Assessment of chitosan-coated zinc cobalt ferrite nanoparticle as a multifunctional theranostic platform facilitating pH-sensitive drug delivery and OCT image contrast enhancement.

Colorectal cancer (CC) is one of the most predominant malignancies in the world, with the current treatment regimen consisting of surgery, radiation therapy, and chemotherapy. Chemotherapeutic drugs, such as 5-fluorouracil (5-FU), have gained popularity as first-line antineoplastic agents against CC but have several drawbacks, including variable absorption through the gastrointestinal tract, inconsistent liver metabolism, short half-life, toxicological reactions in several organ systems, and others. Therefore, herein, we develop chitosan-coated zinc-substituted cobalt ferrite nanoparticles (CZCFNPs) for the pH-sensitive (triggered by chitosan degradation within acidic organelles of cells) and sustained delivery of 5-FU in CC cells in vitro. Additionally, the developed nanoplatform served as an excellent exogenous optical coherence tomography (OCT) contrast agent, enabling a significant improvement in the OCT image contrast in a CC tissue phantom model with a biomimetic microvasculature. Further, this study opens up new possibilities for using OCT for the non-invasive monitoring and/or optimization of magnetic targeting capabilities, as well as real-time tracking of magnetic nanoparticle-based therapeutic platforms for biomedical applications. Overall, the current study demonstrates the development of a CZCFNP-based theranostic platform capable of serving as a reliable drug delivery system as well as a superior OCT exogenous contrast agent for tissue imaging.

Six country vignettes: Strengthening radiotherapy and theranostics.

BACKGROUND: For cancer patient populations worldwide, the synchronous scale-up of diagnostics and treatments yields meaningful gains in survival and quality of life. Among advanced cancer therapies, radiotherapy (RT) and theranostics are key to achieving practical, high-quality, and personalized precision medicine - targeting disease manifestations of individual patients and broad populations, alike. Aiming to learn from one another across different world regions, the six country vignettes presented here depict both challenges and victories in de novo establishment or improvement of RT and theranostics infrastructure. METHODS: The International Atomic Energy Agency (IAEA) convened global RT and theranostics experts from diverse world regions and contexts to identify relevant challenges and report progress in their own six countries: Belgium, Brazil, Costa Rica, Jordan, Mongolia, and South Africa. These accounts are collated, compared, and contrasted herein. RESULTS: Common challenges persist which could be more strategically assessed and addressed. A quantifiable discrepancy entails personnel. The estimated radiation oncologists (ROs), nuclear medicine physicians (NMPs), and medical physicists (MPs for RT and nuclear medicine) per million inhabitants in the six collective countries respectively range between 2.69-38.00 ROs, 1.00-26.00 NMPs, and 0.30-3.45 MPs (Table 1), reflecting country-to-country inequities which largely match World Bank country-income stratifications. CONCLUSION: Established goals for RT and nuclear medicine advancement worldwide have proven elusive. The pace of progress could be hastened by enhanced approaches such as more sustainably phased implementation; better multinational networking to share lessons learned; routine quality and safety audits; as well as capacity building employing innovative, resource-sparing, cutting-edge technologic approaches. Bodies such as ministries of health, professional societies, and the IAEA shall serve critical roles in convening and coordinating more innovative RT and theranostics translational research, including expanding nuanced global database metrics to inform, reach, and potentiate milestones most meaningfully. POLICY SUMMARY: Aligned with WHO 25×25 NCDs target; WHA70.12 and WHA76.5 resolutions.

An MMP-2 Responsive Nanotheranostic Probe Enabled Synergistic Therapy of Rheumatoid Arthritis and MR/CT Assessment of Therapeutic Response In Situ.

This study reports a facile and green synthesis of a new multifunctional nanotheranostic probe for the synergistic therapy of rheumatoid arthritis (RA) and in situ assessment of therapeutic response. The probe is synthesized through a one-step self-assembly of two exquisitely designed peptide-amphiphilic block copolymers (PEG-DTIPA-KGPLGVRK-MTX and Pal-GGGGHHHHD-TCZ) under mild conditions, requiring minimal energy input. The resultant probe demonstrates excellent biocompatibility, water solubility, and colloidal stability. It exhibits a strong IL-6R targeting ability toward inflamed joints, and releases drugs in an MMP-2-responsive manner. The co-loading of methotrexate(MTX) and tocilizumab (TCZ) into the probe enables synergistic RA therapy with improved efficacy by simultaneously decreasing the activity of adenosine synthetase and interfering with the binding of IL-6 to its receptor. In addition, the resultant probe exhibits a high r1 relaxation rate (7.00 mm-1  s-1 ) and X-ray absorption capability (69.04 Hu mm-1 ), enabling sensitive MR and CT dual-modal imaging for simultaneous evaluation of synovial thickness and bone erosion. Both in vitro experiments using lipopolysaccharide-treated RAW264.7 cells and in vivo experiments using collagen-induced arthritis mice demonstrate the probe's high effectiveness in synergistically inhibiting inflammation. This study provides new insights into RA theranostics, therapeutic monitoring, the design of multifunctional theranostic probes, and beyond.

An Assessment of In-vitro and In-vivo Evaluation Methods for Theranostic Nanomaterials.

Nanoparticles (NPs) as nanocarriers have emerged as novel and promising theranostic agents. The term theranostics revealed the properties of NPs capable of diagnosing the disease at an early stage and/or treating the disease. Such NPs are usually developed employing a surface engineering approach. The theranostic agents comprise NPs loaded with a drug/diagnostic agent that delivers it precisely to the target site. Theranostics is a field with promising results in enhancing therapeutic efficacy facilitated through higher payload at the targeted tissue, reduced dose, and dose-dependent side effects. However, controversies in terms of toxicity and size-dependent properties have often surfaced for NPs. Thus, a stringent in-vitro and in-vivo evaluation is required to develop safe and non-toxic NPs as theranostic agents. The review also focuses on the various entry points of NPs in the human system and their outcomes, including toxicity. It elaborates the evaluation criteria to ensure the safe use of NPs for diagnostic and therapeutic purposes.

Synthesis and Preliminary Biological Assessment of Carborane-Loaded Theranostic Nanoparticles to Target Prostate-Specific Membrane Antigen.

Boron neutron capture therapy (BNCT) is an encouraging therapeutic modality for cancer treatment. Prostate-specific membrane antigen (PSMA) is a cell membrane protein that is abundantly overexpressed in prostate cancer and can be targeted with radioligand therapies to stimulate clinical responses in patients. In principle, a spatially targeted neutron beam together with specifically targeted PSMA ligands could enable prostate cancer-targeted BNCT. Thus, we developed and tested PSMA-targeted poly(lactide-co-glycolide)-block-poly(ethylene glycol) (PLGA-b-PEG) nanoparticles (NPs) loaded with carborane and tethered to the radiometal chelator deferoxamine B (DFB) for simultaneous positron emission tomography (PET) imaging and selective delivery of boron to prostate cancer. Monomeric PLGA-b-PEGs were covalently functionalized with either DFB or the PSMA ligand ACUPA. Different nanoparticle formulations were generated by nanoemulsification of the corresponding unmodified and DFB- or ACUPA-modified monomers in varying percent fractions. The nanoparticles were efficiently labeled with 89Zr and were subjected to in vitro and in vivo evaluation. The optimized DFB(25)ACUPA(75) NPs exhibited strong in vitro binding to PSMA in direct binding and competition radioligand binding assays in PSMA(+) PC3-Pip cells. [89Zr]DFB(25) NPs and [89Zr]DFB(25)ACUPA(75) NPs were injected to mice with bilateral PSMA(-) PC3-Flu and PSMA(+) PC3-Pip dual xenografts. The NPs demonstrated twofold superior accumulation in PC3-Pip tumors to that of PC3-Flu tumors with a tumor/blood ratio of 25; however, no substantial effect of the ACUPA ligands was detected. Moreover, fast release of carborane from the NPs was observed, resulting in a low boron delivery to tumors in vivo. In summary, these data demonstrate the synthesis, characterization, and initial biological assessment of PSMA-targeted, carborane-loaded PLGA-b-PEG nanoparticles and establish the foundation for future efforts to enable their best use in vivo.

Unveiling the role of surface, size, shape and defects of iron oxide nanoparticles for theranostic applications.

Iron oxide nanoparticles (IONPs) are well-known contrast agents for MRI for a wide range of sizes and shapes. Their use as theranostic agents requires a better understanding of their magnetic hyperthermia properties and also the design of a biocompatible coating ensuring their stealth and a good biodistribution to allow targeting of specific diseases. Here, biocompatible IONPs of two different shapes (spherical and octopod) were designed and tested in vitro and in vivo to evaluate their abilities as high-end theranostic agents. IONPs featured a dendron coating that was shown to provide anti-fouling properties and a small hydrodynamic size favoring an in vivo circulation of the dendronized IONPs. While dendronized nanospheres of about 22 nm size revealed good combined theranostic properties (r2 = 303 mM s-1, SAR = 395 W gFe-1), octopods with a mean size of 18 nm displayed unprecedented characteristics to simultaneously act as MRI contrast agents and magnetic hyperthermia agents (r2 = 405 mM s-1, SAR = 950 W gFe-1). The extensive structural and magnetic characterization of the two dendronized IONPs reveals clear shape, surface and defect effects explaining their high performance. The octopods seem to induce unusual surface effects evidenced by different characterization techniques while the nanospheres show high internal defects favoring Néel relaxation for magnetic hyperthermia. The study of octopods with different sizes showed that Néel relaxation dominates at sizes below 20 nm while the Brownian one occurs at higher sizes. In vitro experiments demonstrated that the magnetic heating capability of octopods occurs especially at low frequencies. The coupling of a small amount of glucose on dendronized octopods succeeded in internalizing them and showing an effect of MH on tumor growth. All measurements evidenced a particular signature of octopods, which is attributed to higher anisotropy, surface effects and/or magnetic field inhomogeneity induced by tips. This approach aiming at an analysis of the structure-property relationships is important to design efficient theranostic nanoparticles.

Theranostic Gastrointestinal Endoscopy: Bringing Healing Light to the Lumen.

Current conventional endoscopes have restricted the accuracy of treatment delivery and monitoring. Over the past decade, there have been major developments in nanotechnology and light triggered therapy, potentially allowing a better detection of challenging lesions and targeted treatment of malignancies in the gastrointestinal tract. Theranostics is a developing form of personalized medicine because it combines diagnosis and targeted treatment delivered in one step using advances in nanotechnology. This review describes the light-triggered therapies (including photodynamic, photothermal, and photoimmunotherapies), nanotechnological advances with nanopowder, nanostent, nanogels, and nanoparticles, enhancements brought to endoscopic ultrasound, in addition to experimental endoscopic techniques, combining both enhanced diagnoses and therapies, including a developed prototype of a "smart" multifunctional endoscope for localized colorectal cancer, near-infrared laser endoscope targeting the gastrointestinal stromal tumors, the concept of endocapsule for obscure gastrointestinal bleed, and a proof-of-concept therapeutic capsule using ultrasound-mediated targeted drug delivery. Hence, the following term has been proposed encompassing these technologies: "Theranostic gastrointestinal endoscopy." Future efforts for integration of these technologies into clinical practice would be directed toward translational and clinical trials translating into a more personalized and interdisciplinary diagnosis and treatment, shorter procedural time, higher precision, higher cost-effectiveness, and less need for repetitive procedures.

Production of 3D Tumor Models of Head and Neck Squamous Cell Carcinomas for Nanotheranostics Assessment.

As a first approach, standard 2D cell culture techniques are usually employed for the screening of drugs and nanomaterials. Despite the easy handling, findings achieved on 2D cultures are often not efficiently translatable to in vivo preclinical investigations. Furthermore, although animal models are pivotal in preclinical studies, more strict directives have been implemented to promote the use of alternative biological systems. In this context, the development and integration into preclinical research workflow of 3D neoplasm models is particularly appealing to promote the advancement and success of therapeutics in clinical trials while reducing the number of in vivo models. Indeed, 3D tumor models bridge several discrepancies between 2D cell culture and in vivo models, among which are morphology, polarity, drug penetration, osmolality, and gene expressions. Here, we comprehensively describe a robust and high-throughput hanging drop protocol for the production of 3D models of both Human Papillomavirus (HPV)-positive and HPV-negative head and neck squamous cell carcinomas (HNSCCs). We also report the standard cascade assays for their characterization and demonstrate their significance in investigations on these aggressive neoplasms. The employment of relevant 3D cancer models is pivotal to produce more reliable and robust findings in terms of biosafety, theranostic efficacy, and biokinetics as well as to promote further knowledge on HNSCC pathophysiology.

Photoacoustic ratiometric assessment of mitoxantrone release from theranostic ICG-conjugated mesoporous silica nanoparticles.

A theranostic nanosystem based on indocyanine green (ICG) covalently conjugated to mesoporous silica nanoparticles (MSNs) loaded with the anticancer drug mitoxantrone (MTX) is proposed as an innovative photoacoustic probe. Taking advantage of the characteristic PA signal displayed by both ICG and MTX, a PA-ratiometric approach was applied to assess the drug release profile from the MSNs. After complete in vitro characterization of the nanoprobe, a proof-of-concept study has been carried out in tumour-bearing mice to evaluate in vivo its effectiveness for cancer imaging and chemotherapeutic agent delivery.

Traceable in-cell synthesis and cytoplasm-to-nucleus translocation of a zinc Schiff base complex as a simple and economical anticancer strategy.

We have proposed a facile and cheap cancer therapeutic strategy by in-cell synthesizing theranostic Zn Schiff base complexes with nuclear targeting and DNA damaging capability. The in-cell synthesis can be traced via a green-to-blue fluorescence shift, and the subsequent cytoplasm-to-nucleus translocation realizes cancer-specific therapy both in vitro and in vivo.

Preclinical Pharmacokinetics and Dosimetry Studies of 124I/131I-CLR1404 for Treatment of Pediatric Solid Tumors in Murine Xenograft Models.

Cancer is the second leading cause of death for children between the ages of 5 and 14 y. For children diagnosed with metastatic or recurrent solid tumors, for which the utility of external-beam radiotherapy is limited, the prognosis is particularly poor. The availability of tumor-targeting radiopharmaceuticals for molecular radiotherapy (MRT) has demonstrated improved outcomes in these patient populations, but options are nonexistent or limited for most pediatric solid tumors. 18-(p-iodophenyl)octadecylphosphocholine (CLR1404) is a novel antitumor alkyl phospholipid ether analog that broadly targets cancer cells. In this study, we evaluated the in vivo pharmacokinetics of 124I-CLR1404 (CLR 124) and estimated theranostic dosimetry for 131I-CLR1404 (CLR 131) MRT in murine xenograft models of the pediatric solid tumors neuroblastoma, rhabdomyosarcoma, and Ewing sarcoma. Methods: Tumor-bearing mice were imaged with small-animal PET/CT to evaluate the whole-body distribution of CLR 124 and, correcting for differences in radioactive decay, predict that of CLR 131. Image volumes representing CLR 131 provided input for Geant4 Monte Carlo simulations to calculate subject-specific tumor dosimetry for CLR 131 MRT. Pharmacokinetics for CLR 131 were extrapolated to adult and pediatric humans to estimate normal-tissue dosimetry. In neuroblastoma, a direct comparison of CLR 124 with 124I-metaiodobenzylguanidine (124I-MIBG) in an MIBG-avid model was performed. Results: In vivo pharmacokinetics of CLR 124 showed selective uptake and prolonged retention across all pediatric solid tumor models investigated. Subject-specific tumor dosimetry for CLR 131 MRT presents a correlative relationship with tumor-growth delay after CLR 131 MRT. Peak uptake of CLR 124 was, on average, 22% higher than that of 124I-MIBG in an MIBG-avid neuroblastoma model. Conclusion: CLR1404 is a suitable theranostic scaffold for dosimetry and therapy with potentially broad applicability in pediatric oncology. Given the ongoing clinical trials for CLR 131 in adults, these data support the development of pediatric clinical trials and provide detailed dosimetry that may lead to improved MRT treatment planning.

Gold Nanoparticle-Based Fluorescent Theranostics for Real-Time Image-Guided Assessment of DNA Damage and Repair.

Chemotherapeutic dosing, is largely based on the tolerance levels of toxicity today. Molecular imaging strategies can be leveraged to quantify DNA cytotoxicity and thereby serve as a theranostic tool to improve the efficacy of treatments. Methoxyamine-modified cyanine-7 (Cy7MX) is a molecular probe which binds to apurinic/apyrimidinic (AP)-sites, inhibiting DNA-repair mechanisms implicated by cytotoxic chemotherapies. Herein, we loaded (Cy7MX) onto polyethylene glycol-coated gold nanoparticles (AuNP) to selectively and stably deliver the molecular probe intravenously to tumors. We optimized the properties of Cy7MX-loaded AuNPs using optical spectroscopy and tested the delivery mechanism and binding affinity using the DLD1 colon cancer cell line in vitro. A 10:1 ratio of Cy7MX-AuNPs demonstrated a strong AP site-specific binding and the cumulative release profile demonstrated 97% release within 12 min from a polar to a nonpolar environment. We further demonstrated targeted delivery using imaging and biodistribution studies in vivo in an xenografted mouse model. This work lays a foundation for the development of real-time molecular imaging techniques that are poised to yield quantitative measures of the efficacy and temporal profile of cytotoxic chemotherapies.

In vivo imaging biomarkers of neuroinflammation in the development and assessment of stroke therapies - towards clinical translation.

Modulation of the inflammatory microenvironment after stroke opens a new avenue for the development of novel neurorestorative therapies in stroke. Understanding the spatio-temporal profile of (neuro-)inflammatory imaging biomarkers in detail thereby represents a crucial factor in the development and application of immunomodulatory therapies. The early integration of quantitative molecular imaging biomarkers in stroke drug development may provide key information about (i) early diagnosis and follow-up, (ii) spatio-temporal drug-target engagement (pharmacodynamic biomarker), (iii) differentiation of responders and non-responders in the patient cohort (inclusion/exclusion criteria; predictive biomarkers), and (iv) the mechanism of action. The use of targeted imaging biomarkers for may thus allow clinicians to decipher the profile of patient-specific inflammatory activity and the development of patient-tailored strategies for immunomodulatory and neuro-restorative therapies in stroke. Here, we highlight the recent developments in preclinical and clinical molecular imaging biomarkers of neuroinflammation (endothelial markers, microglia, MMPs, cell labeling, future developments) in stroke and outline how imaging biomarkers can be used in overcoming current translational roadblocks and attrition in order to advance new immunomodulatory compounds within the clinical pipeline.

18F-NaF/223RaCl2 theranostics in metastatic prostate cancer: treatment response assessment and prediction of outcome.

Theranostics refers to companion agents with identical or similar structure targeted to a specific biological entity for imaging and treatment. Although the concept has a long history with radioiodine in thyroidology, but it has experienced remarkable recent renaissance in management of neuroendocrine tumors and prostate cancer. Bone scintigraphy based on osteoblastic reaction and targeted radionuclide therapy with the alpha-particle calcium-mimetic agent, 223RaCl2, also form a theranostic model for imaging and treatment of osseous metastatic disease. Since the regulatory approval of 223RaCl2 in 2013, there has been accumulating evidence on the potential use of 18F-NaF PET scintigraphy in the assessment of response and prediction of outcome in males with metastatic castrate-resistant prostate cancer who undergo 223RaCl2 therapy. We review the 18F-NaF/223RaCl2 as theranostic companion in the management of prostate cancer with emphasis on the utility of 18F-NaF and other relevant PET radiotracers in the therapy response and prognosis assessments.

Integration of Fricke gel dosimetry with Ag nanoparticles for experimental dose enhancement determination in theranostics.

The use and implementation of nanoparticles in medicine has grown exponentially in the last twenty years. Their main applications include drug delivery, theranostics, tissue engineering and magneto function. Dosimetry techniques can take advantage of inorganic nanoparticles properties and their combination with gel dosimetry techniques could be used as a first step for their later inclusion in radio-diagnostics or radiotherapy treatments. The present study presents preliminary results of properly synthesized and purified silver nanoparticles integration with Fricke gel dosimeters. Used nanoparticles presented mean sizes ranging from 2 to 20 nm, with a lognormal distribution. Xylenol orange concentration in Fricke gel dosimeter was adjust in order to allow sample's optical readout, accounting nanoparticles plasmon. Dose enhancement was assessed irradiating dosimeters setting X-ray beams energies below and above silver K-edge. Monte Carlo simulations were used to estimate the dose enhancement in the experiments and compare with the trend obtained in the experimental results.

Evaluation of 209At as a theranostic isotope for 209At-radiopharmaceutical development using high-energy SPECT.

The development of alpha-emitting radiopharmaceuticals using 211At requires quantitative determination of the time-dependent nature of the 211At biodistribution. However, imaging-based methods for acquiring this information with 211At have not found wide-spread use because of its low abundance of decay emissions suitable for external detection. In this publication we demonstrate the theranostic abilities of the 211At/209At isotope pair and present the first-ever 209At SPECT images. The VECTor microSPECT/PET/CT scanner was used to image 209At with a collimator suitable for the 511 keV annihilation photons of PET isotopes. Data from distinct photopeaks of the 209At energy spectrum (195 keV (22.6%), 239 keV (12.4 %), 545 keV (91.0 %), a combined 782/790 keV peak (147 %), and 209Po x-rays (139.0 %)) were independently evaluated for use in image reconstructions using Monte Carlo (GATE) simulations and phantom studies. 209At-imaging in vivo was demonstrated in a healthy mouse injected with 10 MBq of free [209At]astatide. Image-based measurements of 209At uptake in organs of interest-acquired in 5 min intervals-were compared to ex vivo gamma counter measurements of the same organs. Simulated and measured data indicated that-due to the large amount of scatter from high energy (>750 keV) gammas-reconstructed images using the x-ray peak outperformed those obtained from other peaks in terms of image uniformity and spatial resolution, determined to be <0.85 mm. 209At imaging using the x-ray peak revealed a biodistribution that matched the known distribution of free astatide, and in vivo image-based measurements of 209At uptake in organs of interest matched ex vivo measurements within 10%. We have acquired the first 209At SPECT images and demonstrated the ability of quantitative SPECT imaging with 209At to accurately determine astatine biodistributions with high spatial and temporal resolution.

Theranostic radiopharmaceuticals: established agents in current use.

Although use of the term "theranostic" is relatively recent, the concept goes back to the earliest days of nuclear medicine, with the use of radioiodine for diagnosis and therapy of benign and malignant thyroid disease being arguably the most successful molecular radiotherapy in history. A diagnostic scan with 123I-, 124I-, or a low activity of 131I-iodide is followed by therapy with high activity 131I-iodide. Similarly, adrenergic tumours such as phaeochromocytoma and neuroblastoma can be imaged with 123I-metaiodobenzylguanidine and treated with 131I-metaiodobenzylguanidine. Bone scintigraphy can be used to select patients with painful bone metastases from prostate cancer who may benefit from treatment with beta- or alpha-particle emitting bone seeking agents, the most recent and successful of which is 223Ra radium chloride. Anti-CD20 monoclonal antibodies can be used to image and treat non-Hodgkins lymphoma, though this has not been as commercially successful as initially predicted. More recently established theranostics include somatostatin receptor targeting peptides for diagnosis and treatment of neuroendocrine tumours with agents such as 68Ga-DOTATATE and 177Lu-DOTATATE, respectively. Finally, agents which target prostate-specific membrane antigen are becoming increasingly widely available, despite the current lack of a commercial product. With the recent licensing of the somatostatin peptides and the rapid adoption of 68Ga- and 177Lu-labelled prostate-specific membrane antigen targeting agents, we have built upon the experience of radioiodine and are already seeing a great expansion in the availability of widely accepted theranostic radiopharmaceuticals.