Theranostic Approach Research Articles

Imaging Cancer-Associated Fibroblasts (CAFs) with FAPi PET.

The tumor microenvironment (TME) surrounding tumor cells is a complex and highly dynamic system that promotes tumorigenesis. Cancer-associated fibroblasts (CAFs) are key elements in TME playing a pivotal role in cancer cells’ proliferation and metastatic spreading. Considering the high expression of the fibroblast activation protein (FAP) on the cell membrane, CAFs emerged as appealing TME targets, namely for molecular imaging, leading to a pan-tumoral approach. Therefore, FAP inhibitors (FAPis) have recently been developed for PET imaging and radioligand therapy, exploring the clinical application in different tumor sub-types. The present review aimed to describe recent developments regarding radiolabeled FAP inhibitors and evaluate the possible translation of this pan-tumoral approach in clinical practice. At present, the application of FAPi-PET has been explored mainly in single-center studies, generally performed in small and heterogeneous cohorts of oncological patients. However, preliminary results were promising, in particular in low FDG-avid tumors, such as primary liver and gastro-entero-pancreatic cancer, or in regions with an unfavorable tumor-to-background ratio at FDG-PET/CT (i.e., brain), and in radiotherapy planning of head and neck tumors. Further promising results have been obtained in the detection of peritoneal carcinomatosis, especially in ovarian and gastric cancer. Data regarding the theranostics approach are still limited at present, and definitive conclusions about its efficacy cannot be drawn at present. Nevertheless, the use of FAPi-based radio-ligand to treat the TME has been evaluated in first-in-human studies and appears feasible. Although the pan-tumoral approach in molecular imaging showed promising results, its real impact in day-to-day clinical practice has yet to be confirmed, and multi-center prospective studies powered for efficacy are needed.

Normal Variants, Pitfalls, and Artifacts in Ga-68 Prostate Specific Membrane Antigen (PSMA) PET/CT Imaging.

The advent of gallium 68 prostate specific membrane antigen (PSMA) PET imaging has revolutionized the diagnosis and treatment of prostate cancer. PSMA is a transmembrane glycoprotein that is overexpressed in prostate cancer and yields images with high tumor-to-background contrast. Effective "one-stop-shop" imaging of the prostate, lymph nodes, soft tissue, and bone is achieved with PSMA PET. Compared to conventional imaging, PSMA PET provides superior sensitivity and specificity and plays a pivotal role in staging high-risk prostate cancer as well as in biochemical recurrence by identifying oligometastatic disease. PSMA PET furthermore assists in the selection of patients with metastatic castrate resistant prostate cancer for possible treatment (e.g., labeled with a beta emitter lutetium 177) by using a theranostic approach. The term "prostate specific" is a misnomer as PSMA is also present in other malignant and benign conditions since it acts as a folate hydrolase. To avoid pitfalls and false-positives, a sound knowledge of the normal biodistribution of PSMA as well as other potential causes for false-positive uptake is imperative. This review will describe the expected patterns of distribution of Ga 68 PSMA PET imaging and the common pitfalls noted in published literature since the topic is still evolving.

Molecular Imaging of Brain Tumors and Drug Delivery Using CEST MRI: Promises and Challenges.

Chemical exchange saturation transfer (CEST) magnetic resonance imaging (MRI) detects molecules in their natural forms in a sensitive and non-invasive manner. This makes it a robust approach to assess brain tumors and related molecular alterations using endogenous molecules, such as proteins/peptides, and drugs approved for clinical use. In this review, we will discuss the promises of CEST MRI in the identification of tumors, tumor grading, detecting molecular alterations related to isocitrate dehydrogenase (IDH) and O-6-methylguanine-DNA methyltransferase (MGMT), assessment of treatment effects, and using multiple contrasts of CEST to develop theranostic approaches for cancer treatments. Promising applications include (i) using the CEST contrast of amide protons of proteins/peptides to detect brain tumors, such as glioblastoma multiforme (GBM) and low-grade gliomas; (ii) using multiple CEST contrasts for tumor stratification, and (iii) evaluation of the efficacy of drug delivery without the need of metallic or radioactive labels. These promising applications have raised enthusiasm, however, the use of CEST MRI is not trivial. CEST contrast depends on the pulse sequences, saturation parameters, methods used to analyze the CEST spectrum (i.e., Z-spectrum), and, importantly, how to interpret changes in CEST contrast and related molecular alterations in the brain. Emerging pulse sequence designs and data analysis approaches, including those assisted with deep learning, have enhanced the capability of CEST MRI in detecting molecules in brain tumors. CEST has become a specific marker for tumor grading and has the potential for prognosis and theranostics in brain tumors. With increasing understanding of the technical aspects and associated molecular alterations detected by CEST MRI, this young field is expected to have wide clinical applications in the near future.

Radiolabeled Somatostatin Analogues for Diagnosis and Treatment of Neuroendocrine Tumors.

Simple SummaryNeuroendocrine neoplasms (NENs) are rare and heterogeneous tumors, presenting in often challenging clinical scenarios, and require multidisciplinary discussion for optimal care. The theranostic approach (DOTA peptides labelled with 68Ga for imaging well-differentiated neuroendocrine tumors NETs, and labelled with 90Y or 177Lu for therapy) plays a crucial role in the management of NENs to assess disease extension and criteria for peptide receptor radionuclide therapy (PRRT) eligibility of based on somatostatin receptor (SSTR) expression. The present paper is an overview of currently employed radiolabeled SSTR analogues used for both diagnosis and therapy of NENs. Further emerging radiopharmaceuticals targeting SSTRs (e.g., fluorinated SSTR agonists, radiolabeled SSTR antagonists) as well as strategies to improve PRRT efficacy (by means of implementation of personalized treatment schemes, dosimetry, amelioration of response assessment strategies, and optimization of treatment sequencing) are also discussed. Finally, although very preliminary, some studies employing radiomic features in various kinds of NET are reported.Neuroendocrine neoplasms (NENs) are rare and heterogeneous tumors that require multidisciplinary discussion for optimal care. The theranostic approach (DOTA peptides labelled with 68Ga for diagnosis and with 90Y or 177Lu for therapy) plays a crucial role in the management of NENs to assess disease extension and as a criteria for peptide receptor radionuclide therapy (PRRT) eligibility based on somatostatin receptor (SSTR) expression. On the diagnostic side, [68Ga]Ga-DOTA peptides PET/CT (SSTR PET/CT) is the gold standard for imaging well-differentiated SSTR-expressing neuroendocrine tumors (NETs). [18F]FDG PET/CT is useful in higher grade NENs (NET G2 with Ki-67 > 10% and NET G3; NEC) for more accurate disease characterization and prognostication. Promising emerging radiopharmaceuticals include somatostatin analogues labelled with 18F (to overcome the limits imposed by 68Ga), and SSTR antagonists (for both diagnosis and therapy). On the therapeutic side, the evidence gathered over the past two decades indicates that PRRT is to be considered as an effective and safe treatment option for SSTR-expressing NETs, and is currently included in the therapeutic algorithms of the main scientific societies. The positioning of PRRT in the treatment sequence, as well as treatment personalization (e.g., tailored dosimetry, re-treatment, selection criteria, and combination with other alternative treatment options), is warranted in order to improve its efficacy while reducing toxicity. Although very preliminary (being mostly hampered by lack of methodological standardization, especially regarding feature selection/extraction) and often including small patient cohorts, radiomic studies in NETs are also presented. To date, the implementation of radiomics in clinical practice is still unclear. The purpose of this review is to offer an overview of radiolabeled SSTR analogues for theranostic use in NENs.

Plant-Based Synthesis of Gold Nanoparticles and Theranostic Applications: A Review.

Bionanotechnology is a branch of science that has revolutionized modern science and technology. Nanomaterials, especially noble metals, have attracted researchers due to their size and application in different branches of sciences that benefit humanity. Metal nanoparticles can be synthesized using green methods, which are good for the environment, economically viable, and facilitate synthesis. Due to their size and form, gold nanoparticles have become significant. Plant materials are of particular interest in the synthesis and manufacture of theranostic gold nanoparticles (NPs), which have been generated using various materials. On the other hand, chemically produced nanoparticles have several drawbacks in terms of cost, toxicity, and effectiveness. A plant-mediated integration of metallic nanoparticles has been developed in the field of nanotechnology to overcome the drawbacks of traditional synthesis, such as physical and synthetic strategies. Nanomaterials′ tunable features make them sophisticated tools in the biomedical platform, especially for developing new diagnostics and therapeutics for malignancy, neurodegenerative, and other chronic disorders. Therefore, this review outlines the theranostic approach, the different plant materials utilized in theranostic applications, and future directions based on current breakthroughs in these fields.

Computational analysis of drug free silver triangular nanoprism theranostic probe plasmonic behavior for in-situ tumor imaging and photothermal therapy

IntroductionThe advanced features of plasmonic nanomaterials enable initial high accuracy detection with different therapeutic intervention. Computational simulations could estimate the plasmonic heat generation with a high accuracy and could be reliably compared to experimental results. This proposed combined theoretical-experimental strategy may help researchers to better understand other nanoparticles in terms of plasmonic efficiency and usability for future nano-theranostic research. ObjectivesTo develop innovative computationally-driven approach to quantify any plasmonic nanoparticles photothermal efficiency and effects before their use as therapeutic agents. MethodsThis report introduces drug free plasmonic silver triangular nanoprisms coated with polyvinyl alcohol biopolymer (PVA-SNT), for in vivo photoacoustic imaging (PAI) guided photothermal treatment (PTT) of triple-negative breast cancer mouse models. The synthesized PVA-SNT nanoparticles were characterized and a computational electrodynamic analysis was performed to evaluate and predict the optical and plasmonic photothermal properties. The in vitro biocompatibility and in vivo tumor abalation study was performed with MDA-MB-231 human breast cancer cell line and in nude mice model. ResultsThe drug free 140 μg∙mL−1 PVA-SNT nanoparticles with 1.0 W∙cm−2 laser irradiation for 7 min proved to be an effective and optimized theranostic approach in terms of PAI guided triple negative breast cancer treatment. The PVA-SNT nanoparticles exhibits excellent biosafety, photostability, and strong efficiency as PAI contrast agent to visualize tumors. Histological analysis and fluorescence-assisted cell shorter assay results post-treatment apoptotic cells, more importantly, it shows substantial damage to in vivo tumor tissues, killing almost all affected cells, with no recurrence. ConclusionThis is a first complete study on computational simulations to estimate the plasmonic heat generation followed by drug free plasmonic PAI guided PTT for cancer treatment. This computationally-driven theranostic approach demonstrates an innovative thought regarding the nanoparticles shape, size, concentration, and composition which could be useful for the prediction of photothermal heat generation in precise nanomedicine applications.

AAZTA-Derived Chelators for the Design of Innovative Radiopharmaceuticals with Theranostic Applications.

With the development of 68Ga and 177Lu radiochemistry, theranostic approaches in modern nuclear medicine enabling patient-centered personalized medicine applications have been growing in the last decade. In conjunction with the search for new relevant molecular targets, the design of innovative chelating agents to easily form stable complexes with various radiometals for theranostic applications has gained evident momentum. Initially conceived for magnetic resonance imaging applications, the chelating agent AAZTA features a mesocyclic seven-membered diazepane ring, conferring some of the properties of both acyclic and macrocyclic chelating agents. Described in the early 2000s, AAZTA and its derivatives exhibited interesting properties once complexed with metals and radiometals, combining a fast kinetic of formation with a slow kinetic of dissociation. Importantly, the extremely short coordination reaction times allowed by AAZTA derivatives were particularly suitable for short half-life radioelements (i.e., 68Ga). In view of these particular characteristics, the scope of this review is to provide a survey on the design, synthesis, and applications in the nuclear medicine/radiopharmacy field of AAZTA-derived chelators.

Normal Variants, Pitfalls and Artifacts in Ga-68 DOTATATE PET/CT Imaging.

Indium 111 DTPA Octreotide (Octreoscan) has been the pillar of Somatostatin receptor (SSTRs) imaging in nuclear medicine for over three decades. The advent of PET/CT brought new analogs of somatostatin that have higher affinity and improved resolution due to their labeling to Gallium 68 for positron imaging. The most used analogs include DOTATATE, DOTATOC and DOTANOC. However, Gallium 68-1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA)-octreotate (DOTATATE) is probably the most common non-FDG (fluoro-2-deoxy glucose) PET tracer alongside PSMA (prostate specific membrane antigen). In contrast to F18-labeled FDG, it does not require proximity to a cyclotron due to the availability of the Ga68 generator. DOTATATE is a somatostatin analog which allows whole body imaging of somatostatin receptors on cell surfaces. 68Ga-DOTA compounds provide the imaging standard for well-differentiated (Grade 1 and low grade 2) neuro-endocrine tumors (NETs) and is utilized in the staging and characterization and restaging of patients with NETs. 68Ga DOTATATE has a complementary role with 18F-FDG where tumors may exhibit varying degrees of differentiation. It furthermore has application as a prelude to therapy in selecting patients for peptide receptor radionuclide therapy using a theranostic approach. A sound knowledge of the normal biodistribution of the radiotracer is imperative for optimal patient outcome and to avoid potential false positives such as inflammation, normal pancreatic uncinate process uptake and osteoblastic activity. In this review, we will describe the normal appearances of the 68Ga DOTATATE and the potential pitfalls with the support of images to aid in improving interpretation of this crucial innovative tool in the management of individuals with tumors expressing SSTRs.

Molecular Imaging in neuroendocrine neoplasias

Molecular imaging, which uses molecular targets due to the overexpression of specific peptide hormone receptors on the tumour surface, has become an indispensable diagnostic technique.Neuroendocrine neoplasms (NENs) especially differentiated NENs or neuroendocrine tumours (NETs) are a rare group of heterogeneous tumours, characterized by the expression of hormone receptors on the tumour cell surface. This property makes them receptive to diagnostic and therapeutic approaches (theranostics) using radiolabelled peptides.Amongst the known hormone receptors, somatostatin receptors (SSTR) are expressed on the majority of NETs and are therefore the most relevant receptors for theranostic approaches. Current research aims to medically upregulate their expression, while other focuses are on the use of different radiopeptides (64Cu and 67Cu) or somatostatin-antagonists instead of the established somatostatin agonists.The GLP-1 receptor is another clinically relevant target, as GLP-1-R imaging has become the new standard for the localisation of insulinomas. For staging and prognostic evaluation in dedifferentiated NENs, 18F-FDG-imaging is useful, but lacks a therapeutic counterpart. Further options for patients with insufficient expression of SSTR involve metaiodobenzylguanidine (MIBG) and the molecular target C-X-C motif chemokine receptor-4 (CXCR4). New targets such as the glucose-dependant insulinotropic polypeptide receptor (GIPR) and the fibroblast activation protein (FAP) have been identified in NENs recently and await further evaluation.For medullary thyroid cancer 18-F-DOPA imaging is standard, however this technique is rather second line for other NENs. In this area, the discovery of minigastrin, which targets the cholecystokinin-2 (CCK2) receptors in medullary thyroid carcinoma and foregut NENs, may improve future management.This review aims to provide an overview of the most commonly used functional imaging modalities for theranostics in NENs today and in the possible future.

Targeted Drug Delivery and Theranostic Strategies in Malignant Lymphomas.

Simple SummaryThe concept of targeted drug delivery (TDD) represents an innovative and effective treatment approach, which was developed with an attempt to minimize damage toward healthy tissues. Radioimmunotherapy (RIT) with radioimmunoconjugates and TDD with antibody–drug conjugates (ADC) both represent drug delivery systems (DDS) based on monoclonal antibody-mediated delivery of toxic payloads toward the lymphoma tissue. Other modalities of TDD are based on new formulations of “old” cytostatic agents and their passive trapping in the tumor bulk by means of enhanced permeability and retention (EPH) effect. These comprise several clinically approved liposomal formulations of anthracyclines and many investigational nanomedicines including pegylated and non-pegylated liposomes, or polymer-based nanoparticles. Currently, the diagnostic and restaging procedures in aggressive lymphomas are based on nuclear imaging, predominantly on 2-[F18] fluoro-2-deoxy-D-glucose (FDG) positron emission tomography (PET). On a preclinical level, it has been repeatedly demonstrated that the assessment of response and therapy delivery can be fused. Such a theranostic approach that would combine the diagnostic or restaging imaging procedure with a targeted therapy represents an appealing innovative strategy in personalized medicine in hemato-oncology.Malignant lymphomas represent the most common type of hematologic malignancies. The first clinically approved TDD modalities in lymphoma patients were anti-CD20 radioimmunoconjugates (RIT) 131I-tositumomab and 90Y-ibritumomab-tiuxetan. The later clinical success of the first approved antibody–drug conjugate (ADC) for the treatment of lymphomas, anti-CD30 brentuximab vedotin, paved the path for the preclinical development and clinical testing of several other ADCs, including polatuzumab vedotin and loncastuximab tesirine. Other modalities of TDD are based on new formulations of “old” cytostatic agents and their passive trapping in the lymphoma tissue by means of the enhanced permeability and retention (EPR) effect. Currently, the diagnostic and restaging procedures in aggressive lymphomas are based on nuclear imaging, namely PET. A theranostic approach that combines diagnostic or restaging lymphoma imaging with targeted treatment represents an appealing innovative strategy in personalized medicine. The future of theranostics will require not only the capability to provide suitable disease-specific molecular probes but also expertise on big data processing and evaluation. Here, we review the concept of targeted drug delivery in malignant lymphomas from RIT and ADC to a wide array of passively and actively targeted nano-sized investigational agents. We also discuss the future of molecular imaging with special focus on monoclonal antibody-based and monoclonal antibody-derived theranostic strategies.

Fibroblast Activation Protein Inhibitor Imaging and Therapy in a Patient With Multiple Endocrine Neoplasia Type 2A Syndrome.

A patient with multiple endocrine neoplasia type 2A syndrome who had exhausted several surgeries and radiotherapy was referred to nuclear medicine department for theranostic approaches. [68Ga]-DOTATATE PET/CT and [131I]I-mIBG SPECT/CT were performed, but the degree of uptake was insufficient for using the treatment companion of these tracers. Finally, 1 year later, [68Ga]-FAPI-46 PET/CT showed progressive disease with metastases to the lung, liver, bone, and lymph nodes with intense [68Ga]-FAPI-46 uptake. Treatment with [177Lu]Lu-FAPI-46 was done, and the patient tolerated treatment and showed evidence of clinical improvement following therapy.

Biodegradable polyphosphazene-based nanodrug to regulate redox homeostasis for augmented chemo-photodynamic therapy

Photodynamic therapy (PDT) is more precise than traditional tumor therapy. Nevertheless, PDT efficiency often is hindered by the antioxidant defense system which deplete the required reactive oxide species (ROS). Here we developed a simple but universal method by assembling anticancer drug (resveratrol, RV), photosensitizer (methylene blue, MB) and glutathione (GSH)-sensitive molecules (bis-(4-hydroxyphenyl)-disulfide, HPS) to covalent linking with hexachlorocyclotriphosphazene (HCCP) onto the Fe3O4 to construct a versatile drug delivery nanosystem (FHRHM). Notably, as a multifunctional nanodrug it shows good physiological stability, biocompatibility, and pH/GSH-responsive property to realize the RV and MB controlled release in tumor microenvironment (TME), maximum magnetic resonance (MR)/fluorescence (FL) imaging guided for synergistic chemo-photodynamic therapy (CT-PDT). Especially, the cross-linked FHRHM could be decomposed via reacting with high level of GSH to accelerate release MB for exogenous ROS generation, as well as disrupted disulfide bond (-S-S-) of HPS through depleting GSH to further reduce the endogenous ROS scavenging in TME, thus double amplifying the PDT and simultaneously enhancing CT to induce Hela cells death. This work highlights a novel strategy to construct TME-dissociable nanodrug for augmented CT-PDT via regulation of redox homeostasis, may provide a promising translational approach for tumor theranostics.

Auger Emitter Conjugated PARP Inhibitor for Therapy in Triple Negative Breast Cancers: A Comparative In-Vitro Study.

Simple SummaryTriple negative breast cancer (TNBC) is an aggressive subtype of breast cancer, with a high recurrence rate. Since treatment of BRCAmut TNBC patients with PARP inhibitor (PARPi), targeting the nuclear protein PARP1, shows varied responses, its therapeutic efficacy is currently evaluated in combination with chemotherapy. Auger emitters (AEs) are radionuclides that can cause DNA damage when delivered close to the DNA. Due to the nuclear location of PARP1, radiolabelling of PARPi with AEs provide an efficient nuclear delivery mechanism. This study shows the radiosynthesis of an AE radiolabelled PARPi ([125I]-PARPi-01) and its therapeutic effect as monotherapy or in combination with chemotherapeutics in a panel of TNBC cell lines. We found that [125I]-PARPi-01 efficiently induces DNA damage with therapeutic effect irrespective of BRCA mutation. All responsive cell lines have homologous recombination deficiency. Short pretreatment with doxorubicin significantly reduces clonogenic survival of both responsive and resistant cell lines.PARP1 inhibitors (PARPi) are currently approved for BRCAmut metastatic breast cancer, but they have shown limited response in triple negative breast cancer (TNBC) patients. Combination of an Auger emitter with PARPis enables PARP inhibition and DNA strand break induction simultaneously. This will enhance cytotoxicity and additionally allow a theranostic approach. This study presents the radiosynthesis of the Auger emitter [125I] coupled olaparib derivative: [125I]-PARPi-01, and its therapeutic evaluation in a panel of TNBC cell lines. Specificity was tested by a blocking assay. DNA strand break induction was analysed by γH2AX immunofluorescence staining. Cell cycle analysis and apoptosis assays were studied using flow cytometry in TNBC cell lines (BRCAwt/mut). Anchorage independent growth potential was evaluated using soft agar assay. [125I]-PARPi-01 showed PARP1-specificity and higher cytotoxicity than olaparib in TNBC cell lines irrespective of BRCA their status. Cell lines harbouring DNA repair deficiency showed response to [125I]-PARPi-01 monotherapy. Combined treatment with Dox-NP further enhanced therapeutic efficiency in metastatic resistant BRCAwt cell lines. The clonogenic survival was significantly reduced after treatment with [125I]-PARPi-01 in all TNBC lines investigated. Therapeutic efficacy was further enhanced after combined treatment with chemotherapeutics. [125I]-PARPi-01 is a promising radiotherapeutic agent for low radiation dosages, and mono/combined therapies of TNBC.

The role of positron emission tomography in the diagnosis and treatment of oncological diseases of the hepatobiliary system

The article highlights the role of PET and SIRT in the diagnosis and treatment of cholangiocarcinoma and HCR. In HCR, PET can be useful in detecting distant metastases, assessing overall and recurrence-free survival. In the case of cholangiocarcinoma, PET is more diagnostically informative than CT when detecting distant metastases and plays an important role in predicting recurrence after surgical resection. Data on the use of various types of radiopharmaceuticals and their combinations are provided. A comparison of their sensitivity and specificity is presented, which showed the best results when using the combination of FDG + choline. The effectiveness of PET in the selection of patients before transplantation, the ability to assess the distribution of activity and to quantify the absorbed dose in SIRT, which in turn allows to predict the therapeutic response and outcome, has been demonstrated. Different types of microspheres for SIRT are considered, in particular, 90Y-resin, 90Y-glass, and 166Ho-poly-L-lactic acid (PLLA). Among them, the most interesting are 166Ho microspheres, which have the advantage of being able to perform diagnostics and treatment with the same radiological label, i.e., to be used in a theranostic approach, theoretically reducing discrepancies between the planning and treatment procedure. SIRT can be used both alone and in combination with other types of treatment at different stages of tumor disease.

Theranostic mesoporous silica nanoparticles made of multi-nuclear gold or carbon quantum dots particles serving as pH responsive drug delivery system

Mesoporous silica nanoparticles are promising candidates to deliver proteins, antibodies, and anticancer drugs and to be served as an adsorbent of various types of substrate. Herein, a theranostic approach, in the preparation of fluorescence-type mesoporous silica for pH-responsive delivery of anticancer drug, doxorubicin, is introduced. By this mean, three types of mesoporous silica were synthesized. The ordinary type of mesoporous silica nanoparticles containing propylamine functional groups was synthesized by a controlled-size technique. Two types of fluorescence mesoporous silica were prepared, doped with gold or quantum dots nanoparticles. The fluorescence imaging has shown that the optical properties of the gold or carbon quantum dots have been transferred to the mesoporous matrix in doping processes. The as-prepared mesoporous materials were conjugated to doxorubicin via Schiff-base linkage. Several characterization techniques were utilized to detect the structure of the particles including FT-IR spectroscopy, XRD, N 2 adsorption/desorption, transition, and scanning electron microscopy. The amount of conjugated doxorubicin was analyzed by UV–Vis spectroscopy. The pH-responsive character was proved assessing the release profile in different pH ranges including physiological pH. The safety of the particles was evaluated by cell cytotoxicity assay on breast cancer cell line, MCF-7. As-prepared particles showed no cytotoxic behavior, but when they were loaded by doxorubicin, the appreciable release of the drug and subsequent cytotoxicity resulted against MCF-7 cells. The hemolytic study was conducted to prove the biocompatibility of these particles in the blood. Altogether, the proposed materials are suitable to be considered as safe and to be used as a theranostic platform for therapeutic and imaging purposes. • Three types of MSN were prepared and applied for drug delivery. • The fluorophore MSNs of GNP@MSN and QCD@MSN were organized for theranostic purpose. • DOX was conjugated to MSNs, and released through pH responsive profile. • The fluorophore MSNs showed biocompatibility and fluorescent contrast in MCF-7 cells. • MSNs@DOX showed toxicity in parallel and even higher than of free DOX in MCF-7 cell.

Versatile carbon nanoplatforms for cancer treatment and diagnosis: strategies, applications and future perspectives.

Despite the encouraging breakthroughs in medical development, cancer remains one of the principle causes of death and threatens human health around the world. Conventional treatment strategies often kill cancer cells at the expense of serious adverse effects or great pain, which yet is not able to achieve an effective cure. Therefore, it is urgent to seek for other novel anticancer approaches to improve the survival rate and life quality of cancer patients. During the past decades, nanotechnology has made tremendous progress in cancer therapy due to many advantages such as targeted drug delivery, decreased dosage-related adverse effects and prolonged drug circulation time. In the context of nanomedicine, carbon nanomaterials occupy very significant positions. Owing to their innate outstanding optical, thermal, electronic, and mechanic features, easy functionalization possibility and large surface for drug loading, carbon nanomaterials serve as not only drug carriers, but also multifunctional platforms to combine with diverse treatment and diagnosis modalities against cancer. Therefore, developing more carbon-based nanoplatforms plays a critical role in cancer theranostics and an update overview that summarizes the recent achievement of carbon nanomaterial-mediated anticancer theranostic approaches is of necessity. In this review, five typical and widely investigated carbon nanomaterials including graphene, graphdiyne, fullerene, carbon nanotubes and carbon quantum dots are introduced in detail from the aspect of treatment strategies based on both cancer cells and tumor microenvironment-involved therapeutic targets. Meanwhile, modern diagnostic methods and clinical translatability of carbon nanomaterials will be highlighted as well.

Translational immunoPET imaging using a radiolabeled GD2-specific antibody in neuroblastoma.

Background: Antibodies targeting surface expressed disialoganglioside GD2 are increasingly used in neuroblastoma immunotherapy and might also have potential for use in radioimmunotherapy. As such targeted treatments might benefit from a dedicated theranostic approach, we studied the influence of radiolabeling on the binding characteristics of ch14.18 antibodies produced by Chinese hamster ovary (CHO) cells and evaluated the benefit of GD2-ImmunoPET as a potential tool for therapy planning.Methods: 64Cu was used to reduce radiation burden, which is of high importance especially in a pediatric patient population. 64Cu-labeling was accomplished using the chelators NOTA- or DOTAGA-NCS. Radiolabeled antibodies were characterized in vitro. [64Cu]Cu-DOTAGA-ch14.18/CHO was studied in a neuroblastoma mouse model (subcutaneous CHP-134 xenografts). In vivo PET and MR images were acquired at 3 h, 24 h, and 48 h p.i. The specificity of binding was verified using GD2-negative tumors (HEK-293 xenografts), a control antibody and in vivo blocking. A first translational application was performed by PET/MRI in a patient with metastasized neuroblastoma.Results: Radiolabeling at an antibody-to-chelator ratio ≥1:10 yielded a product with a radiochemical purity of ≥90% and a specific activity of 0.2-1.0 MBq/µg. Radiochelation was stable over 48 h in PBS, mouse serum or EDTA, and 50.8 ± 3.5% and 50.8 ± 2.0% of the radiolabeled conjugates, prepared at antibody-to-chelator ratios of 1:10 or 1:15, were immunoreactive. In vivo, highly specific accumulation (31.6 ± 5.8% ID/g) in neuroblastoma was shown preclinically. Clinical PET/MR scans using [64Cu]Cu-NOTA-ch14.18/CHO (NOTA used for safety reasons) could visualize neuroblastoma metastases.Conclusions: In vivo, 64Cu-labeled ch14.18/CHO is suitable for specific identification of neuroblastoma in PET. A first patient PET indicated the feasibility of the method for clinical translation and the potential utility in image-guided therapy.

Polyglutamate-based nanoconjugates for image-guided surgery and post-operative melanoma metastases prevention.

Rationale: Cutaneous melanoma is the most aggressive and deadliest of all skin malignancies. Complete primary tumor removal augmented by advanced imaging tools and effective post-operative treatment is critical in the prevention of tumor recurrence and future metastases formation.Methods: To meet this challenge, we designed novel polymeric imaging and therapeutic systems, implemented in a two-step theranostic approach. Both are composed of the biocompatible and biodegradable poly(α,L-glutamic acid) (PGA) nanocarrier that facilitates extravasation-dependent tumor targeting delivery. The first system is a novel, fluorescent, Turn-ON diagnostic probe evaluated for the precise excision of the primary tumor during image-guided surgery (IGS). The fluorescence activation of the probe occurs via PGA degradation by tumor-overexpressed cathepsins that leads to the separation of closely-packed, quenched FRET pair. This results in the emission of a strong fluorescence signal enabling the delineation of the tumor boundaries. Second, therapeutic step is aimed to prevent metastases formation with minimal side effects and maximal efficacy. To that end, a targeted treatment containing a BRAF (Dabrafenib - mDBF)/MEK (Selumetinib - SLM) inhibitors combined on one polymeric platform (PGA-SLM-mDBF) was evaluated for its anti-metastatic, preventive activity in combination with immune checkpoint inhibitors (ICPi) αPD1 and αCTLA4.Results: IGS in melanoma-bearing mice led to a high tumor-to-background ratio and reduced tumor recurrence in comparison with mice that underwent surgery under white light (23% versus 33%, respectively). Adjuvant therapy with PGA-SLM-mDBF combined with ICPi, was well-tolerated and resulted in prolonged survival and prevention of peritoneal and brain metastases formation in BRAF-mutated melanoma-bearing mice.Conclusions: The results reveal the great clinical potential of our PGA-based nanosystems as a tool for holistic melanoma treatment management.

Sequential Administrations of a Vascular-Disrupting Agent, High-Intensity Focused Ultrasound, and a Radioactively labeled Necrosis Avid Compound for Eradicating Solid Malignancies.

Radical treatment of malignant solid tumors should aim to be less traumatic, precise, and effective. OncoCiDia, as a noninvasive, sequential dual-targeting, small-molecule, broad spectrum anticancer theranostic approach, may fulfill these requirements of solid cancer (Onco) treatment with both tumoricidal (Ci) and diagnostic (Dia) effects. However, it is unlikely to cure patients with cancer, especially those with large and irregular tumors and with tumors residing in certain organs, such as the brain and pancreas, because of insufficient necrosis generation. To amplify ablative efficacy, this shortcoming could be overcome by combining high-intensity focused ultrasound (HIFU) with the use of a vascular-disrupting agent (VDA) and a radioactively labeled necrosis avid compound (NAC), such as 131I-Hypericin (131I-Hyp), which are the first and second targeting drugs used in OncoCiDia. This study proposes the combined use of OncoCiDia and HIFU (Onco-HIFU-CiDia) as a synergistic treatment for malignant tumors to achieve a curative multimodality and multidrug regimen for patients with solid cancers, in accordance with the current trend of cancer patient care.

Faisability pilot study to explore inflammation with 18F-DPA-714 PET CT versus immunochemistry in triple negative breast cancer: Design protocol

The Triple Negative Breast Cancer (TNBC), despite a good initial response to conventional chemotherapy, relapses frequently and has a poor prognosis after the onset of metastases. It is therefore interesting to develop new relevant targets to establish a prognosis but also potentially to propose a targeted therapy for a theranostic approach. A high density of M2-type macrophages presence in the primary TNBC tumor predicted an unfavorable prognosis. The presence of activated M2-type macrophages can be evaluated by measuring the expression of a translocating protein (TSPO) with [18F]-DPA-714 PETCT. This proof-of-concept study with [18F]-DPA-714 PET-CT has a design to establish the correlation between immunohistochemistry tumor characterization and in vivo imaging. If a valid correlation will be established, [18F]-DPA-714 PET-CT could be a based image prognosis biomarker, apart from pathological data, which can be fragmented as biopsy or modified by previous treatments. It would allow adapting early the type/dose-intensity of treatment and considering developments of treatments targeting M2-type macrophages