Nanoparticles as Drug Delivery Systems for the Targeted Treatment of Atherosclerosis.

Atherosclerosis continues to be a leading cause of morbidity and mortality globally. The precise evaluation of the extent of an atherosclerotic plaque is essential for forecasting its likelihood of causing health concerns and tracking treatment outcomes. When compared to conventional methods used, nanoparticles offer clear benefits and excellent development opportunities for the detection and characterisation of susceptible atherosclerotic plaques. In this review, we analyse the recent advancements of nanoparticles as theranostics in the management of atherosclerosis, with an emphasis on applications in drug delivery. Furthermore, the main issues that must be resolved in order to advance clinical utility and future developments of NP research are discussed. It is anticipated that medical NPs will develop into complex and advanced next-generation nanobotics that can carry out a variety of functions in the bloodstream.

Protein nanoparticles as drug delivery systems for cancer theranostics.

Protein-based nanoparticles have garnered significant attention in theranostic applications due to their superior biocompatibility, exceptional biodegradability and ease of functionality. Compared to other nanocarriers, protein-based nanoparticles offer additional advantages, including biofunctionality and precise molecular recognition abilities, which make them highly effective in navigating complex biological environments. Moreover, proteins can serve as powerful tools with self-assembling structures and reagents that enhance cell penetration. And their derivation from abundant renewable sources and ability to degrade into harmless amino acids further enhance their suitability for biomedical applications. However, protein-based nanoparticles have so far not realized their full potential. In this review, we summarize recent advances in the use of protein nanoparticles in tumor diagnosis and treatment and outline typical methods for preparing protein nanoparticles. The review of protein nanoparticles may provide useful new insights into the development of biomaterial fabrication.

Self-assembling dendrimer nanosystems for specific fluorine magnetic resonance imaging and effective theranostic treatment of tumors.

Fluorine magnetic resonance imaging (19F-MRI) is particularly promising for biomedical applications owing to the absence of fluorine in most biological systems. However, its use has been limited by the lack of safe and water-soluble imaging agents with high fluorine contents and suitable relaxation properties. We report innovative 19F-MRI agents based on supramolecular dendrimers self-assembled by an amphiphilic dendrimer composed of a hydrophobic alkyl chain and a hydrophilic dendron. Specifically, this amphiphilic dendrimer bears multiple negatively charged terminals with high fluorine content, which effectively prevented intra- and intermolecular aggregation of fluorinated entities via electrostatic repulsion. This permitted high fluorine nuclei mobility alongside good water solubility with favorable relaxation properties for use in 19F-MRI. Importantly, the self-assembling 19F-MRI agent was able to encapsulate the near-infrared fluorescence (NIRF) agent DiR and the anticancer drug paclitaxel for multimodal 19F-MRI and NIRF imaging of and theranostics for pancreatic cancer, a deadly disease for which there remains no adequate early detection method or efficacious treatment. The 19F-MRI and multimodal 19F-MRI and NIRF imaging studies on human pancreatic cancer xenografts in mice confirmed the capability of both imaging modalities to specifically image the tumors and demonstrated the efficacy of the theranostic agent in cancer treatment, largely outperforming the clinical anticancer drug paclitaxel. Consequently, these dendrimer nanosystems constitute promising 19F-MRI agents for effective cancer management. This study offers a broad avenue to the construction of 19F-MRI agents and theranostics, exploiting self-assembling supramolecular dendrimer chemistry.

Novel Lipid Nanocomplex Co-Carrying Bcl2 siRNA and Quantum Dots for EGF Receptor-Targeted Anti-Cancer Theranosis.

Many different types of nanoparticles have been suggested for tumor-targeted theranosis. However, most systems were prepared through a series of complicated processes and could not even overcome the blood-immune barriers. For the accurate diagnosis and effective treatment of cancers, herein we suggested the lipid micellar structure capturing quantum dot (QD) for cancer theranosis. The QD/lipid micelles (QDMs) were prepared using a simple self-assembly procedure and then conjugated with anti-epidermal growth factor receptor (EGFR) antibodies for tumor targeting. As a therapeutic agent, Bcl2 siRNA-cholesterol conjugates were loaded on the surface of QDMs. The EGFR-directed QDMs containing Bcl2 siRNA, so-called immuno-QDM/siBcl2 (iQDM/siBcl2), exhibited the more effective delivery of QDs and siBcl2 to target human colorectal cancer cells in cultures as well as in mouse xenografts. The effective in vivo targeting of iQDM/siBcl2 resulted in a more enhanced therapeutic efficacy of siBcl2 to the target cancer in mice. Based on the results, anti-EGFR QDM capturing therapeutic siRNA could be suggested as an alternative modality for tumor-targeted theranosis.

Theranostic nanoparticles ZIF-8@ICG for pH/NIR-responsive drug-release and NIR-guided chemo-phototherapy against non-small-cell lung cancer.

This study leverages nanotechnology by encapsulating indocyanine green (ICG) and paclitaxel (Tax) using zeolitic imidazolate frameworks-8 (ZIF-8) as a scaffold. This study aims to investigate the chemo-photothermal therapeutic potential of ZIF-8@ICG@Tax nanoparticles (NPs) in the treatment of non-small cell lung cancer (NSCLC). An "all-in-one" theranostic ZIF-8@ICG@Tax NPs was conducted by self-assembly based on electrostatic interaction. First, the photothermal effect, stability, pH responsiveness, drug release, and blood compatibility of ZIF-8@ICG@Tax were evaluated through in vitro testing. Furthermore, the hepatic and renal toxicity of ZIF-8@ICG@Tax were assessed through in vivo testing. Additionally, the anticancer effects of these nanoparticles were investigated both in vitro and in vivo. Uniform and stable chemo-photothermal ZIF-8@ICG@Tax NPs had been successfully synthesized and had outstanding drug releasing capacities. Moreover, ZIF-8@ICG@Tax NPs showed remarkable responsiveness dependent both on pH in the tumor microenvironment and NIR irradiation, allowing for targeted drug delivery and controlled drug release. NIR irradiation can enhance the tumor cell response to ZIF-8@ICG@Tax uptake, thereby promoting the anti-tumor growth in vitro and in vivo. ZIF-8@ICG@Tax and NIR irradiation have demonstrated remarkable synergistic anti-tumor growth properties compared to their individual components. This novel theranostic chemo-photothermal NPs hold great potential as a viable treatment option for NSCLC.

PSMA-targeted radiotheranostics in modern nuclear medicine: then, now, and what of the future?

In 1853, the perception of prostate cancer (PCa) as a rare ailment prevailed, was described by the eminent Londoner surgeon John Adams. Rapidly forward to 2018, the landscape dramatically altered. Currently, men face a one-in-nine lifetime risk of PCa, accentuated by improved diagnostic methods and an ageing population. With more than three million men in the United States alone grappling with this disease, the overall risk of succumbing to stands at one in 39. The intricate clinical and biological diversity of PCa poses serious challenges in terms of imaging, ongoing monitoring, and disease management. In the field of theranostics, diagnostic and therapeutic approaches that harmoniously merge targeted imaging with treatments are integrated. A pivotal player in this arena is radiotheranostics, employing radionuclides for both imaging and therapy, with prostate-specific membrane antigen (PSMA) at the forefront. Clinical milestones have been reached, including FDA- and/or EMA-approved PSMA-targeted radiodiagnostic agents, such as [18F]DCFPyL (PYLARIFY®, Lantheus Holdings), [18F]rhPSMA-7.3 (POSLUMA®, Blue Earth Diagnostics) and [68Ga]Ga-PSMA-11 (Locametz®, Novartis/ ILLUCCIX®, Telix Pharmaceuticals), as well as PSMA-targeted radiotherapeutic agents, such as [177Lu]Lu-PSMA-617 (Pluvicto®, Novartis). Concurrently, ligand-drug and immune therapies designed to target PSMA are being advanced through rigorous preclinical research and clinical trials. This review delves into the annals of PSMA-targeted radiotheranostics, exploring its historical evolution as a signature molecule in PCa management. We scrutinise its clinical ramifications, acknowledge its limitations, and peer into the avenues that need further exploration. In the crucible of scientific inquiry, we aim to illuminate the path toward a future where the enigma of PCa is deciphered and where its menace is met with precise and effective countermeasures. In the following sections, we discuss the intriguing terrain of PCa radiotheranostics through the lens of PSMA, with the fervent hope of advancing our understanding and enhancing clinical practice.

Curcumin loaded ß-cyclodextrin-magnetic graphene oxide nanoparticles decorated with folic acid receptors as a new theranostic agent to improve prostate cancer treatment.

This article presents a novel approach to treating prostate cancer using a nanocarrier composed of folic acid (FA), ß-cyclodextrin (ß-CD), and magnetic graphene oxide (MGO) as a theranostic agent. The carrier is designed to improve the solubility and bioavailability of curcumin, a potential therapeutic substance against prostate cancer. Folic acid receptors overexpressed on the surface of solid tumors, including prostate cancer, may facilitate targeted drug delivery to tumor cells while avoiding nonspecific effects on healthy tissues. The anticancer efficacy of Folic acid-curcumin@ß-CD-MGO in vitro was also examined on LNCaP (an androgen-dependent) and PC3 (an androgen-independent) prostate cancer cells. The relaxivity of nanoparticles in MRI images was also investigated as a diagnostic factor. The results showed a concentration-dependent inhibitory effect on cell proliferation, induction of oxidative damage, and apoptotic effects. Also, nanoparticle relaxometry shows that this agent can be used as a negative contrast agent in MRI images. Overall, this study represents a promising theranostic agent to improve the delivery and trace of curcumin and enhance its therapeutic potential in the treatment of prostate cancer.

TME-Triggered Degradable Phototheranostic Nanoplatform for NIR-II Fluorescence Bioimaging-Guided Phototherapies and Immune Activation.

The low therapeutic efficacy and potential long-term toxicity of antitumor treatments seriously limit the clinical application of phototherapies. Herein, we develop a degradable phototheranostic nanoplatform for NIR-II fluorescence bioimaging-guided synergistic photothermal (PTT) and photodynamic therapies (PDT) and immune activation to inhibit tumor growth. The phototheranostic nanoplatform (CX@PSS) consists of multidisulfide-containing polyurethane loaded with a photosensitizer CX, which can be specifically degraded in the GSH overexpressed tumor microenvironment (TME) and exhibits good NIR-II fluorescence, photodynamic, and photothermal properties. Under 808 nm light irradiation, CX@PSS exhibits efficient photothermal conversion and ROS generation, which further induces immunogenic cell death (ICD), releasing tumor-associated antigens and activating the immune response. In vitro and in vivo studies confirm the potential of CX@PSS in NIR II FL imaging-guided tumor treatments by synergistic PTT, PDT, and immune activation. This work is expected to provide a new pathway for clinical applications of imaging-guided tumor diagnosis and treatments.

Construction and Application of a PD-L1-Targeted Multimodal Diagnostic and Dual-Functional Theranostics Nanoprobe.

Background: In recent years, PD-L1 has been primarily utilized as an immune checkpoint marker in cancer immunotherapy. However, due to tumor heterogeneity, the response rate to such therapies often falls short of expectations. In addition to its role in immunotherapy, PD-L1 serves as a specific target on the surface of tumor cells for targeted diagnostic and therapeutic interventions. There is an absence of a fully developed PD-L1-targeted diagnostic and therapeutic probe for clinical use, which constrains the exploration and clinical exploitation of this target. Methods and Results: In this study, we engineered a PD-L1-targeted probe with multimodal imaging and dual therapeutic functionalities utilizing organic melanin nanoparticles. Functionalization with the WL12-SH peptide endowed the nanoprobe with specific targeting capabilities. Subsequent radiolabeling with 89Zr (half-life: 100.8 hours) and chelation of Mn2+ ions afforded the probe the capacity for simultaneous PET and MRI imaging modalities. Cellular uptake assays revealed pronounced specificity, with -positive cells exhibiting significantly higher uptake than -negative counterparts (p < 0.05). Dual-modal PET/MRI imaging delineated rapid and sustained accumulation at the neoplastic site, yielding tumor-to-non-tumor (T/NT) signal ratios at 24 hours post-injection of 16.67±3.45 for PET and 6.63±0.64 for MRI, respectively. We conjugated the therapeutic radionuclide 131I (half-life: 8.02 days) to the construct and combined low-dose radiotherapy and photothermal treatment (PTT), culminating in superior antitumor efficacy while preserving a high safety profile. The tumors in the cohort receiving the dual-modality therapy exhibited significantly reduced volume and weight compared to those in the control and monotherapy groups. Conclusion: We developed and applied a novel -targeted multimodal theranostic nanoprobe, characterized by its high specificity and superior imaging capabilities as demonstrated in PET/MRI modalities. Furthermore, this nanoprobe facilitates potent therapeutic efficacy at lower radionuclide doses when used in conjunction with PTT.

Glycosylated nanoplatforms: From glycosylation strategies to implications and opportunities for cancer theranostics.

Glycosylated nanoplatforms have emerged as promising tools in the field of cancer theranostics, integrating both therapeutic and diagnostic functionalities. These nanoscale platforms are composed of different materials such as lipids, polymers, carbons, and metals that can be modified with glycosyl moieties to enhance their targeting capabilities towards cancer cells. This review provides an overview of different modification strategies employed to introduce glycosylation onto nanoplatforms, including chemical conjugation, enzymatic methods, and bio-orthogonal reactions. Furthermore, the potential applications of glycosylated nanoplatforms in cancer theranostics are discussed, focusing on their roles in drug delivery, imaging, and combination therapy. The ability of these nanoplatforms to selectively target cancer cells through specific interactions with overexpressed glycan receptors is highlighted, emphasizing their potential for enhancing efficacy and reducing the side effects compared to conventional therapies. In addition, the incorporation of diagnostic components onto the glycosylated nanoplatforms provided the capability of simultaneous imaging and therapy and facilitated the real-time monitoring of treatment response. Finally, challenges and future perspectives in the development and translation of glycosylated nanoplatforms for clinical applications are addressed, including scalability, biocompatibility, and regulatory considerations. Overall, this review underscores the significant progress made in the field of glycosylated nanoplatforms and their potential to revolutionize cancer theranostics.

Novel thymohydroquinone gallate derivative loaded ligand modified quantum dots as pH-sensitive multi-modal theragnostic agent for cancer treatment.

BACKGROUND: Nanomedicine, as the combination of radiopharmaceutical and nanocarrier (QDs), is developed for treating cancer. Gallic acid is antimutagenic, anti-inflammatory, and anti-carcinogenic. Typical retention time of gallic acid is approximately 4 to 8 h. To increase the retention time gallic acid is converted to prodrug by adding lipophilic moieties, encapsulating in lipophilic nanoparticles, or liposome formation. Similarly, thymoquinone is powerful antioxidant, anti-apoptotic, and anti-inflammatory effect, with reduced DNA damage. METHODS: In this study, a hydrophilic drug (gallic acid) is chemically linked to the hydrophobic drug (thymohydroquinone) to overcome the limitations of co-delivery of drugs. Thymohydroquinone (THQG) as the combination of gallic acid (GA) and thymoquinone (THQ) is loaded onto the PEI functionalized antimonene quantum dots (AM-QDs) and characterized by FTIR, UV-visible spectroscopy, X-ray powder diffraction, Zeta sizer, SEM and AFM, in-vitro and in-vivo assay, and hemolysis. RESULTS: The calculated drug loading efficiency is 90 %. Drug release study suggests the drug combination is pH sensitive and it can encounters acidic pH, releasing the drug from the nanocarrier. The drug and drug-loaded nanocarrier possesses low cytotoxicity and cell viability on MCF-7 and Cal-27 cell lines. The proposed drug delivery system is radiolabeled with Iodine-131 (131I) and Technetium (99mTc) and its deposition in various organs of rats' bodies is examined by SPECT-CT and gamma camera. Hemolytic activity of 2, 4, 6, and 8 µg/mL is 1.78, 4.16, 9.77, and 15.79 %, respectively, reflecting low levels of hemolysis. The system also sustains oxidative stress in cells and environment, decreasing ROS production to shield cells and keep them healthy. CONCLUSIONS: The results of this study suggest that the proposed drug carrier system can be used as a multi-modal theragnostic agent in cancer treatment.

Targeted Nanotheransotics: Integration of Preclinical MRI and CT in the Molecular Imaging and Therapy of Advanced Diseases.

The integration of preclinical magnetic resonance imaging (MRI) and computed tomography (CT) methods has significantly enhanced the area of therapy and imaging of targeted nanomedicine. Nanotheranostics, which make use of nanoparticles, are a significant advancement in MRI and CT imaging. In addition to giving high-resolution anatomical features and functional information simultaneously, these multifunctional agents improve contrast when used. In addition to enabling early disease detection, precise localization, and personalised therapy monitoring, they also enable early disease detection. Fusion of MRI and CT enables precise in vivo tracking of drug-loaded nanoparticles. MRI, which provides real-time monitoring of nanoparticle distribution, accumulation, and release at the cellular and tissue levels, can be used to assess the efficacy of drug delivery systems. The precise localization of nanoparticles within the body is achievable through the use of CT imaging. This technique enhances the capabilities of MRI by providing high-resolution anatomical information. CT also allows for quantitative measurements of nanoparticle concentration, which is essential for evaluating the pharmacokinetics and biodistribution of nanomedicine. In this article, we emphasize the integration of preclinical MRI and CT into molecular imaging and therapy for advanced diseases.

Treg-Derived Extracellular Vesicles: Roles in Diseases and Theranostics.

Regulatory T cells (Tregs), a subset of CD4+ T cells, are indispensable in maintaining immune self-tolerance and have been utilized in various diseases. Treg-derived extracellular vesicles (Treg-EVs) have been discovered to play an important role in the mechanism of Treg functions. As cell-derived membranous particles, EVs carry multiple bioactive substances that possess tremendous potential for theranostics. Treg-EVs are involved in numerous physiological and pathological processes, carrying proteins and miRNAs inherited from the parental cells. To comprehensively understand the function of Treg-EVs, here we reviewed the classification of Treg-EVs, the active molecules in Treg-EVs, their various applications in diseases, and the existing challenges for Treg-EVs based theranostics. This Review aims to clarify the feasibility and potential of Treg-EVs in diseases and theranostics, facilitating further research and application of Treg-EVs.

A Nanorobotics-Based Approach of Breast Cancer in the Nanotechnology Era.

We are living in an era of advanced nanoscience and nanotechnology. Numerous nanomaterials, culminating in nanorobots, have demonstrated ingenious applications in biomedicine, including breast cancer (BC) nano-theranostics. To solve the complicated problem of BC heterogeneity, non-targeted drug distribution, invasive diagnostics or surgery, resistance to classic onco-therapies and real-time monitoring of tumors, nanorobots are designed to perform multiple tasks at a small scale, even at the organelles or molecular level. Over the last few years, most nanorobots have been bioengineered as biomimetic and biocompatible nano(bio)structures, resembling different organisms and cells, such as urchin, spider, octopus, fish, spermatozoon, flagellar bacterium or helicoidal cyanobacterium. In this review, readers will be able to deepen their knowledge of the structure, behavior and role of several types of nanorobots, among other nanomaterials, in BC theranostics. We summarized here the characteristics of many functionalized nanodevices designed to counteract the main neoplastic hallmark features of BC, from sustaining proliferation and evading anti-growth signaling and resisting programmed cell death to inducing angiogenesis, activating invasion and metastasis, preventing genomic instability, avoiding immune destruction and deregulating autophagy. Most of these nanorobots function as targeted and self-propelled smart nano-carriers or nano-drug delivery systems (nano-DDSs), enhancing the efficiency and safety of chemo-, radio- or photodynamic therapy, or the current imagistic techniques used in BC diagnosis. Most of these nanorobots have been tested in vitro, using various BC cell lines, as well as in vivo, mainly based on mice models. We are still waiting for nanorobots that are low-cost, as well as for a wider transition of these favorable effects from laboratory to clinical practice.

Cucurbit[8]uril-based supramolecular theranostics.

Different from most of the conventional platforms with dissatisfactory theranostic capabilities, supramolecular nanotheranostic systems have unparalleled advantages via the artful combination of supramolecular chemistry and nanotechnology. Benefiting from the tunable stimuli-responsiveness and compatible hierarchical organization, host-guest interactions have developed into the most popular mainstay for constructing supramolecular nanoplatforms. Characterized by the strong and diverse complexation property, cucurbit[8]uril (CB[8]) shows great potential as important building blocks for supramolecular theranostic systems. In this review, we summarize the recent progress of CB[8]-based supramolecular theranostics regarding the design, manufacture and theranostic mechanism. Meanwhile, the current limitations and corresponding reasonable solutions as well as the potential future development are also discussed.

Recent advances in cell membrane camouflaged nanotherapeutics for the treatment of bacterial infection.

Infectious diseases caused by bacterial infections are common in clinical practice. Cell membrane coating nanotechnology represents a pioneering approach for the delivery of therapeutic agents without being cleared by the immune system in the meantime. And the mechanism of infection treatment should be divided into two parts: suppression of pathogenic bacteria and suppression of excessive immune response. The membrane-coated nanoparticles exert anti-bacterial function by neutralizing exotoxins and endotoxins, and some other bacterial proteins. Inflammation, the second procedure of bacterial infection, can also be suppressed through targeting the inflamed site, neutralization of toxins, and the suppression of pro-inflammatory cytokines. And platelet membrane can affect the complement process to suppress inflammation. Membrane-coated nanoparticles treat bacterial infections through the combined action of membranes and nanoparticles, and diagnose by imaging, forming a theranostic system. Several strategies have been discovered to enhance the anti-bacterial/anti-inflammatory capability, such as synthesizing the material through electroporation, pretreating with the corresponding pathogen, membrane hybridization, or incorporating with genetic modification, lipid insertion, and click chemistry. Here we aim to provide a comprehensive overview of the current knowledge regarding the application of membrane-coated nanoparticles in preventing bacterial infections as well as addressing existing uncertainties and misconceptions.

Ultrasmall Fe3O4 nanoparticles self-assembly induced dual-mode T1/T2-weighted magnetic resonance imaging and enhanced tumor synergetic theranostics.

Individual theranostic agents with dual-mode MRI responses and therapeutic efficacy have attracted extensive interest due to the real-time monitor and high effective treatment, which endow the providential treatment and avoid the repeated medication with side effects. However, it is difficult to achieve the integrated strategy of MRI and therapeutic drug due to complicated synthesis route, low efficiency and potential biosafety issues. In this study, novel self-assembled ultrasmall Fe3O4 nanoclusters were developed for tumor-targeted dual-mode T1/T2-weighted magnetic resonance imaging (MRI) guided synergetic chemodynamic therapy (CDT) and chemotherapy. The self-assembled ultrasmall Fe3O4 nanoclusters synthesized by facilely modifying ultrasmall Fe3O4 nanoparticles with 2,3-dimercaptosuccinic acid (DMSA) molecule possess long-term stability and mass production ability. The proposed ultrasmall Fe3O4 nanoclusters shows excellent dual-mode T1 and T2 MRI capacities as well as favorable CDT ability due to the appropriate size effect and the abundant Fe ion on the surface of ultrasmall Fe3O4 nanoclusters. After conjugation with the tumor targeting ligand Arg-Gly-Asp (RGD) and chemotherapy drug doxorubicin (Dox), the functionalized Fe3O4 nanoclusters achieve enhanced tumor accumulation and retention effects and synergetic CDT and chemotherapy function, which serve as a powerful integrated theranostic platform for cancer treatment.

Navigating through the coordination preferences of heavy alkaline earth metals: Laying the foundations for 223Ra- and 131/135mBa-based targeted alpha therapy and theranostics of cancer.

The clinical success of [223Ra]RaCl2 (Xofigo®) for the palliative treatment of bone metastases in patients with prostate cancer has highlighted the therapeutic potential of α-particle emission. Expanding the applicability of radium-223 in Targeted Alpha Therapy of non-osseous tumors is followed up with significant interest, as it holds the potential to unveil novel treatment options in the comprehensive management of cancer. Moreover, the use of barium radionuclides, like barium-131 and -135m, is still unfamiliar in nuclear medicine applications, although they can be considered as radium-223 surrogates for imaging purposes. Enabling these applications requires the establishment of chelators able to form stable complexes with radium and barium radionuclides. Until now, only a limited number of ligands have been suggested and these molecules have been primarily inspired by existing structures known for their ability to complex large metal cations. However, a systematic inspection of chelators specifically tailored to Ra2+ and Ba2+ has yet to be conducted. This work delves into a comprehensive investigation of a series of small organic ligands, aiming to unveil the coordination preferences of both radium-223 and barium-131/135m. Electronic binding energies of both metal cations to each ligand were theoretically computed via Density Functional Theory calculations (COSMO-ZORA-PBE-D3/TZ2P), while thermodynamic stability constants were experimentally determined for Ba2+-ligand complexes by potentiometry, NMR and UV-Vis spectroscopies. The outcomes revealed malonate, 2-hydroxypyridine 1-oxide and picolinate as the most favorable building blocks to design multidentate chelators. These findings serve as foundation guidelines, propelling the development of cutting-edge radium-223- and barium-131/135m-based radiopharmaceuticals for Targeted Alpha Therapy and theranostics of cancer.