Standard Radio-Iodine Labeling Protocols Impaired the Functional Integrity of Mesenchymal Stem/Stromal Cell Exosomes.

Mesenchymal stem/stromal cells (MSCs) are an extensively studied cell type in clinical trials due to their easy availability, substantial ex vivo proliferative capacity, and therapeutic efficacy in numerous pre-clinical animal models of disease. The prevailing understanding suggests that their therapeutic impact is mediated by the secretion of exosomes. Notably, MSC exosomes present several advantages over MSCs as therapeutic agents, due to their non-living nature and smaller size. However, despite their promising therapeutic potential, the clinical translation of MSC exosomes is hindered by an incomplete understanding of their biodistribution after administration. A primary obstacle to this lies in the lack of robust labels that are highly sensitive, capable of directly and easily tagging exosomes with minimal non-specific labeling artifacts, and sensitive traceability with minimal background noise. One potential candidate to address this issue is radioactive iodine. Protocols for iodinating exosomes and tracking radioactive iodine in live imaging are well-established, and their application in determining the biodistribution of exosomes has been reported. Nevertheless, the effects of iodination on the structural or functional activities of exosomes have never been thoroughly examined. In this study, we investigate these effects and report that these iodination methods abrogate CD73 enzymatic activity on MSC exosomes. Consequently, the biodistribution of iodinated exosomes may reflect the biodistribution of denatured exosomes rather than functionally intact ones.

Safety and efficacy of peptide receptor radionuclide therapy in patients with advanced pheochromocytoma and paraganglioma: A single-institution experience and review of the literature.

INTRODUCTION: Despite advances in diagnosis and management, patients with advanced pheochromocytomas and paragangliomas (PPGL) face limited treatment options. This study aims to evaluate the safety and efficacy of peptide receptor radionuclide therapy (PRRT) in patients with advanced PPGL, based on a single-institution experience and provide a comprehensive review of the literature. METHODS: A retrospective analysis was conducted on patients with advanced pheochromocytoma and paraganglioma who received PRRT at a single institution from April 2012 to March 2022. Clinical characteristics, treatment response, adverse events, and survival outcomes were assessed. A systematic literature review was also performed. RESULTS: A total of 15 patients with advanced PPGL were included, the majority of whom had both metastatic and functional disease. Most patients received four infusions of 177Lu-DOTATATE (73%). The median therapeutic 177Lu-DOTATATE radioactivity for each infusion was 7.4 GBq. Only one patient was treated with one infusion of 90Y-DOTATATE (4.2 GBq) in addition to three infusions of Lu-177 DOTATATE. Overall, PRRT suggests a promising efficacy with disease control rate of 63.6% by RECIST v1.1. The median overall survival (OS) was not reached and the median progression free survival (PFS) was 25.9 months. In terms of safety, PRRT was well tolerated. Review of the literature revealed consistent findings, supporting the efficacy and safety of PRRT in PPGL. CONCLUSION: This study suggests that PRRT is a safe and effective therapeutic option for patients with PPGL. Our findings align with the existing literature, providing additional evidence to support the use of PRRT in this challenging patient population.

Radiolabeled Liposomes for Nuclear Imaging Probes.

Quantitative nuclear imaging techniques are in high demand for various disease diagnostics and cancer theranostics. The non-invasive imaging modality requires radiotracing through the radioactive decay emission of the radionuclide. Current preclinical and clinical radiotracers, so-called nuclear imaging probes, are radioisotope-labeled small molecules. Liposomal radiotracers have been rapidly developing as novel nuclear imaging probes. The physicochemical properties and structural characteristics of liposomes have been elucidated to address their long circulation and stability as radiopharmaceuticals. Various radiolabeling methods for synthesizing radionuclides onto liposomes and synthesis strategies have been summarized to render them biocompatible and enable specific targeting. Through a variety of radionuclide labeling methods, radiolabeled liposomes for use as nuclear imaging probes can be obtained for in vivo biodistribution and specific targeting studies. The advantages of radiolabeled liposomes including their use as potential clinical nuclear imaging probes have been highlighted. This review is a comprehensive overview of all recently published liposomal SPECT and PET imaging probes.

Outcomes and prognostic predictors of Lu-177 PSMA radioligand therapy in metastatic castration-resistant prostate cancer (Asian Population Study).

AIM: Lutetium-177 (Lu-177) prostate-specific membrane antigen radioligand therapy (PSMA-RLT) is a promising therapy for metastatic castration-resistant prostate cancer (mCRPC), but there is limited data of its efficacy and safety in Asian population. We aim to explore the clinical outcomes of Lu-177 PSMA-RLT in this population. METHODS: We evaluated 84 patients with progressive mCRPC receiving Lu-177 PSMA-RLT between 9 May 2018 and 21 February 2022. Lu-177-PSMA-I&T was administered at 6-8-week intervals. Primary end point was overall survival (OS), and secondary end points included prostate-specific antigen (PSA) progression-free survival (PFS), PSA response rate, clinical response, toxicity assessment, and prognostic indicators. RESULTS: The median OS and PSA PFS were 12.2 and 5.2 months, respectively. PSA decline of ≥50% was observed in 51.8% of patients. Patients achieving PSA response had longer median OS (15.0 vs. 9.5 months, p = .03) and PSA PFS (6.5 vs. 2.9 months, p < .001). Pain score improvement was seen in 19 out of 34 patients. A hematotoxicity of ≥grade 3 was observed in 13 out of 78 patients. Multivariable analyses showed that PSA velocity, alkaline phosphatase, hemoglobin (Hb), and the number of treatment cycles were independent prognostic indicators for OS. The retrospective design was the main limitation of the study. CONCLUSIONS: Our study demonstrated a similar safety and efficacy of Lu-177 PSMA-RLT in Asian mCRPC patients compared to the existing literature. A PSA decline ≥50% was associated with longer OS and PSA PFS. Several prognostic indicators for patient outcomes were also identified.

Radiochemical Feasibility of Mixing of 99mTc-MAA and 90Y-Microspheres with Omnipaque Contrast.

Yttrium-90 (90Y) microspheres are widely used for the treatment of liver-dominant malignant tumors. They are infused via catheter into the hepatic artery branches supplying the tumor under fluoroscopic guidance based on pre-therapy angiography and Technetium-99m macroaggregated albumin (99mTc-MAA) planning. However, at present, these microspheres are suspended in radiolucent media such as dextrose 5% (D5) solution. In order to monitor the real-time implantation of the microspheres into the tumor, the 90Y microspheres could be suspended in omnipaque contrast for allowing visualization of the correct distribution of the microspheres into the tumor. The radiochemical purity of mixing 90Y-microspheres in various concentrations of omnipaque was investigated. The radiochemical purity and feasibility of mixing 99mTc-MAA with various concentrations of a standard contrast agent were also investigated. Results showed the radiochemical feasibility of mixing 90Y-microspheres with omnipaque is radiochemically acceptable for allowing real-time visualization of radioembolization under fluoroscopy.

Selective Internal Radiation Therapy with Yttrium-90 Resin Microspheres Followed by Gemcitabine plus Cisplatin for Unresectable Intrahepatic Cholangiocarcinoma: A Phase 2 Single-Arm Multicenter Clinical Trial.

Introduction: This investigator-initiated clinical trial aims to study the efficacy and safety of administering selective internal radiation therapy with resin yttrium-90 microspheres (SIRT) followed by standard chemotherapy in unresectable intrahepatic cholangiocarcinoma (ICC). Methods: A phase 2 single-arm multicenter study was conducted in patients with unresectable ICC (NCT02167711). SIRT was administered at dose of 120 Gy targeted at tumor followed by commencement of gemcitabine 1,000 mg/m2 and cisplatin 25 mg/m2 on days one and eight of a 21-day cycle. The primary endpoint was overall survival (OS), and the secondary endpoints include progression-free survival (PFS), response rate according to Response Evaluation Criteria in solid tumors 1.1, toxicity, and time from SIRT to commencement of chemotherapy. Results: Total 31 patients were screened and twenty-four were recruited. All patients completed SIRT and 16 of them underwent subsequent chemotherapy. The median cycle of chemotherapy was 5 (range: 1-8). The median OS was 13.6 months (95% CI: 5.4-21.6) for the intent-to-treat population. Among 16 patients undergoing chemotherapy, the median OS was 21.6 months (95% CI: 7.3-25.2) and the median PFS was 9 months (95% CI: 3.2-13.1). The response rate was 25% (95% CI: 3.8-46.2%), and the disease control rate was 75% (95% CI: 53.8-96.2%). No new safety signal was observed, with fewer than 10% of patients suffering from grade 3 or higher treatment-related adverse events. The median time from SIRT to chemotherapy was 29 (range: 7-42) days. Eight patients could not receive chemotherapy due to rapid progressive disease (n = 4), underlying treatment unrelated comorbidities (n = 2), and withdrawal of consent due to personal reasons (n = 2). Conclusions: Treatment of SIRT followed by standard gemcitabine and cisplatin chemotherapy is feasible and effective for unresectable ICC. Further studies are required to study the optimal sequence of SIRT and chemotherapy.

The Role of Catheter-Directed CT-Angiography in Radioembolisation.

Radioembolisation is an established transarterial therapy for hepatocellular carcinoma and liver metastasis. Success of radioembolisation depends on meticulous angiography and accurate dosimetry. Intra-procedure catheter-directed CT-angiography is commonly performed to improve the efficacy and safety of radioembolisation. This review article will (1) introduce the differences between cone beam CT and hybrid angiography-CT, and (2) describe the benefits of catheter-directed CT-angiography in radioembolisation from both an interventional radiology and nuclear medicine perspective.

Nanomaterial Probes for Nuclear Imaging.

Nuclear imaging is a powerful non-invasive imaging technique that is rapidly developing in medical theranostics. Nuclear imaging requires radiolabeling isotopes for non-invasive imaging through the radioactive decay emission of the radionuclide. Nuclear imaging probes, commonly known as radiotracers, are radioisotope-labeled small molecules. Nanomaterials have shown potential as nuclear imaging probes for theranostic applications. By modifying the surface of nanomaterials, multifunctional radio-labeled nanomaterials can be obtained for in vivo biodistribution and targeting in initial animal imaging studies. Various surface modification strategies have been developed, and targeting moieties have been attached to the nanomaterials to render biocompatibility and enable specific targeting. Through integration of complementary imaging probes to a single nanoparticulate, multimodal molecular imaging can be performed as images with high sensitivity, resolution, and specificity. In this review, nanomaterial nuclear imaging probes including inorganic nanomaterials such as quantum dots (QDs), organic nanomaterials such as liposomes, and exosomes are summarized. These new developments in nanomaterials are expected to introduce a paradigm shift in nuclear imaging, thereby creating new opportunities for theranostic medical imaging tools.

Positron emission tomographic imaging in drug discovery.

Positron emission tomography (PET) is an extensively used nuclear functional imaging technique, especially for central nervous system (CNS) and oncological disorders. Currently, drug development is a lengthy and costly pursuit. Imaging with PET radiotracers could be an effective way to hasten drug discovery and advancement, because it facilitates the monitoring of key facets, such as receptor occupancy quantification, drug biodistribution, pharmacokinetic (PK) analyses, validation of target engagement, treatment monitoring, and measurement of neurotransmitter concentrations. These parameters demand careful analyses for the robust appraisal of newly formulated drugs during preclinical and clinical trials. In this review, we discuss the usage of PET imaging in radiopharmaceutical development; drug development approaches with PET imaging; and PET developments in oncological and cardiac drug discovery.

A Multiplex Thyroid-Specific Assay for Quantification of Circulating Thyroid Cell-Free RNA in Plasma of Thyroid Cancer Patients.

BACKGROUND: The standard of care for thyroid cancer management is thyroidectomy and adjuvant radioactive iodine (RAI). There is a paucity of clinical tool that quantifies residual thyroid volume reliably for precise adjuvant RAI dosing. Serum thyroglobulin (TG), tumour marker for thyroid cancer, takes 4 weeks for complete clearance due to its long half-life, and might be undetectable in 12% of structural disease patients. It detects recurrence with a sensitivity of 19-40%, mainly attributed to issue of TG antibody interference with TG immunometric assay. We hypothesise that the quantity of thyroid-specific cell-free RNA (cfRNA) is indicative of amount of thyroid tissues, and that during thyroid surgery, cfRNA levels decrease accordingly. METHODS: We identified 11 biologically significant and highly expressed thyroid-specific targets from Human Protein Atlas and literature. To assess for a fall in thyroid-specific cfRNA level, we recruited 16 patients undergoing thyroid surgery or RAI for malignant or benign thyroid disease, and tracked longitudinal trend of cfRNA. To assess the utility of cfRNA in detecting metastatic thyroid cancer, cfRNA of 11 patients at intermediate to high risk of recurrence was measured during surveillance and at time of clinical recurrence. RESULTS: The multiplex assay was capable of amplifying and quantifying multiple thyroid-specific genes in a single reaction. The selected targets were amplified successfully from RNA extracted directly from the thyroid (positive control), indicating that they were highly expressed within thyroid tissue. These cfRNAs were present in plasma, in amounts quantifiable using qRT-PCR. Four cfRNA transcripts (TPO, GFRA2, IVD, TG) fell post-treatment in more than 50% of cohort. The thyroid peroxidase (TPO) cfRNA fell post-therapy in 63% of cohort by 80%, as early as 1 day post-treatment, supporting the potential role as early indicator of remnant thyroid tissue volume. We demonstrated the clinical relevance of circulating TPO cfRNA by tracking temporal changes in setting of peri-treatment, recurrence, and TG Ab positive state. CONCLUSION: Using a multiplex pre-amplification approach, the TPO cfRNA was a potential biomarker that can track residual thyroid mass. It can be further optimised for quantification of thyroid volume to guide RAI doses and for detection of thyroid cancer recurrence.

Real-World Data on Clinical Outcomes of Patients with Liver Cancer: A Prospective Validation of the National Cancer Centre Singapore Consensus Guidelines for the Management of Hepatocellular Carcinoma.

INTRODUCTION: Real-world management of patients with hepatocellular carcinoma (HCC) is crucially challenging in the current rapidly evolving clinical environment which includes the need for respecting patient preferences and autonomy. In this context, regional/national treatment guidelines nuanced to local demographics have increasing importance in guiding disease management. We report here real-world data on clinical outcomes in HCC from a validation of the Consensus Guidelines for HCC at the National Cancer Centre Singapore (NCCS). METHOD: We evaluated the NCCS guidelines using prospectively collected real-world data, comparing the efficacy of treatment received using overall survival (OS) and progression-free survival (PFS). Treatment outcomes were also independently evaluated against 2 external sets of guidelines, the Barcelona Clinic Liver Cancer (BCLC) and Hong Kong Liver Cancer (HKLC). RESULTS: Overall treatment compliance to the NCCS guidelines was 79.2%. Superior median OS was observed in patients receiving treatment compliant with NCCS guidelines for early (nonestimable vs. 23.5 months p < 0.0001), locally advanced (28.1 vs. 22.2 months p = 0.0216) and locally advanced with macrovascular invasion (10.3 vs. 3.3 months p = 0.0013) but not for metastatic HCC (8.1 vs. 6.8 months p = 0.6300), but PFS was similar. Better clinical outcomes were seen in BCLC C patients who received treatment compliant with NCCS guidelines than in patients with treatment only allowed by BCLC guidelines (median OS 14.2 vs. 7.4 months p = 0.0002; median PFS 6.1 vs. 4.0 months p = 0.0286). Clinical outcomes were, however, similar for patients across all HKLC stages receiving NCCS-recommended treatment regardless of whether their treatment was allowed by HKLC. CONCLUSION: The high overall compliance rate and satisfactory clinical outcomes of patients managed according to the NCCS guidelines confirm its validity. This validation using real-world data considers patient and treating clinician preferences, thus providing a realistic analysis of the usefulness of the NCCS guidelines when applied in the clinics.

The exact Deauville score, NABS score and high SUVmax predicts outcome in extranodal natural killer/T-cell lymphoma.

OBJECTIVE: Natural killer T-cell lymphoma (NKTCL) is an aggressive type of non-Hodgkin's lymphoma. While FDG-PET/CT imaging has been increasingly utilized for disease assessment, its prognostic value and potential utility in NKTCL patient stratification remain controversial. We aim to investigate the prognostic utility of FDG-PET/CT and its role in complementing clinical indices. METHODS: We conducted a retrospective review of 72 patients from a tertiary National Cancer Centre with biopsy-proven NKTCL and available FDG-PET/CT data (either baseline, end of treatment or both). Survival analysis was performed using the Kaplan-Meier method and multivariable Cox proportional regression. RESULTS: High initial SUVmax was significantly associated with advanced Ann-Arbor stage (p = 0.0352), elevated LDH levels (p = 0.0059) and plasma EBV DNA detection (p = 0.0278). SUVmax correlated with worse progression-free survival (PFS) (HR 3.68, 95% CI 1.56-8.69, p = 0.0030) and a trend toward worse overall survival (OS) (HR 2.06, 95% CI 0.95-4.45, p = 0.0676). End of treatment Deauville scores of 4-5, as compared to scores of 1-3, was associated with worse PFS (HR 2.72, 95% CI 1.04-7.12, p = 0.0419). Notably, while all patients with scores of 5 developed progressive disease, only 2 of 5 patients with scores of 4 eventually relapsed. Clinical indices (NABS score) were still able to stratify survival outcomes regardless of end-of-treatment Deauville scores. CONCLUSIONS: A Deauville score of 5 is more diagnostic of true disease progression than a score of 4, and NABS score may be used in patients who achieve Deauville scores of 1-3 for further risk stratification. A higher SUVmax at baseline portends a worse prognosis in NKTCL.

Reconfiguring the radiology leadership team for crisis management during the COVID-19 pandemic in a large tertiary hospital in Singapore.

The coronavirus 2019 (COVID-19) outbreak poses a serious public health risk. To date, the disease has affected almost all countries in the world. The enormous scale of the outbreak and the relative lack of knowledge and information regarding a new virus, as well as the unpredictability of events, make it challenging for leadership teams to respond. This paper shares how we have reconfigured our radiology leadership team into a smaller disease outbreak task force (DOTF) to respond and coordinate all related efforts during this ongoing COVID-19 pandemic. The DOTF format is modelled after the military with domain groups looking at manpower, intelligence, operations, and logistics matters on a daily basis so that timely decisions can be made and action plans executed promptly. In managing the DOTF, discipline, flexibility, and teamwork are key principles, and these are built upon a strong foundation of focus on infection prevention and control, and patient and staff safety as well as staff well-being. The DOTF has positioned us well to confront the many challenges to date. We believe it will also help us navigate the complex issues that will arise with future surges in cases and in formulating strategies to manage exit from the present and future lockdowns. KEY POINTS: • In a pandemic, regular and directed meetings by a smaller leadership core group are required, for prompt decision making and execution of action plans. • The military format, with domain groups to look at manpower, intelligence, operations, and logistics matters, is useful in managing a pandemic. • Discipline, flexibility, and teamwork with strong focus on infection prevention and control, and patient and staff safety as well as staff well-being are key principles for leadership teams managing a pandemic.

Frequent neck US in papillary thyroid cancer likely detects non-actionable findings.

BACKGROUND: American Thyroid Association (ATA) low-intermediate-risk papillary thyroid cancer (PTC) patients without structural and biochemical evidence of disease on initial post-treatment evaluation have a low risk of recurrence. Studies have shown that with current ultrasound scans (US) and thyroglobulin assays, recurrences mostly occurred 2-8 years after initial therapy. The ATA recommends that neck US be done 6-12 months after surgery to establish patient's response to therapy, then periodically depending on risk of recurrence. The lack of clarity in recommendations on timing of follow-up US and fear of recurrence leads to frequent tests. OBJECTIVES: To evaluate the utility of routine neck US in ATA low-intermediate-risk PTC patients with no structural disease on neck US and non-stimulated thyroglobulin <1.0 ng/mL after initial therapy. METHODS: A retrospective study of 93 patients from Singapore, Saudi Arabia and Argentina with ATA low (n = 49) to intermediate (n = 44) risk PTC was conducted between 1998 and 2017. The outcome was to measure the frequency of identifying structural disease recurrence and non-actionable US abnormalities. RESULTS: Over a median follow-up of 5 years, five of the 93 patients (5.4%) developed structural neck recurrence on US at a median of 2.5 years after initial treatment. Indeterminate US abnormalities were detected in 19 of the 93 patients (20.4%) leading to additional tests, which did not detect significant disease. CONCLUSION: In ATA low-intermediate-risk PTC with no suspicious findings on neck US and a non-stimulated thyroglobulin of <1.0 ng/mL after initial therapy, frequent US is more likely to identify non-actionable abnormalities than clinically significant disease.

Molecular Imaging and Therapy of Liver Tumors.

Liver cancer is one of the top leading causes of mortality worldwide. Conventional imaging using contrast enhanced CT and MRI are currently the mainstay of oncologic imaging of the liver for the diagnosis and management of cancer. In the past two decades, especially since the advent of hybrid imaging in the form of PET/CT and SPECT/CT, molecular imaging has been increasingly utilized for oncologic imaging and the variety of radionuclide probes for imaging liver cancers have been expanding. Beyond the usual workhorse of FDG as an oncologic tracer, there is a growing body of evidence showing that radiolabeled choline tracers, C-11 acetate and other new novel tracers may have increasing roles to play for the imaging of liver tumors. On the therapy front, there have also been advances in recent times in terms of targeted therapies for both primary and secondary liver malignancies, particularly with transarterial radioembolization. The concept of theranostics can be applied to transarterial radioembolization by utilizing a pretreatment planning scan, such as Tc-99m macroaggregated albumin scintigraphy, coupled with post treatment imaging. Radiation dose planning by personalized dosimetric calculations to the liver tumors is also being advocated. This article explores the general trends in the field of nuclear medicine for the imaging and treatment of liver cancer above and beyond routine diagnosis and management.

Clinical outcomes of 177lutetium-prostate-specific membrane antigen therapy in advanced prostate cancer-a prospective pilot study in an Asian population.

OBJECTIVE: Metastatic castration-resistant prostate cancers are aggressive tumors with poor prognosis. Prostate-specific membrane antigen-targeted radionuclide therapy is a potential treatment for these patients. Here, we report our initial experience in Singapore. METHODS: Twenty men (median age 70) with progressive disease were prospectively recruited. Prostate-specific membrane antigen and fluorodeoxyglucose-PET/computed tomography were performed to confirm high prostate-specific membrane antigen-expression. Up to four cycles of lutetium-prostate-specific membrane antigen-I&T at 6-8 weekly intervals were administered. Patients were restaged 3 months following treatment. Primary endpoints were prostate-specific antigen decline ≥50% and treatment-related toxicity. Additional endpoints included radiological and clinical response as well as progression-free survival and overall survival from first cycle. RESULTS: Sixty-seven cycles were administered (median 4 cycles per patient, mean 6.5 GBq per cycle). Sixty five percent had ≥1 line of prior chemotherapy, 90% abiraterone, enzalutamide or both, and 30% radium-223 radionuclide therapy. All had bone metastases and 35% had visceral metastases. Prostate-specific antigen decline ≥50% was achieved in 50%. Grade 3-4 hematotoxicity was seen in up to 15%. Grade 3-4 non-hematotoxicity was not observed. Eleven patients had restaging scans 3 months post-treatment (5 = partial response, 6 = progressive disease). Fifty-seven percent (4/7) with bone pain had pain improvement. Median progression-free survival was 5.9 months and median overall survival 13.1 months. Patients with prostate-specific antigen decline ≥50% had longer progression-free survival and overall survival. CONCLUSION: Lutetium-prostate-specific membrane antigen-I&T therapy is effective with tolerable side effects in our local setting. Prostate-specific antigen decline ≥50% is associated with longer progression-free survival and overall survival.

Facing a disruptive threat: how can a nuclear medicine service be prepared for the coronavirus outbreak 2020?

PURPOSE: The aim of this short communication is to outline our experience in policies and processes of a nuclear medicine service during the COVID-19 outbreak in Singapore. METHODS: We describe the key considerations of policies and processes that have been implemented in our nuclear medicine service since the first case of COVID-19 was confirmed in Singapore General Hospital on 23 January 2020, up to the present time. RESULTS: Infection control, screening of patients and visitors, segregation of risk groups, segregation of staff and service continuity plans, communication and staff welfare, using electronic platforms for multi-disciplinary meetings and tele-reporting are discussed. CONCLUSION: Since our hospital received the first patient with COVID-19 in Singapore, our centre has managed 16 COVID-19 cases to date. There has not been any healthcare worker in our institution who has contracted COVID-19 through patient contact. We have highlighted for discussion some of the policies and processes to prepare a nuclear medicine service for the COVID-19 threat.

Gadolinium-based bimodal probes to enhance T1-Weighted magnetic resonance/optical imaging.

Gd3+-based contrast agents have been extensively used for signal enhancement of T1-weighted magnetic resonance imaging (MRI) due to the large magnetic moment and long electron spin relaxation time of the paramagnetic Gd3+ ion. The key requisites for the development of Gd3+-based contrast agents are their relaxivities and stabilities which can be achieved by chemical modifications. These modifications include coordinating Gd3+ with a chelator such as diethylenetriamine pentaacetic acid (DTPA) or 1,4,7,10-Tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA), encapsulating Gd3+ in nanoparticles, conjugation to biomacromolecules such as polymer micelles and liposomes, or non-covalent binding to plasma proteins. In order to have a coherent diagnostic and therapeutic approach and to understand diseases better, the combination of MRI and optical imaging (OI) techniques into one technique entity has been developed to overcome the conventional boundaries of either imaging modality used alone through bringing the excellent spatial resolution of MRI and high sensitivity of OI into full play. Novel MRI and OI bimodal probes have been extensively studied in this regard. This review is an attempt to shed some light on the bimodal imaging probes by summarizing all recent noteworthy publications involving Gd3+ containing MR-optical imaging probes. The several key elements such as novel synthetic strategy, high sensitivity, biocompatibility, and targeting of the probes are highlighted in the review. STATEMENT OF SIGNIFICANCE: The present article aims at giving an overview of the existing bimodal MRI and OI imaging probes. The review structured as a series of examples of paramagnetic Gd3+ ions, either as ions in the crystalline structure of inorganic materials or chelates for contrast enhancement in MRI, while they are used as optical imaging probes in different modes. The comprehensive review focusing on the synthetic strategies, characterizations and properties of these bimodal imaging probes will be helpful in a way to prepare related work.