Emerging Innovations in Gadolinium-Based Imaging and Therapy

Received 30 Mar, 2025

Accepted 31 Jul, 2025

Published 30 Sep, 2025

Gadolinium, a 64-atomic-number rare-earth lanthanide metal, is crucial in modern diagnostic medicine due to its paramagnetic properties. Its strong magnetic properties speed up the relaxation of water protons in MRI, making Gadolinium-Based Contrast Agents (GBCAs) important for accurate and early disease diagnosis. Gadolinium has also found utility in nuclear medicine, particularly in neutron capture therapy (NCT) for certain cancers. It is also explored in advanced bioimaging techniques due to its luminescence when doped with ligands or nanostructures. However, the clinical application of gadolinium is not without risks, including the toxic nature of free Gd³⁺ ions and potential side effects, especially in patients with impaired renal function. A recent review focuses on improving the biocompatibility and safety of GBCAs by developing macromolecular carriers, nanoparticle formulations and smart ligands that release gadolinium only under specific physiological conditions. These innovations aim to optimize distribution, minimise toxicity, and broaden the scope of gadolinium’s biomedical applications.

INTRODUCTION

Gadolinium, a soft, silvery-white rare-earth metal, reacts with oxygen, and water, forming an oxide layer that tarnishes its surface. In moist air, it oxidises to gadolinium oxide, while in water, it forms hydroxides, and hydrogen gas¹. The trivalent ionic form (Gd³⁺) in MRI studies is effective due to its seven unpaired electrons, enhancing picture contrast, and enabling better differentiation between normal, and diseased tissues². Gadolinium, a 64-atomic rare earth element, is known for its exceptional magnetic properties, particularly in its trivalent ionic state (Gd³⁺), which contains seven unpaired electrons, making it highly paramagnetic³. Gadolinium’s use has expanded beyond imaging to include targeted therapy, radiation, and theranostics, a unique paradigm that combines therapeutic, and diagnostic modalities on one platform⁴.

Gadolinium-Based Contrast Agents (GBCAs) are crucial in diagnostic radiology, particularly in MRI, due to their ability to shorten the T1 relaxation time of water protons. These agents enhance signal intensity in T1-weighted images, allowing for clearer visualisation of soft tissues, the brain, the spinal cord, and vasculature. Gadolinium is also being explored in theranostics, integrating diagnostic imaging with targeted therapy. Gadolinium is incorporated into nanoplatforms for simultaneous imaging, and drug delivery, improving treatment accuracy, and patient outcomes in oncology, and beyond⁵.

Due to its inherent qualities, gadolinium is a perfect fit for this dual purpose. Neutron capture therapy (NCT) is one of its main theranostic uses⁶. When neutrons are captured, the isotope gadolinium-157, which has a very high neutron capture cross-section, releases Auger electrons, and gamma rays, which can cause localised cytotoxicity⁷. Moreover, multifunctional agents that may target tumours, deliver medications, and give real-time imaging are being created using gadolinium-based nanoparticles⁸. Gadolinium’s use in targeted therapy, imaging, and drug delivery is expanding beyond conventional limits, transforming personalised, and precision medicine as research advances in gadolinium-based chemicals⁹. Table 1 highlights the Gadolinium Clinical implications. This review aims to explore the emerging innovations, and biomedical applications of gadolinium-based compounds, focusing on their roles in diagnostic imaging-particularly magnetic resonance imaging (MRI)-and therapeutic interventions. It highlights recent advancements, discusses safety considerations, and evaluates the potential of gadolinium agents in next-generation theranostics.

Gadolinium-Based Contrast Agents (GBCAs)
Classification: Gadolinium-Based Contrast Agents (GBCAs) are used in MRI to improve diagnostic accuracy by shortening the T1 relaxation time of water protons. This allows radiologists to distinguish between normal, and pathological tissues, enabling the detection of tumours, inflammation, vascular abnormalities, and structural anomalies. Gadolinium, a rare-earth element with seven unpaired electrons, is safe for intravenous administration when chelated with stable organic ligands. The GBCAs are useful in neuroimaging, musculoskeletal studies, cardiovascular evaluations, oncology , and oncology for soft tissue contrast. However, safety concerns persist, especially in patients with renal impairment. The current review focuses on developing next-generation GBCAs with improved safety profiles, relaxivity, and targeted delivery capabilities¹⁰. Despite their effectiveness, the long-term safety has been reevaluated due to worries about gadolinium retention in the brain, and other tissues. The GBCAs have been linked to nephrogenic systemic fibrosis (NSF)¹¹, an uncommon but crippling disease in people with severe renal failure. This concern has led to the issuance of patient screening guidelines, and the preference for macrocyclic medicines by regulatory organisations. One recent advancement is the creation of high-relaxivity drugs, like gadopiclenol, which enable lower dosages without sacrificing image quality. With possible uses in targeted imaging, and medication delivery, the integration of GBCAs into theranostic platforms, and nanoparticle-based delivery systems is also being researched. The safety profile, pharmacokinetics, and novel formulations of GBCAs are still being researched, and developed as MRI continues to change. Table 2 summarizes the pharmacokinetics, safety profiles, and diverse clinical applications of Gadolinium-Based Contrast Agents (GBCAs), highlighting their use in enhanced imaging¹².

GBCAs are classified according to their ionic charge, and chemical structure: Macrocyclic versus Linear. While macrocyclic agents have a cage-like structure that firmly binds the gadolinium ion, and lowers the possibility of its release into the body, linear agents have an open-chain structure^23,24. Ionic vs. Non-Ionic: While non-ionic agents are not charged, ionic agents are. Their osmolality, and risk of negative reactions are impacted by this difference^25,26.

Table 1:

Feature, and description of Gadolinium

Feature	Description
Central focus	Gadolinium as the core ion for imaging and therapy
Branching	Four major innovation areas: Contrast agents, Theranostics, Targeting, Safety
Theranostics	Emphasis on multifunctional platforms (e.g., Gd-based liposomes or dendrimers)
Targeted delivery	Includes bioconjugates for precision therapy (e.g., antibodies, sugars)
Safety emphasis	Deposition issues → solution strategies (macrocyclic ligands, alternative metals)
Clinical applications	Highlight MRI expansion into neurology, cancer, heart and multimodal fields

Table 2

Pharmacokinetics, safety, and clinical applications of Gadolinium-Based Contrast Agents (GBCAs)

S. No.	Structure type	Pharmacokinetics and safety	Clinical applications	Advances in GBCAs/ Nano-technology	Reference
1	Linear non-ionic	Moderate stability, risk of Gd release	Brain, liver imaging	-	Iyad et al.13
2	Macrocyclic ionic	High stability, minimal NSF risk	Neurology,	-	Ataur Rahman et al.14
3	Macrocyclic non-ionic	Excellent safety profile	Whole-body MRI	-	Dufort et al.15
4	Linear ionic	Less stable, potential Gd retention	Angiography	-	Edwards et al.16
5	Macrocyclic	Favorable PK, reduced brain deposition	Oncologic imaging	Theranostics emerging	Clough et al.17
6	Linear	Higher Gd dissociation rate	Tumor perfusion	-	Wermuth and Jimenez18
7	Macrocyclic	Minimal gadolinium deposition	MS diagnosis	-	Loevner et al.19
8	Macrocyclic	No confirmed NSF cases	Liver lesion detection	-	Kuhl et al.20
9	Linear	Reported brain Gd deposits	Brain tumor assessment	-	Alsogati et al.21
10	Macrocyclic	Excellent chelate stability	Pediatric neuroimaging	-	Vymazal and Rulseh22

Mechanism of action: To increase the signal intensity on T1-weighted MRI images, GBCAs reduce the T1 relaxation time of adjacent hydrogen protons in water molecules. This improvement makes it possible to see blood vessels, tumours, and inflammatory areas more clearly²⁷.

Mechanism of action: Gadolinium-Based Contrast Agents (GBCAs): By taking advantage of the paramagnetic characteristics of gadolinium ions (Gd³⁺)^28,29, Gadolinium-Based Contrast Agents (GBCAs) improve picture contrast in magnetic resonance imaging (MRI). One of the most potent paramagnetic materials is gadolinium, which has seven unpaired electrons in its 4f orbital. This characteristic is essential to its MRI contrast-enhancing method of action^30,31.

Chelation of gadolinium: Because free gadolinium ions disrupt cellular processes that depend on calcium, they are extremely hazardous. Gd³⁺ is firmly bound with a chelating ligand to reduce toxicity by blocking its contact with bodily tissues. Stability, and safety are impacted by the chelate’s ionic or non-ionic, linear or macrocyclic nature^32,33.

Relaxivity and MRI signal enhancement: T1 relaxation time shortening is the main way that GBCAs function. The time it takes for protons in tissues-mostly water-to realign with the magnetic field following excitation by a radiofrequency pulse is known as T1 relaxation in MRI^34,35. By boosting the longitudinal relaxation rate (1/T1) through dipole-dipole interactions with neighbouring water protons, gadolinium speeds up this realignment. Consequently, gadolinium-containing tissues show up as brighter on T1-weighted imaging^36,37.

Water exchange and inner sphere mechanism: Inner sphere relaxivity, where water molecules are directly coupled to the Gd³⁺ ion, determines how effective a GBCA is. Second sphere, and outer sphere relaxivity: the presence of magnetic effects in the vicinity of water molecules that are not directly linked to Gd³⁺. Over time, Gd³⁺ can improve the relaxation of many protons because water molecules exchange in, and out of the coordination sphere at a rate of about 10^-8 to 10^-9 sec³⁸.

Biodistribution and clearance: The majority of GBCAs are extracellular fluid agents that are found in the interstitial, and intravascular spaces³⁹. Both the blood-brain, and blood-testis barriers remain intact. In people with normal renal function, GBCAs have a 1.5 hrs plasma half-life, and are mainly eliminated unaltered by the kidneys^40,41.

Clinical applications of Gadolinium-Based Contrast Agents (GBCAs): Diagnostic imaging has been transformed by GBCAs, especially in neurology, identifying vascular anomalies, multiple sclerosis lesions, and brain malignancies^42,43:

	•	Oncology: Recognising, and describing malignancies, evaluating the effectiveness of treatment, and spotting metastases44,45
	•	Cardiology: Assessing the viability, and perfusion of the heart46
	•	Musculoskeletal imaging: Evaluating infections, soft tissue malignancies, and joint diseases47

The particular clinical situation, patient characteristics, and the intended imaging results all influence the choice of GBCA. Since they allow for accurate anatomical, and functional imaging in a variety of medical specialties, Gadolinium-Based Contrast Agents or GBCAs, have become essential in clinical MRI practice⁴⁸. In multiple sclerosis, contrast enhancement shows tumour margins, identifies recurrence, and tracks demyelinating plaques. Because of their strong relaxivity, and stable macrocyclic architectures, GBCAs like gadobutrol, and gadoterate have demonstrated great dependability⁴⁹. GBCAs have a major positive impact on cardiovascular imaging, particularly in myocardial tissue characterisation, and MR angiography (MRA)⁵⁰. Gadolinium-enhanced MRI helps in tumour staging, treatment planning, and assessing therapy response in oncology⁵¹. Hepatocyte uptake is provided by liver-specific GBCAs such as gadoxetate disodium (Eovist), which enhances the detection of Hepatocellular Carcinoma (HCC)⁵². Dynamic Contrast-Enhanced MRI (DCE-MRI) enhances lesion detection in breast cancer, particularly in high-risk groups or in dense breast tissue⁵³. Applications in the musculoskeletal system include the assessment of bone marrow disease, soft tissue cancers, synovitis, and joint inflammation. Gadolinium-enhanced MRIs can identify postoperative problems in orthopaedic patients or distinguish between active inflammation, and chronic illness in rheumatoid arthritis⁵⁴. Careful GBCA selection is essential despite their wide range of applications, especially for patients who need serial imaging or have renal impairment. Because of their better safety profiles, macrocyclic agents are typically chosen⁵⁵. Figure 1 highlights the Gadolinium applications as a contrast agent in MRI to enhance the image quality, and visualize soft tissues, and Toxicity Concerns of

Fig. 1: Gadolinium theragnosis: Diagnosis, and visualization for various clinical conditions

Gadolinium-Based Contrast Agents (GBCAs) Because of their exceptional capacity to improve image contrast, gadolinium-based contrast agents or GBCAs, have been employed extensively in MRI. GBCAs are risky, even though they are normally safe. Particularly with repeated use or in susceptible groups, worries concerning gadolinium retention, nephrogenic systemic fibrosis (NSF), and hypersensitivity reactions have gained more attention⁵⁶.

Retention of gadolinium: Even in patients with normal renal function, recent research has demonstrated that trace levels of gadolinium can remain in the brain, bones, skin, and other organs for a considerable amount of time following GBCA delivery. By forming cage-like complexes that more firmly bind gadolinium, macrocyclic agents such as gadobutrol, gadoterate, and gadoteridol decrease the release, and retention of free Gd³⁺. Although gadolinium is present in tissues, there is currently no conclusive evidence linking retention to clinical damage in persons with normal renal function. However, care should be taken, particularly in groups that need MRI scans frequently⁵⁷. Older linear nonionic drugs, such as gadodiamide, have a much higher risk of NSF. The use of these high-risk agents has been limited since 2007. When taken at the lowest effective dose, newer macrocyclic GBCAs are thought to be safe for patients with renal impairment, and exhibit a small incidence of NSF^58,59.

Hypersensitivity and allergic reactions: Hypersensitivity reactions to GBCAs can range from minor rashes to severe anaphylaxis, albeit they are uncommon (affecting approximately 0.1 to 0.1% of individuals). With linear medicines, reactions occur more frequently, and are typically immediate (less than an hour after injection)^59,60.

Paediatric and pregnancy considerations: Children’s lower glomerular filtration rates, and undeveloped renal function may cause gadolinium retention to last longer. Although there is little information on GBCAs’ teratogenicity, they pass through the placenta, and reach the foetal blood. GBCAs fall under pregnancy category C, and ought to be taken sparingly^60,61.

Recent advances: Gadopiclenol, a next-generation, macrocyclic, non-ionic gadolinium-based contrast agent (GBCA), has been developed to offer superior imaging performance, and improved safety. Approved for clinical use in the US, and EU, gadopiclenol possesses high relaxivity, allowing it to produce stronger MRI signal enhancement at lower doses. Its macrocyclic structure reduces the risk of gadolinium ion release, which can cause adverse effects like nephrogenic systemic fibrosis. Gadopiclenol’s non-ionic nature also improves biocompatibility, and reduces allergic or hypersensitivity reactions. This makes it suitable for various clinical applications, including paediatric, and high-risk populations. Gadopiclenol sets a new benchmark in contrast agent development⁶².

CONCLUSION

Gadolinium’s unique paramagnetic, and luminescent properties make it invaluable in MRI diagnostics, and emerging cancer therapies. However, its clinical use is limited by toxicity concerns, especially in vulnerable patients. Recent innovations-such as gadolinium-loaded nanoparticles, smart ligands, and macromolecular carriers-aim to enhance safety, precision, and therapeutic utility. These advancements hold promise for safer, more effective imaging, and treatment strategies, ultimately improving diagnostic accuracy, and patient outcomes.

SIGNIFICANCE STATEMENT

The review article highlights the development of novel gadolinium-based nanoparticles, and complexes to improve the safety, and efficacy of gadolinium-based contrast agents in MRI. The gadolinium exhibits enhanced relaxivity, targeted delivery, and reduced toxicity, potentially improving MRI diagnostic accuracy, and enabling targeted therapy, especially for cancer treatment. This could lead to improved patient outcomes, and treatment options.

ACKNOWLEDGMENT

Authors are thankful to the S.M.B.T. College of Pharmacy, Maharashtra, India.

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