ER with the PET tracer 16-α-[18F]fluoro-17-β-estradiol (FES) has shown a good correlation between FES tumor uptake and ER density. This tracer is currently being tested for various applications in clinical trials. The field of visualizing growth factors and growth factor receptors is evolving rapidly. We imaged HER2 in breast cancer patients with the SPECT tracer 111In-trastuzumab and recently also with the PET tracer 89Zr-trastuzumab. With 111In-trastuzumab SPECT we showed that in 13 out of 15 patients with metastatic HER2 overexpressing disease more lesions were detected than with conventional staging procedures. Additionally the PET tracer 89Zr-trastuzumab shows excellent, quantifiable, and specific tumor uptake. In addition, we have developed 111In-bevacizumab for SPECT and 89Zr-bevacizumab for PET-imaging of vascular endothelial growth factor (VEGF) activity as an angiogenic marker. In melanoma patients small tumor lesions proved to be clearly visible with 111In-bevacizumab. Apart from using these techniques for staging and determination of drug targets, it is possible to evaluate modulation of these targets by drugs. Both HER2 and VEGF are downregulated by inhibitors of the heat shock protein (HSP) 90 and imaging of their expression was preclinically in vivo an excellent readout for the early molecular tumor response to HSP90 inhibitors. This is currently translated to clinical trials. Lastly, tracers for the receptors EGFR, IGF-1R, and the ligand TGFβ and are under development. Supported by grants from Dutch Cancer Society, Pink Ribbon and Pink Ribbon Gala. Citation Information: Clin Cancer Res 2010;16(7 Suppl):ED4-2

The application of molecular and cellular imaging in ophthalmology has numerous benefits. It can enable the early detection and diagnosis of ocular diseases, facilitating timely intervention and improved patient outcomes. Molecular imaging techniques can help identify disease biomarkers, monitor disease progression, and evaluate treatment responses. Furthermore, these techniques allow researchers to gain insights into the pathogenesis of ocular diseases and develop novel therapeutic strategies. Molecular and cellular imaging can also allow basic research to elucidate the normal physiological processes occurring within the eye, such as cell signaling, tissue remodeling, and immune responses. By providing detailed visualization at the molecular and cellular level, these imaging techniques contribute to a comprehensive understanding of ocular biology. Current clinically available imaging often relies on confocal microscopy, multi-photon microscopy, PET (positron emission tomography) or SPECT (single-photon emission computed tomography) techniques, optical coherence tomography (OCT), and fluorescence imaging. Preclinical research focuses on the identification of novel molecular targets for various diseases. The aim is to discover specific biomarkers or molecular pathways associated with diseases, allowing for targeted imaging and precise disease characterization. In parallel, efforts are being made to develop sophisticated and multifunctional contrast agents that can selectively bind to these identified molecular targets. These contrast agents can enhance the imaging signal and improve the sensitivity and specificity of molecular imaging by carrying various imaging labels, including radionuclides for PET or SPECT, fluorescent dyes for optical imaging, or nanoparticles for multimodal imaging. Furthermore, advancements in technology and instrumentation are being pursued to enable multimodality molecular imaging. Integrating different imaging modalities, such as PET/MRI (magnetic resonance imaging) or PET/CT (computed tomography), allows for the complementary strengths of each modality to be combined, providing comprehensive molecular and anatomical information in a single examination. Recently, photoacoustic microscopy (PAM) has been explored as a novel imaging technology for visualization of different retinal diseases. PAM is a non-invasive, non-ionizing radiation, and hybrid imaging modality that combines the optical excitation of contrast agents with ultrasound detection. It offers a unique approach to imaging by providing both anatomical and functional information. Its ability to utilize molecularly targeted contrast agents holds great promise for molecular imaging applications in ophthalmology. In this review, we will summarize the application of multimodality molecular imaging for tracking chorioretinal angiogenesis along with the migration of stem cells after subretinal transplantation in vivo.

Background: Radioligand therapy (RLT) is an emerging treatment modality that has shown potential to improve survival in cancer patients that often have limited or non-effective therapeutic options. We previously demonstrated that anti-HER3 antibody radioconjugate (HER3 ARC) has antitumor efficacy against HER3 expressing tumor xenograft models. One important step in the early development of RLT is to understand the targeting properties and the distribution of the RLT in vivo. Non-invasive molecular imaging such as single photon emission computed tomography (SPECT) and positron emission tomography (PET) offer unique opportunities to understand drug behavior in vivo, permitting real time drug targeting and distribution analysis. In this study, we assessed the targeting properties and distribution of our HER3 ARC in HER3 expressing preclinical xenograft tumor models using both SPECT and PET. Methods: HER3 monoclonal antibody was conjugated with p-SCN-Bn-deferoxamine (DFO) or p-SCN-Bn-DOTA (DOTA) then labeled with Zirconium-89 (89Zr) or Indium-111 (111In), respectively. Flow cytometry and gamma counting was used to characterize HER3 ARC biological activity in HER3-expressing tumor cell lines. Balb/c mice subcutaneously inoculated with HER3-expressing xenograft tumors (lung, ovarian and colorectal) were intravenously administered with 89Zr-DFO-HER3 or 111In-DOTA-HER3. PET or SPECT scans were acquired 72 and 120-144hrs post injection of the radiotracer. Separate cohorts of mice were simultaneously administered with 89Zr-DFO-HER3 or 111In-DOTA-HER3 and 20-fold excess of native HER3 antibody as control to block radiotracer binding. Tissue uptake was quantified by drawing 3D or 2D regions of interest (ROI) for PET or SPECT images, respectively. Results: HER3 ARC radiotracers were successfully prepared and demonstrated similar binding to HER3 expressing cells compared to native HER3 antibody. In tumor-bearing mice, 89Zr-DFO-HER3 and 111In-DOTA-HER3 specifically accumulated in HER3 expressing tumors and cleared throughout the reticuloendothelial system. High tumor uptake was observed 120hrs post radiotracer injection using both imaging modalities. In mice pre-treated with 20-fold excess of native antibody, tumor uptake was significantly lower, showing tumor binding specificity of ARC. PET and SPECT images showed similar tracer distribution profile in the HER3 tumors. As expected, radiotracer clearance organ signals were also visualized. Conclusions: In this study we show that PET or SPECT imaging using 89Zr or 111In, respectively, offers the potential to assess the distribution of HER3 targeted radioligand therapy during early stages of drug development. HER3 ARC showed highly specific HER3 tumor uptake that remained at least 120hrs post injection. Our findings warrant further investigation to support advancement of HER3 ARC as a therapeutic option. Citation Format: Sumit Mukherjee, Debbie Lewis, Jason Li, Le-Cun Xu, Amanda Chin, Mary Chen, Monideepa Roy, Patrik Brodin, William van der Touw, Helen Kotanides, Denis Beckford-Vera. Characterization of HER3 targeted radioligand therapy using molecular imaging [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr A149.

Nanoparticles in practice for molecular-imaging applications: An overview

Molecular imaging such as positron emission tomography (PET) and single-photon emission computed tomography (SPECT) can provide the crucial pharmacokinetic-pharmacodynamic information of a drug non-invasively at an early stage of clinical drug development. Nevertheless, not much has been known how molecular imaging has been actually used in drug development studies. We searched PubMed using such keywords as molecular imaging, PET, SPECT, drug development, and new drug, or any combination of those to select papers in English, published from January 1, 1990, to December 31, 2015. The information about the publication year, therapeutic area of a drug candidate, drug development phase, and imaging modality and utility of imaging were extracted. Of 10,264 papers initially screened, 208 papers met the eligibility criteria. The more recent the publication year, the bigger the number of papers, particularly since 2010. The two major therapeutic areas using molecular imaging to develop drugs were oncology (47.6%) and the central nervous system (CNS, 36.5%), in which efficacy (63.5%) and proof-of-concept through either receptor occupancy (RO) or other than RO (29.7%), respectively, were the primary utility of molecular imaging. PET was used 4.7 times more frequently than SPECT. Molecular imaging was most frequently used in phase I clinical trials (40.8%), whereas it was employed rarely in phase 0 or exploratory IND studies (1.4%). The present study confirmed the trend that molecular imaging has been more actively employed in recent clinical drug development studies although its adoption was rather slow and rare in phase 0 studies.

In Part I of this consensus article, the imaging methodology, evolving imaging technology, and development of novel targeted molecular probes relevant to the developing field of cardiovascular molecular imaging were reviewed. Novel reporter gene and reporter probe imaging approaches for tracking of cardiac transgene expression were also discussed and have important future implications for evaluation of gene- and cell-based therapies for the failing heart. The current role of metabolic and receptor imaging was also briefly reviewed, as these represent the beginning of our clinical application of molecular imaging within the cardiovascular system. Part II will summarize the available targeted imaging probes as well as specific future applications of molecular imaging for identification and evaluation of critical pathophysiological processes of the cardiovascular system.

"Advances in cancer imaging and technology"-special collection -introductory Editorial.