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PURPOSE: Fibroblast Activation Protein (FAP) is an emerging theranostic target that is highly expressed on cancer-associated fibroblasts and on certain tumor cells including sarcoma. We investigated the anti-tumor efficacy of [225Ac]Ac-FAPI-46 as monotherapy or in combination with immune checkpoint blockade (ICB) in immunocompetent murine models of sarcoma sensitive or resistant to ICB. METHODS: [68Ga]Ga- and [225Ac]Ac-FAPI-46 were tested in subcutaneous FAP+ FSA fibrosarcoma bearing C3H/Sed/Kam mice. The efficacy of up to three cycles of 60 kBq [225Ac]Ac-FAPI-46 was evaluated as monotherapy and in combination with an anti-PD-1 antibody. Efficacy of [225Ac]Ac-FAPI-46 and/or ICB was further compared in FAP-overexpressing FSA (FSA-F) tumors that were sensitive to ICB or rendered ICB-resistant by tumor-induction in the presence of Abatacept. RESULTS: [225Ac]Ac-FAPI-46 was well tolerated up to 3 × 60 kBq but had minimal effect on FSA tumor growth. The combination of three cycles [225Ac]Ac-FAPI-46 and ICB resulted in growth delay in 55% of mice (6/11) and partial tumor regression in 18% (2/11) of mice. In FSA-F tumors with FAP overexpression, both [225Ac]Ac-FAPI-46 and ICB were effective without additional benefits from the combination. In locally immunosuppressed and ICB resistant FAP-F tumors, however, [225Ac]Ac-FAPI-46 restored responsiveness to ICB, resulting in significant tumor regression and tumor-free survival of 56% of mice in the combination group up to 60 days post treatment. CONCLUSION: [225Ac]Ac-FAPI-46 efficacy is correlated with tumoral FAP expression levels and can restore responsiveness to PD-1 ICB. These data illustrate that careful patient selection based on target expression and rationally designed combination therapies are critically important to maximize the therapeutic impact of FAP-targeting radioligands.

Biocompatible CaCO3 nanoclusters were prepared by using a simple biomineralization technique. Employing CaCO3 nanoclusters in breast cancer treatment provides an exciting avenue for theranostics, which merges precise imaging with individualized treatment plans. They were highly suitable for improving the efficacy and precision of breast cancer detection and therapy with minimal adverse effects due to their biocompatibility, controlled drug release, pH sensitivity, and adaptability. In our current study, we proposed a palbociclib (PBB)-loaded fluorescent calcium nanocluster-based redox-sensitive drug delivery system for efficient breast cancer imaging and therapy. The developed nanoparticles were analyzed for their morphology and various physicochemical properties. The particle sizes of the formulated FNC-PBB-CS-NPs (nonredox-sensitive) and FNC-PBB-CS-SS-NPs (redox-sensitive) nanoparticles were 150.2 ± 2.1 and 160.4 ± 1.4 nm, respectively. The zeta potential of nonredox-sensitive nanoparticles was measured to be +17.12 ± 1.34 mV, while the zeta potential of redox-sensitive nanoparticles was +14.32 ± 1.17 mV. The entrapment efficiencies of FNC-PBB-CS-NPs and FNC-PBB-CS-SS-NPs were determined to be 88.74 ± 2.34 and 89.26 ± 1.21%, respectively. FNC-PBB-CS-SS-NPs demonstrated quicker drug release at acidic pH compared to FNC-PBB-CS-NPs. The cytotoxicity assay conducted on MCF-7 and T-47D cells indicated that FNC-PBB-CS-NPs and FNC-PBB-CS-SS-NPs exhibited greater cytotoxicities than free PBB. Furthermore, the Hoechst/PI dual-staining experiment demonstrated the superior activity of FNC-PBB-CS-SS-NPs over FNC-PBB-CS-NPs and free PBB. Ultrasound/photoacoustic imaging revealed that FNC-PBB-CS-SS-NPs effectively reduced tumor size, hypoxic tumor regions, and tumor vascularity compared to FNC-PBB-CS-NPs and free PBB. Additionally, in vivo optical imaging showed that the FNC-PBB-CS-SS-NPs accumulated more specifically in tumors than the other formulations. [ABSTRACT FROM AUTHOR]

The human retina is a fragile and sophisticated light-sensitive tissue in the central nervous system. Unhealthy retinas can cause irreversible visual deterioration and permanent vision loss. Effective therapeutic strategies are restricted to the treatment or reversal of these conditions. In recent years, nanoscience and nanotechnology have revolutionized targeted management of retinal diseases. Pharmaceuticals, theranostics, regenerative medicine, gene therapy, and retinal prostheses are indispensable for retinal interventions and have been significantly advanced by nanomedical innovations. Hence, this review presents novel insights into the use of versatile nanomaterial-based nanocomposites for frontier retinal applications, including non-invasive drug delivery, theranostic contrast agents, therapeutic nanoagents, gene therapy, stem cell-based therapy, retinal optogenetics and retinal prostheses, which have mainly been reported within the last 5 years. Furthermore, recent progress, potential challenges, and future perspectives in this field are highlighted and discussed in detail, which may shed light on future clinical translations and ultimately, benefit patients with retinal disorders. [ABSTRACT FROM AUTHOR]

It is urgent to exploit multifunctional materials and combined approaches for efficient antitumor effects. Copper-based metal–organic frameworks (Cu-MOFs) have excellent performances in catalysis, biocompatibility, photothermal conversion, and regulate metabolism, which make them attract more and more attention in antitumor application. Therefore, in this review, representative ligands, synthetic methods, antitumor mechanism, and antitumor applications of Cu-MOFs were provided. Special emphasis is placed on the recent antitumor applications of Cu-MOFs in drug carriers, antitumor therapy, tumor imaging, and theranostic, which are summarized with examples. Finally, we presented the dilemma faced by Cu-MOFs and offered a new perspective for future antitumor application. Hopefully, this review may serve as a reference for further development and application of Cu-MOFs. [ABSTRACT FROM AUTHOR]

In inflammatory diseases or following an injury, dysregulated inflammation is a common driver of pain and tissue damage. Macrophages are immune cells that contribute to the initiation, maintenance, and resolution of inflammation due to their phenotypic plasticity in response to signals from inflammatory microenvironments. Macrophages infiltrate and polarize toward a pro-inflammatory phenotype (M1-like), thereby increasing the severity of inflammation. Therefore, we aimed to suppress the pro-inflammatory activity of M1-like macrophages and decrease their infiltration at the site of inflammatory insult to resolve tissue inflammation. To achieve this, we developed a theranostic curcumin-loaded nanoemulsion platform that delivers a low dose of curcumin, a known anti-inflammatory phytochemical, to macrophages and allows in vivo tracking of macrophages by near-infrared fluorescence (NIRF) imaging technique. In vitro, we showed that curcumin-loaded nanoemulsion suppressed polarization of macrophages towards M1-like phenotype, consequently decreasing the release of pro-inflammatory cytokines and mediators like IL-6, IL- TNF- , and nitric oxide (NO). Furthermore, curcumin-loaded nanoemulsion increased the level of IL-10, an anti-inflammatory cytokine, and protected macrophages against ferroptosis compared to drug-free nanoemulsion. In a rodent model of Complete Freund's adjuvant (CFA)-induced inflammation, we demonstrated that infiltrating macrophages sequestered curcumin-loaded nanoemulsion droplets and acted as cellular drug depots at the site of inflammation. This consequently decreased macrophage infiltration at the CFA-induced inflammation site in both sexes compared to drug-free nanoemulsion, as demonstrated by NIRF imaging, H&E staining, and immunofluorescence. Taken together, our results indicated that the anti-inflammatory efficacy of curcumin was significantly improved when directly delivered to pro-inflammatory macrophages via theranostic nanoemulsion. This work opens an avenue for exploring theranostic nanoemulsions as a platform for delivering natural anti-inflammatory products for immune modulation. [ABSTRACT FROM AUTHOR]

In this study, DOX (Doxorubicin) and Fe3O4 magnetic nanocrystals (SPIONs (Superparamagnetic iron oxide nanocrystals)) were encapsulated in the PLGA-PEG: poly(lactide-co-glycolide)-b-poly(ethylene glycol) nanoparticles for theranostic purposes. The final prepared formulation which is called NPs (Nanoparticles) exhibited a particle size with a mean diameter of ~ 209 nm and a sufficient saturation magnetization value of 1.65 emu/g. The NPs showed faster DOX release at pH 5.5 compared to pH 7.4. Also, the cytotoxicity effect of NPs increased compared to Free-DOX alone in C6 glioma cancer cells. For in vivo investigations, the 2.2 Kg rabbits were injected with NPs formulations via a central articular anterior vein in their ears. Furthermore, the images of rabbit organs were depicted via MR (Magnetic resonance) and fluorescent imaging techniques. A negative contrast (dark signal) was observed in T2 (Relaxation Time) weighted MR images of IV (Intravenously)-injected rabbits with NPs compared to the control ones. The organ's florescent images of NPs-injected rabbits showed a high density of red color related to the accumulation of DOX in liver and kidney organs. These data showed that the NPs have no cytotoxicity effect on the heart. Also, the results of histopathological tests of different organs showed that the groups receiving NPs and Free-DOX were almost similar and no significant difference was seen, except for the cardiac tissue in which the pathological effects of NPs were significantly less than the Free-DOX. Additionally, pharmacokinetic studies were also conducted at the sera and whole bloods of IV-injected rabbits with NPs and Free-DOX. The pharmacokinetic parameters showed that NPs could enhance the DOX retention in the serum compared to the Free-DOX. Altogether, we aimed to produce a powerful delivery nanosystem for its potential in dual therapeutic and diagnostic applications which are called theranostic agents. [ABSTRACT FROM AUTHOR]

Theranostics is a way of treating illness that blends medicine with testing. Specific characteristics should be present in the best theranostic agents for cancer: (1) the drugs should be safe and non-toxic; (2) they should be able to treat cancer selectively; and (3) they should be able to build up only in the cancerous tissue. Liposomes (LPs) are one of the most efficient drug delivery methods based on nanotechnology. Stealth LPs and commercial LPs have recently had an impact on cancer treatment. Using the valuable information from each imaging technique, along with the multimodality imaging functionality of liposomal therapeutic agents, makes them very appealing for personalized monitoring of how well therapeutic drugs are working against cancer in vivo and for predicting how well therapies will work. On the other hand, their use as nanoparticle delivery systems is currently in the research and development phase. Nanoscale delivery system innovation has made LP-nanoparticle hybrid structures very useful for combining therapeutic and imaging methods. LP-hybrid nanoparticles are better at killing cancer cells than their LP counterparts, making them excellent options for in vivo and in vitro drug delivery applications. Hybrid liposomes (HLs) could be used in the future as theranostic carriers to find and treat cancer targets. This would combine the best features of synthetic and biological drug delivery systems. Overarchingly, this article provided a comprehensive overview of the many LP types used in cancer detection, therapy, and theranostic analysis. An evaluation of the pros and cons of the many HLs types used in cancer detection and treatment has also been conducted. The study also included recent and significant research on HLs for cancer theranostic applications. We conclude by outlining the potential benefits and drawbacks of this theranostic approach to the concurrent detection and treatment of different malignancies, as well as its prospects. [ABSTRACT FROM AUTHOR]

Despite intensive clinical and scientific efforts, the mortality rate of sepsis remains high due to the lack of precise biomarkers for patient stratification and therapeutic guidance. Interleukin 40 (IL-40), a novel cytokine with immune regulatory functions in human diseases, was elevated at admission in two independent cohorts of patients with sepsis. High levels of secreted IL-40 in septic patients were positively correlated with PCT, CRP, lactate (LDH), and Sequential Organ Failure Assessment (SOFA) scores, in which IL-40 levels were used to stratify the early death of critically ill patients with sepsis. Moreover, genetic knockout of IL-40 (IL-40−/−) improved outcomes in mice with experimental sepsis, as evidenced by attenuated cytokine storm, multiple-organ failure, and early mortality, compared with those of wild-type (WT) mice. Mechanistically, single-cell RNA sequencing (scRNA-seq) and bulk RNA sequencing (RNA-seq) have revealed that S100A8/9hi neutrophil influx into the peritoneal cavity along with neutrophil extracellular trap (NETs) formation accounts predominantly for the IL-40-mediated worsening of sepsis outcomes. Clinically, the IL-40 level was positively correlated with the NET-related MPO/dsDNA ratio in septic patients. Finally, with antibiotics (gentamycin), genetic knockout of IL-40 prevented polymicrobial sepsis fatalities more efficiently than without gentamycin treatment. In summary, these data reveal a novel prognostic strategy for sepsis and that IL-40 may serve as a novel therapeutic target for sepsis. [ABSTRACT FROM AUTHOR]

Polymer microbubbles have garnered broad interest as potential theranostic agents. However, the capabilities of polymer MBs can be greatly enhanced, particularly regarding the imaging performance and functional versatility of the platform. This study investigates integrating fluorescent carbon nanodots within polylactic acid (PLA) microbubbles. First, the formulations are characterized by their size, microbubble counts, zeta potential, and resonance frequency. Then, the fluorescence capabilities, nanoparticle loading, and acoustic capabilities are examined. Unmodified (U-), carboxylated (C-), and aminated graphene quantum dots (A-GQDs) were separately suspended and synthesized at a 2% w/w ratio with PLA in the organic phase of the water/oil/water double emulsion process. The new microbubbles were characterized using an AccuSizer, Zetasizer, scanning electron microscopy, fluorescence microscopy and fluorimetry, a custom-built acoustic setup, and clinical ultrasound. The GQD microbubbles were sized between 1.4 and 1.9 µm (U = 1.90, C = 1.44, A = 1.72, Unloaded = 2.02 µm). The U-GQD microbubble exhibited a higher bubble concentration/mg PLA (p <.05) and the A-GQD microbubbles exhibited the greatest shift in zeta potential. Electron microscopy revealed smooth surfaces and a spherical shape, showing that the nanoparticle addition was not deleterious. The A-GQD microbubbles were specifically detectable using DAPI-filtering with fluorescence microscopy and had the highest TRITC-filtered fluorescence. The C-GQD microbubbles had the highest loading efficiency at 59.4% (p <.05), and the lowest max acoustic enhancement at 5 MHz (U = 19.8, C = 17.6, A = 18.9, Unloaded = 18.5 dB; p <.05). Additionally, all microbubbles were visible and susceptible to inertial cavitation utilizing clinical ultrasound. The A-GQDs showed promise toward improving the theranostic capabilities of the microbubble platform. They have imbued the most advantageous fluorescence capability and slightly improved backscatter enhancement while retaining all the necessary capabilities of an ultrasound contrast agent. Future studies will investigate the coloading potential of A-GQDs and drug within microbubbles. [ABSTRACT FROM AUTHOR]

Ocular cystinosis is a disease in which accumulated cystine crystals cause damage to the eyes, necessitating timely treatment and ongoing monitoring of cystine levels. The current treatment involves frequent administration of cysteamine eye drops, which suffer from low bioavailability and can lead to drug toxicity, making it essential to prescribe an appropriate dosage based on the patient's condition. Additionally, cystine crystal levels are typically assessed subjectively via slit-lamp examination, requiring frequent clinical visits and causing discomfort for the patient. In this study, we propose a theranostic contact lens that simultaneously performs therapy and diagnosis on a single platform utilizing gold nanoparticles (GNPs). The binding interactions between GNPs and cystine were confirmed in solution, and thermodynamic analysis further elucidated the bonding force between the two substances. With a comprehensive understanding of these interactions, we investigated the potential of the theranostic GNP-loaded contact lens (GNP-CL). Upon exposure to various concentrations of cystine, the GNP-CL demonstrated distinct color changes, transitioning from red to blue. This color shift enabled quantitative monitoring of cystine levels. The treatment efficacy was validated by confirming a reduction in cystine concentration following the reaction. This platform has the potential to improve disease management in ocular cystinosis by reducing the reliance on cysteamine and offering an objective self-monitoring tool that does not require specialized equipment. [ABSTRACT FROM AUTHOR]

Abstract Global mortality data indicates cancer as the second-leading cause of death worldwide. Therefore, there’s a pressing need to innovate effective treatments to address this significant medical and societal challenge. In recent years, X-ray-induced photodynamic therapy (X-PDT) has emerged as a promising advancement, revolutionizing traditional photodynamic therapy (PDT) for deeply entrenched malignancies by harnessing penetrating X-rays as external stimuli. Recent developments in X-ray photodynamic therapy have shown a trend toward minimizing radiation doses to remarkably low levels after the proof-of-concept demonstration. Early detection and real-time monitoring are crucial aspects of effective cancer treatment. Sophisticated X-ray imaging techniques have been enhanced by the introduction of X-ray luminescence nano-agents, alongside contrast nanomaterials based on X-ray attenuation. X-ray luminescence-based in vivo imaging offers excellent detection sensitivity and superior image quality in deep tissues at a reasonable cost, due to unhindered penetration and unimpeded auto-fluorescence of X-rays. This review emphasizes the significance of X-ray responsive theranostics, exploring their mechanism of action, feasibility, biocompatibility, and promising prospects in imaging-guided therapy for deep-seated tumors. Additionally, it discusses promising applications of X-PDT in treating breast cancer, liver cancer, lung cancer, skin cancer, and colorectal cancer. Graphical Abstract

Prostate cancer ranks as the fourth most common cancer among men, with approximately 1.47 million new cases reported annually. The emergence of prostate-specific membrane antigen (PSMA) as a critical biomarker has revolutionized the diagnosis and treatment of prostate cancer. Recent advancements in low-molecular-weight PSMA inhibitors, with their diverse chemical structures and binding properties, have opened new avenues for research and therapeutic applications in prostate cancer management. These novel agents exhibit enhanced tumor targeting and specificity due to their small size, facilitating rapid uptake and localization at the target site while minimizing the retention in non-target tissues. The primary aim of this study is to evaluate the potential of low-molecular-weight PSMA inhibitors labeled with radioisotopes as theranostic agents for prostate cancer. This includes assessing their efficacy in targeted imaging and therapy and understanding their pharmacokinetic properties and mechanisms of action. This study is a literature review focusing on in vitro and clinical research data. The in vitro studies utilize PSMA-targeted radioligands labeled with radioisotopes to assess their binding affinity, specificity, and internalization in prostate cancer cell lines. Additionally, the clinical studies evaluate the safety, effectiveness, and biodistribution of radiolabeled PSMA ligands in patients with advanced prostate cancer. The findings indicate promising outcomes regarding the safety and efficacy of PSMA-targeted radiopharmaceuticals in clinical settings. The specific accumulation of these agents in prostate tumor lesions suggests their potential for various applications, including imaging and therapy. This research underscores the promise of radiopharmaceuticals targeting PSMA in advancing the diagnosis and treatment of prostate cancer. These agents improve diagnostic accuracy and patients' outcomes by enhancing imaging capabilities and enabling personalized treatment strategies. [ABSTRACT FROM AUTHOR]

Simple Summary: The growing interest in the development of fibroblast activation protein (FAP)-targeted radiotheranostics is sustained by their potential applicability for precision therapy of epithelial malignancies. However, tumor uptake retention and effective clearance from normal tissues remain to be addressed for further translational planning and clinical use. In this work, we report an effective strategy to present an FAP-targeting moiety on a bifunctional chelator scaffold (BFS) reported by us to optimize the design of FAP-targeted copper radiopharmaceuticals. Biological studies using clinically relevant in vitro and in vivo models demonstrate that the multi-presentation approach enabled by the BFS has great potential to achieve the desired therapeutic index for FAP-targeted radiotheranostics. Background: Fibroblast activation protein (FAP)-targeted theranostic radiopharmaceuticals have shown desired tumor-to-background organ selectivity due to the ubiquitous presence of FAP within the tumor microenvironment. However, suboptimal tumor retention and fast clearance have hindered their use to deliver effective cancer therapies. With well-documented FAP-targeting moieties and linkers appending them to optimal chelators, the development of copper radiopharmaceuticals has attracted considerable interest, given the fact that an ideal theranostic pair of copper radionuclides (64Cu: t1/2 = 12.7 h; 17.4% β+; Eβ+max = 653 keV and 67Cu: t1/2 = 2.58 d; 100% β−; Eβ−max = 562 keV) are available. Herein, we report our design, synthesis, and comparative evaluation of monovalent and divalent FAP-targeted theranostic conjugates constructed from our previously reported bifunctional chelator scaffold (BFS) based on 1,4,8,11-tetraaza-bicyclo [6.6.2]hexadecane-4,11-diacetic acid (CB-TE2A), which forms the most stable complex with Cu(II). Methods: After synthesis and characterization, the monovalent and divalent conjugates were radiolabeled with 64Cu for in vitro cell assays, followed by in vivo positron emission tomography (PET) imaging evaluation in relevant mouse models. Results: Both 64Cu-labeled conjugates showed high in vitro stability and anticipated FAP-mediated cell binding and internalization. The divalent one showed significantly higher FAP-specific tumor uptake than its monovalent counterpart. Conclusions: Our results demonstrate that the BFS-based multivalent approach can be practically used to generate FAP-targeted radiotheranostic agents for effective cancer diagnosis and treatment. [ABSTRACT FROM AUTHOR]

Since iron oxide nanoparticles (IONPs) are expected to be important tools in medical care, patients with inflammatory diseases will be increasingly exposed to IONPs in the future. Here, we assessed the short- and long-term impact of polysaccharide (PS)-coated IONPs on mice with persistent systemic inflammation. To this end, PS-IONPs were synthetized by a core-shell method. Mice were regularly injected with sterile zymosan. PS-IONPs were administered intravenously. At specific nanoparticle injection post-observation times, the organ iron concentration was determined via atomic absorption spectrometry, the expression of NF-κB-related proteins using SDS-PAGE and immunoblotting, as well as body weight and haemograms. Finally, the mediator secretion in blood plasma was analysed using multiplexed ELISA. Our data show that PS-IONPs induce short-term changes of iron levels in distinct organs and of NF-κB p65 and p50, p100, COX-2s, and Bcl-2 protein expression in the liver of inflammatory stressed mice. In the long term, there was an attenuated expression of several NF-κB–related proteins and attenuated features of inflammatory-based anaemia in blood. PS-IONPs weakly influenced the blood cytokine levels. PS-IONPs are biocompatible, but given their short-term pro-inflammatory impact, they should prospectively be applied with caution in patients with inflammatory diseases of the liver. [ABSTRACT FROM AUTHOR]

Cell-secreted nanovesicles of endosomal origin, called exosomes, are vital for mediating intracellular communication. As local or distal transporters of intracellular cargo, they reflect the unique characteristics of secretory cells and establish cell-specific interactions via characteristic surface proteins and receptors. With the advent of rapid isolation, purification, and identification techniques, exosomes have become an attractive choice for disease diagnosis (exosomal content as biomarkers), cell-free therapy, and tissue regeneration. Mesenchymal stem cell (MSC)-derived exosomes (MSC-exosomes) display angiogenic, immune-modulatory, and other therapeutic effects crucial for cytoprotection, ischemic wound repair, myocardial regeneration, etc. The primary focus of this review is to highlight the widespread application of MSC-exosomes in therapeutics, theranostics, and tissue regeneration. After a brief introduction of exosome properties, biogenesis, isolation, and functions, recent studies on therapeutic and regenerative applications of MSC-exosomes are described, focusing on bone, cartilage, periodontal, cardiovascular, skin, and nerve regeneration. Finally, the review highlights the theranostic potential of exosomes followed by challenges, summary, and outlook. [ABSTRACT FROM AUTHOR]

Chitosan, a biocompatible and biodegradable polymer, has attracted significant interest in the development of nanoformulations for targeted drug delivery and therapeutic applications. The versatility of chitosan lies in its modifiable functional groups, which can be tailored to diverse applications. Nanoparticles derived from chitosan and its derivatives typically exhibit a positive surface charge and mucoadhesive properties, enabling them to adhere to negatively charged biological membranes and gradually release therapeutic agents. This comprehensive review investigates the manifold roles of chitosan-based nanocarriers, ranging from preclinical research to theranostic applications and clinical trials, across a spectrum of diseases, including neurological disorders, cardiovascular diseases, cancer, wound healing, gastrointestinal disorders, and pulmonary diseases. The exploration starts with an overview of preclinical studies, emphasizing the potential of chitosan-based nanoformulations in optimizing drug delivery, improving therapeutic outcomes, and mitigating adverse effects in various disease categories. Advancements in theranostic applications of chitosan-based nanoformulations highlight their adaptability to diverse diseases. As these nanoformulations progress toward clinical translation, this review also addresses the regulatory challenges associated with their development and proposes potential solutions. [ABSTRACT FROM AUTHOR]

Background: CI-8993 is a fully human IgG1κ monoclonal antibody (mAb) that binds specifically to immune checkpoint molecule VISTA (V-domain Ig suppressor of T-cell activation). Phase I safety has been established in patients with advanced cancer (NCT02671955). To determine the pharmacokinetics and biodistribution of CI-8993 in patients, we aimed to develop 89Zr-labelled CI-8993 and validate PET imaging and quantitation in preclinical models prior to a planned human bioimaging trial. Methods: CI-8993 and human isotype IgG1 control were conjugated to the metal ion chelator p-isothiocyanatobenzyl-desferrioxamine (Df). Quality of conjugates were assessed by SE-HPLC, SDS-PAGE, and FACS. After radiolabelling with zirconium-89 (89Zr), radioconjugates were assessed for radiochemical purity, immunoreactivity, antigen binding affinity, and serum stability in vitro. [89Zr]Zr-Df-CI-8993 alone (1 mg/kg, 4.6 MBq) or in combination with 30 mg/kg unlabelled CI-8993, as well as isotype control [89Zr]Zr-Df-IgG1 (1 mg/kg, 4.6 MBq) were assessed in human VISTA knock-in female (C57BL/6 N-Vsirtm1.1(VSIR)Geno, huVISTA KI) or control C57BL/6 mice bearing syngeneic MB49 bladder cancer tumours; and in BALB/c nu/nu mice bearing pancreatic Capan-2 tumours. Results: Stable constructs with an average chelator-to-antibody ratio of 1.81 were achieved. SDS-PAGE and SE-HPLC showed integrity of CI-8993 was maintained after conjugation; and ELISA indicated no impact of conjugation and radiolabelling on binding to human VISTA. PET imaging and biodistribution in MB49 tumour-bearing huVISTA KI female mice showed specific localisation of [89Zr]Zr-Df-CI-8993 to VISTA in spleen and tumour tissues expressing human VISTA. Specific tumour uptake was also demonstrated in Capan-2 xenografted BALB/c nu/nu mice. Conclusions: We radiolabelled and validated [89Zr]Zr-Df-CI-8993 for specific binding to huVISTA in vivo. Our results demonstrate that 89Zr-labelled CI-8993 is now suitable for targeting and imaging VISTA expression in human trials. [ABSTRACT FROM AUTHOR]

Purpose: Fibroblast Activation Protein (FAP) is an emerging theranostic target that is highly expressed on cancer-associated fibroblasts and on certain tumor cells including sarcoma. We investigated the anti-tumor efficacy of [225Ac]Ac-FAPI-46 as monotherapy or in combination with immune checkpoint blockade (ICB) in immunocompetent murine models of sarcoma sensitive or resistant to ICB. Methods: [68Ga]Ga- and [225Ac]Ac-FAPI-46 were tested in subcutaneous FAP+ FSA fibrosarcoma bearing C3H/Sed/Kam mice. The efficacy of up to three cycles of 60 kBq [225Ac]Ac-FAPI-46 was evaluated as monotherapy and in combination with an anti-PD-1 antibody. Efficacy of [225Ac]Ac-FAPI-46 and/or ICB was further compared in FAP-overexpressing FSA (FSA-F) tumors that were sensitive to ICB or rendered ICB-resistant by tumor-induction in the presence of Abatacept. Results: [225Ac]Ac-FAPI-46 was well tolerated up to 3 × 60 kBq but had minimal effect on FSA tumor growth. The combination of three cycles [225Ac]Ac-FAPI-46 and ICB resulted in growth delay in 55% of mice (6/11) and partial tumor regression in 18% (2/11) of mice. In FSA-F tumors with FAP overexpression, both [225Ac]Ac-FAPI-46 and ICB were effective without additional benefits from the combination. In locally immunosuppressed and ICB resistant FAP-F tumors, however, [225Ac]Ac-FAPI-46 restored responsiveness to ICB, resulting in significant tumor regression and tumor-free survival of 56% of mice in the combination group up to 60 days post treatment. Conclusion: [225Ac]Ac-FAPI-46 efficacy is correlated with tumoral FAP expression levels and can restore responsiveness to PD-1 ICB. These data illustrate that careful patient selection based on target expression and rationally designed combination therapies are critically important to maximize the therapeutic impact of FAP-targeting radioligands. [ABSTRACT FROM AUTHOR]

Background: Cancer is one of the leading causes of death worldwide. The tumor microenvironment makes the tumor difficult to treat, favoring drug resistance and the formation of metastases, resulting in death. Methods: Stimuli-responsive nanoparticles have shown great capacity to be used as a powerful strategy for cancer treatment, diagnostic, as well as theranostic. Nanocarriers are not only able to respond to internal stimuli such as oxidative stress, weakly acidic pH, high temperature, and the high expression of particular enzymes, but also to external stimuli such as light and paramagnetic characteristics to be exploited. Results: In this work, stimulus-responsive nanocarriers functionalized with arginine-glycine-aspartic acid (Arg-Gly-Asp) sequence as well as mimetic sequences with the capability to recognize integrin receptors are analyzed. Conclusions: This review highlights the progress that has been made in the development of new nanocarriers, capable of responding to endogenous and exogenous stimuli essential to combat cancer. [ABSTRACT FROM AUTHOR]

Background: Superparamagnetic properties and excitation independence have been incorporated into carbon-decorated manganese ferrite nanodots (MnFe@C) to introduce an economical and safer multimodal agent for use in both T1-T2 MRI and fluorescence-based imaging to replace the conventional highly toxic heavy metal contrast agents. Methods: The surface conjugation of 8-anilino-1-naphthalenesulfonate (ANS) to MnFe@C nanodots (ANS-MnFe@C) enhances both longitudinal and transverse MRI relaxation, improves fluorescence for optical imaging, and increases protein detection sensitivity, showing higher multimodal efficacy in terms of molar relaxivity, radiant efficiencies, and fluorescence sensitivity compared to MnFe@C. Results: The band gap energy was determined using Tauc's equation to be 3.32 eV, while a 72% quantum yield demonstrated that ANS-MnFe@C was highly fluorescent, with the linear range and association constant calculated using the Stern–Volmer relation. The synthesized ANS-MnFe@C demonstrated excellent selectivity and sensitivity for bovine serum albumin (BSA), with a nanomolar detection limit of 367.09 nM and a broad linear range from 0.015 to 0.225 mM. Conclusions: In conclusion, ANS-MnFe@C holds ease of fabrication, good biocompatibility, as assessed in A375 cells, and an effective pH-sensitive doxorubicin release profile to establish anticancer activity in lung cancer cell line (A549), highlighting its potential as an affordable therapeutic agent for multimodal imaging, drug delivery, and protein sensing. [ABSTRACT FROM AUTHOR]

Integrins, an important superfamily of cell adhesion receptors, play an essential role in cancer progression, metastasis, and angiogenesis, establishing them as prime targets for both diagnostic and therapeutic applications. Despite their significant potential, integrin-targeted therapies have faced substantial challenges in clinical trials, including variable efficacy and unmet high expectations. Nevertheless, the consistent expression of integrins on tumor and stromal cells underscores their ongoing relevance and potential. Traditional RGD-based imaging and therapeutic agents have faced limitations, such as inconsistent target expression and rapid systemic clearance, which have reduced their effectiveness. To overcome these challenges, recent research has focused on advancing RGD-based strategies and exploring innovative solutions. This review offers a thorough analysis of the latest developments in the RGD–integrin field, with a particular focus on addressing previous limitations. It delves into new dual-targeting approaches and cutting-edge RGD-based agents designed to improve both tumor diagnosis and therapeutic outcomes. By examining these advancements, this review illuminates new pathways for enhancing the specificity and efficacy of integrin-targeted therapies, paving the way for more effective cancer diagnosis and treatment strategies. [ABSTRACT FROM AUTHOR]

Despite the advent of various medical interventions for cancer treatment, the disease continues to pose a formidable global health challenge, necessitating the development of new therapeutic approaches for more effective treatment outcomes. Photodynamic therapy (PDT), which utilizes light to activate a photosensitizer to produce cytotoxic reactive oxygen species (ROS) for eradicating cancer cells, has emerged as a promising approach for cancer treatment due to its high spatiotemporal precision and minimal invasiveness. However, the widespread clinical use of PDT faces several challenges, including the inefficient production of ROS in the hypoxic tumor microenvironment, the limited penetration depth of light in biological tissues, and the inadequate accumulation of photosensitizers at the tumor site. Over the past decade, there has been increasing interest in the utilization of photofunctional transition metal complexes as photosensitizers for PDT applications due to their intriguing photophysical and photochemical properties. This review provides an overview of the current design strategies used in the development of transition metal complexes as innovative phototherapeutics, aiming to address the limitations associated with PDT and achieve more effective treatment outcomes. The current challenges and future perspectives on the clinical translation of transition metal complexes are also discussed. [ABSTRACT FROM AUTHOR]

Introduction: The expression of alpha-five beta-three (αVβ3) integrins is upregulated in various malignancies undergoing angiogenesis. The development of integrin antagonists as diagnostic probes makes the αVβ3 integrin a suitable candidate for targeting tumor angiogenesis. The goal of this study was to optimize the radiolabeling and evaluate the potential of conjugated integrin antagonist carbamate (IAC), a peptidomimetic, as a theranostic radiopharmaceutical for targeting tumor angiogenesis. Methodology: Radiolabeling of DOTAGA [2,2′,2"–{10-(2,6-dioxotetrahydro-2H-pyran-3-yl)−1,4,7,10-tetraazacyclododecane-1,4,7-triyl} triacetic-acid]-IAC with [68Ga]Ga, [177Lu]Lu, and [225Ac]Ac was optimized. The binding affinity (Kd) of DOTAGA-IAC for the αVβ3 receptor and cancer cell lines was quantified. The biodistribution studies were conducted in healthy Wistar rats. Dosimetry analysis was performed on [177Lu]Lu-DOTAGA-IAC distribution data. A pilot study of [68Ga]Ga-DOTAGA-IAC and [18F]FDG Positron Emission Tomography (PET/CT) imaging was performed in five patients with histopathologically confirmed breast cancer. PET/CT findings were compared between [68Ga]Ga-DOTAGA-IAC and [18F]FDG in these patients. Results: Radiopharmaceuticals were prepared with high radiochemical purity (>99.9%). Kd and Bmax measurements were 15.02 nM and 417 fmol for αVβ3 receptor protein: 115.7 nM and 295.3 fmol for C6 glioma cells. Biodistribution studies in rats suggested the excretion via kidneys and partially through the hepatobiliary route. The effective dose of [177Lu]Lu-DOTAGA-IAC was found to be 0.17 mSv/MBq. The dynamic study in patients revealed the optimal imaging time to be 30–35 mins postadministration. Out of the cohort, [68Ga]Ga-DOTAGA-IAC detected the primary lesions in all five patients with a mean standard uptake value (SUVmax) of 3.94 ± 0.58 compared with [18F]FDG (SUVmax 13.8 ± 6.53). Conclusion: The study demonstrates that DOTAGA-IAC exhibits strong binding to αVβ3 integrin, positioning it as a promising PET agent for assessing primary and metastatic cancers. The outcomes from the pilot study suggest the potential of [68Ga]Ga-DOTAGA-IAC PET/CT in breast carcinoma diagnosis. While recognizing the theranostic potential of DOTAGA-IAC for αVβ3 integrin-expressing tumors, further clinical investigations are warranted to comprehensively assess therapeutic efficacy. [ABSTRACT FROM AUTHOR]

Global mortality data indicates cancer as the second-leading cause of death worldwide. Therefore, there's a pressing need to innovate effective treatments to address this significant medical and societal challenge. In recent years, X-ray-induced photodynamic therapy (X-PDT) has emerged as a promising advancement, revolutionizing traditional photodynamic therapy (PDT) for deeply entrenched malignancies by harnessing penetrating X-rays as external stimuli. Recent developments in X-ray photodynamic therapy have shown a trend toward minimizing radiation doses to remarkably low levels after the proof-of-concept demonstration. Early detection and real-time monitoring are crucial aspects of effective cancer treatment. Sophisticated X-ray imaging techniques have been enhanced by the introduction of X-ray luminescence nano-agents, alongside contrast nanomaterials based on X-ray attenuation. X-ray luminescence-based in vivo imaging offers excellent detection sensitivity and superior image quality in deep tissues at a reasonable cost, due to unhindered penetration and unimpeded auto-fluorescence of X-rays. This review emphasizes the significance of X-ray responsive theranostics, exploring their mechanism of action, feasibility, biocompatibility, and promising prospects in imaging-guided therapy for deep-seated tumors. Additionally, it discusses promising applications of X-PDT in treating breast cancer, liver cancer, lung cancer, skin cancer, and colorectal cancer. [ABSTRACT FROM AUTHOR]

Delivery of diagnostic drugs via nanobubbles (NBs) has shown to be an emerging field of study. Due to their small size, NBs may more easily travel through constricted blood vessels and precisely target certain bodily parts. NB is considered the major treatment for cancer treatment and other diseases which are difficult to diagnose. The field of NBs is dynamic and continues to grow as researchers discover new properties and seek practical applications in various fields. The predominant usage of NBs in novel drug delivery is to enhance the bioavailability, and controlled drug release along with imaging properties NBs are important because they may change interfacial characteristics including surface force, lubrication, and absorption. The quick diffusion of gas into the water was caused by a hypothetical film that was stimulated and punctured by a strong acting force at the gas/water contact of the bubble. In this article, various prominent aspects of NBs have been discussed, along with the long-acting nature, and the theranostical aspect which elucidates the potential marketed drugs along with clinical trial products. The article also covers quality by design aspects, different production techniques that enable method-specific therapeutic applications, increasing the floating time of the bubble, and refining its properties to enhance the prepared NB’s quality. NB containing both analysis and curing properties makes it special from other nano-carriers. This work includes all the possible methods of preparing NB, its application, all marketed drugs, and products in clinical trials.

64Cu is gaining recognition not only for its diagnostic capabilities in nuclear medical imaging but also for its therapeutic and theranostic potential. The simultaneous βˉ and Auger emissions of 64Cu can be utilized to induce a therapeutic effect on cancerous lesions. The finding of the exceptional biodistribution characteristics of the radionuclide 64Cu, when administered as basic copper ions, has highlighted its potential therapeutic application in cancer treatment. Preclinical and clinical research on the effectiveness of [64Cu]CuCl2 as a theranostic radiopharmaceutical has commenced only in the past decade. Current clinical studies are increasingly demonstrating the high specificity and uptake of [64Cu]Cu2+ by malignant tissues during early cancer progression, indicating its potential for early cancer diagnosis across various organs. This short review aims to present the latest preclinical studies involving [64Cu]CuCl2, offering valuable insights for researchers planning new in vitro and in vivo studies to explore the theranostic potential of [64Cu]Cu2+. [ABSTRACT FROM AUTHOR]

Indocyanine green (ICG), the only near-infrared (NIR) dye approved for clinical use, has received increasing attention as a theranostic agent wherein diagnosis (fluorescence) is combined with therapy (phototherapy), but suffers rapid hepatic clearance, poor photostability, and limited accumulation at tumor sites. Here we report that dimerized ICG can self-assemble to form zwitterionic nanoparticles (ZN-dICG), which generate fluorescence self-quenching but exhibit superior photothermal and photodynamic properties over ICG. The zwitterionic moieties confer ZN-dICG an ultralow critical micelle concentration and high colloidal stability with low non-specific binding in vivo. In addition, ZN-dICG can respond to the over-generated reactive oxygen species (ROSs) and dissociate to restore NIR fluorescence of ICG, amplifying the sensitivity via albumin binding for low-background imaging of tumors. Following systemic administration, ZN-dICG accumulated in tumors of xenograft-bearing mice for imaging primary and metastatic tumors, and induced tumor ablation under laser irradiation. The discovery of ZN-dICG would contribute to the design of translational phototheranostic platform with high biocompatibility. Indocyanine green (ICG) has been extensively studied as a phototheranostic agent that combines imaging with phototherapies, but it suffers from rapid hepatic clearance, poor photostability, and limited accumulation at tumor sites. Here, we report a strategy to construct ICG dimers (ICG-tk-ICG) by conjugating two ICG molecules via a thioketal bond, which can self-assemble into zwitterionic nanoparticles (ZN-dICG) at ultralow critical micelle concentrations, exhibiting superior photothermal and photodynamic properties over ICG. ZN-dICG responds to the over-generated ROS in tumors and dissociates to restore the NIR fluorescence of ICG, enhancing the sensitivity via albumin binding for low-background imaging of tumors. This study offers a supramolecular strategy that may potentiate the clinical translation of ICG in imaging-guided cancer phototherapy. [Display omitted] [ABSTRACT FROM AUTHOR]

Background: Near-infrared II theranostic agents have gained great momentum in the research field of AD owing to the appealing advantages. Recently, an array of activatable NIR-II fluorescence probes has been developed to specifically monitor pathological targets of AD. Furthermore, various NIR-II-mediated nanomaterials with desirable photothermal and photodynamic properties have demonstrated favorable outcomes in the management of AD. Methods: We summerized amounts of references and focused on small-molecule probes, nanomaterials, photothermal therapy, and photodynamic therapy based on NIR-II fluorescent imaging for the diagnosis and treatment in AD. In addition, design strategies for NIR-II-triggered theranostics targeting AD are presented, and some prospects are also addressed. Results: NIR-II theranostic agents including small molecular probes and nanoparticles have received the increasing attention for biomedical applications. Meanwhile, most of the theranostic agents exhibited the promising results in animal studies. To our surprise, the multifunctional nanoplatforms also show a great potential in the diagnosis and treatment of AD. Conclusions: Although NIR-II theranostic agents showed the great potential in diagnosis and treatment of AD, there are still many challenges: 1) Faborable NIR-II fluorohpores are still lacking; 2) Biocompatibility, bioseurity and dosage of NIR-II theranostic agents should be further revealed; 3) New equipment and software associated with NIR-II imaging system should be explored. [ABSTRACT FROM AUTHOR]

Since the discovery of cisplatin's antitumoral activity and its approval as an anticancer drug, significant efforts have been made to enhance its physiological stability and anticancer efficacy and to reduce its side effects. With the rapid development of targeted and personalized therapies, and the promising theranostic approach, platinum drugs have found new opportunities in more sophisticated systems. Theranostic agents combine diagnostic and therapeutic moieties in one scaffold, enabling simultaneous disease monitoring, therapy delivery, response tracking, and treatment efficacy evaluation. In these systems, the platinum core serves as the therapeutic agent, while the functionalized ligand provides diagnostic tools using various imaging techniques. This review aims to highlight the significant role of platinum–based complexes in theranostic applications, and, to the best of our knowledge, this is the first focused contribution on this type of platinum compounds. This review presents a brief introduction to the development of platinum chemotherapeutic drugs, their limitations, and resistance mechanisms. It then describes recent advancements in integrating platinum complexes with diagnostic agents for both tumor treatment and monitoring. The main body is organized into three categories based on imaging techniques: fluorescence, positron emission tomography (PET), single–photon emission computed tomography (SPECT), and magnetic resonance imaging (MRI). Finally, this review outlines promising strategies and future perspectives in this evolving field. [ABSTRACT FROM AUTHOR]

Photothermal therapy (PTT) can overcome cancer treatment resistance by enhancing the cell membrane permeability, facilitating drug accumulation, and promoting drug release within the tumor tissue. Iron oxide nanoparticles (IONPs) have emerged as effective agents for PTT due to their unique properties and biocompatibility. Approved for the treatment of anemia, as MRI contrast agents, and as magnetic hyperthermia mediators, IONPs also offer excellent light-to-heat conversion and can be manipulated using external magnetic fields for targeted accumulation in specific tissue. Optimizing parameters such as the laser wavelength, power density, shape, size, iron oxidation state, functionalization, and concentration is crucial for IONPs' effectiveness. In addition to PTT, IONPs enhance other cancer treatment modalities. They improve tumor oxygenation, enhancing the efficacy of radiotherapy and photodynamic therapy. IONPs can also trigger ferroptosis, a programmed cell death pathway mediated by iron-dependent lipid peroxidation. Their magneto-mechanical effect allows them to exert a mechanical force on cancer cells to destroy tumors, minimizing the damage to healthy tissue. This review outlines strategies for the management of the photothermal performance and PTT efficiency with iron oxide nanoparticles, as well as synergies with other cancer therapies. [ABSTRACT FROM AUTHOR]

Aim: Nano-hydroxyapatite (nHA) is a good nanocarrier to load 223Ra, but the low specific activity (sp.act.) of 223Ra@nHA limits its application in medicine. Methods: We proposed a method for preparing nHA using PEG as a template, which significantly increases the sp.act of 223Ra@nHA and a new method to loaded 99mTc for in vivo tracking. Results: The nHA synthesized using PEG as a template was associated with higher sp.act for 223Ra in comparison to nHA with identical particle size and without PEG. The nHA load 99mTc-MDP was associated with higher labeling rate and stability in comparison to 99mTc. Conclusion: All these findings suggest that using PEG as a template and 99mTc-MDP could be the most effective of synthetic 223Ra/99mTc@nHA. Article highlights The excellent therapeutic effect of 223Ra in bone metastases prompted the exploration of nanomaterial labelled nuclide for enhancement of the efficacy of 223Ra in primary bone tumors treatment. A nanosystem for theranostic based on 223Ra and 99mTc-MDP labelled was developed, providing a potential new technology for in vivo tracer of 223Ra in tumor therapy. PEG@nHA nanoparticles have a particle size of 80–100 nm. The sp.act value of 223Ra is 74 kBq/mg, which is significantly higher than that of nHA(without) PEG with the same particle size (22.2kBq /mg). The 120-hour stability at different pH values indicated that the release rate of 223Ra from 223Ra@nHA was significantly increased under the acidic condition at pH 4.0, which might ensure the effective release of the drug at the tumor site. 223Ra@nHA has excellent stability, and the stability is ≥95% after 7 days in FBS and PBS. The labeling efficiency and stability of 99mTc@nHA were lower than that of 99mTc-MDP based nHA labeling method. Simultaneous labeling of 223Ra and 99mTc does not affect the loading capacity of nuclides and the stability after loading of nanomaterials. 223Ra/99mTcM@nHA nanoparticles have generated stronger cell death effect. [ABSTRACT FROM AUTHOR]

Prostate-specific membrane antigen (PSMA) has proven to be an important target for diagnostic imaging in prostate cancer. As PSMA is overexpressed on the surface of prostate cancer cells, numerous targeted PSMA ligands have been developed. The emergence of PSMA targeting based on small molecules, such as the PSMA-11 ligand (or PSMA-HBED-CC), has led to breakthroughs, such as [68Ga]Ga-PSMA-11, for positron emission tomography (PET) imaging of biochemically recurrent or metastatic castration-resistant prostate cancer (mCRPC). In addition, the recent approval of [177Lu]Lu-PSMA-617 for the treatment of adult patients with PSMA-positive mCRPC represents an important milestone in prostate cancer therapy. These advances underscore the growing confidence in the use of PSMA-targeted radiopharmaceuticals for the diagnosis and treatment of prostate cancer patients. PSMA-targeted radiopharmaceuticals have been shown to significantly impact treatment planning and clinical decision-making and facilitate the customisation of treatment regimens. [ABSTRACT FROM AUTHOR]

In this study, we address the critical need for advanced theranostic drug delivery systems by synthesizing and characterizing surface-functionalized superparamagnetic iron oxide nanoparticles (SPIONs). Acyclovir is an effective antiviral drug with poor water solubility leading to limitations in its administrations and effectivity. Our investigation into the drug-loading capacity of acyclovir reveals that surface-functionalized SPIONs with an average size of 8.1 nm exhibit a notable increase in drug-loading capacity proportional to drug concentration. Specifically, at drug concentrations of 752.21 μg, 1774.32 μg, and 3799.09 μg, we achieved loading efficiencies and capacities of 40.89%, 51.62%, and 50.14% respectively. Alongside, they have high biocompatibility as observed from the hemolysis assay and MTT assay. Moreover, the multifunctionality of these SPIONs extends beyond drug delivery, as they demonstrate high relaxivity suitable for magnetic resonance imaging (MRI) studies at remarkably low concentrations in the micromolar range. Specifically, the relaxivity value (r2) for the said SPIONs was calculated to 10.99 L/mmol−s which is higher than many commercially used iron oxide-based contrast agents. The multifunctional attributes of these SPIONs position them as versatile and easily customisable platform for diverse therapeutic molecules. This study not only underscores the feasibility of utilizing surface-modified SPIONs as efficient carriers for acyclovir or other therapeutic molecules but also paves the way for evaluating the feasibility of next-generation theranostic materials for biomedical applications. [ABSTRACT FROM AUTHOR]