A Novel PSMA-Targeted Probe for NIRF-Guided Surgery and Photodynamic Therapy: Synthesis and Preclinical Validation

A total of 20% to 50% of prostate cancer (PCa) patients leave the surgery room with positive tumour margins. The intraoperative combination of fluorescence guided surgery (FGS) and photodynamic therapy (PDT) may be very helpful for improving tumour margin delineation and cancer therapy. PSMA is a transmembrane protein overexpressed in 90–100% of PCa cells. The goal of this work is the development of a PSMA-targeted Near InfraRed Fluorescent probe to offer the surgeon a valuable intraoperative tool for allowing a complete tumour removal, implemented with the possibility of using PDT to kill the eventual not resected cancer cells. PSMA-617 binding motif was conjugated to IRDye700DX-NHS and the conjugation did not affect the photophysical characteristics of the fluorophore. The affinity of IRDye700DX-PSMA-617 towards PCa cells followed the order of their PSMA expression, i.e., PC3-PIP > LNCaP > PC3, PC3-FLU. NIRF imaging showed a significant PC3-PIP tumour uptake after the injection of 1 or 5 nmol with a maximum tumour-to-muscle ratio (ca. 60) observed for both doses 24 h post-injection. Importantly, urine, healthy prostate, and the bladder were not fluorescent at 24 h post-injection. Flow cytometry and confocal images highlighted a co-localization of PSMA+ cells with IRDye700DX-PSMA uptake. Very interestingly, ex vivo analysis on a tumour specimen highlighted a significant PSMA expression by tumour-associated macrophages, likely attributable to extracellular vesicles secreted by the PSMA(+) tumour cells. FGS proved that IRDye700DX-PSMA was able to easily delineate tumour margins. PDT experiments showed a concentration-dependent decrease in cell viability (from 75% at 10 nM to 12% at 500 nM), whereas controls did not show any cytotoxicity. PC3-PIP tumour-bearing mice subjected to photodynamic therapy showed a delayed tumour growth. In conclusion, a novel PSMA-targeted NIRF dye with dual imaging-PDT capabilities was synthesized and displayed superior specificity compared to other small PSMA targeted molecules

NSCLC Biomarkers to Predict Response to Immunotherapy with Checkpoint Inhibitors (ICI): From the Cells to In Vivo Images

SIMPLE SUMMARY: Lung cancer and in particular non-small cell lung cancer (NSCLC) remains the leading cause of cancer-related death. The development of new therapeutic approaches, including immunotherapy, has led to substantial improvement in survival time and quality of life. However, the clinical benefit of immunotherapy-based strategies is still limited to a minority of patients, reflecting the need to identify predictive biomarkers of response, which are any substance, structure, or process or its products that can be measured in the body and that can influence or predict clinical response. In this work, we provide an overview of the approved and the most promising investigational biomarkers, which have been assessed in vitro/ex vivo and in vivo, to identify patients who could benefit the most from immunotherapy-based treatment. ABSTRACT: Lung cancer remains the leading cause of cancer-related death, and it is usually diagnosed in advanced stages (stage III or IV). Recently, the availability of targeted strategies and of immunotherapy with checkpoint inhibitors (ICI) has favorably changed patient prognosis. Treatment outcome is closely related to tumor biology and interaction with the tumor immune microenvironment (TME). While the response in molecular targeted therapies relies on the presence of specific genetic alterations in tumor cells, accurate ICI biomarkers of response are lacking, and clinical outcome likely depends on multiple factors that are both host and tumor-related. This paper is an overview of the ongoing research on predictive factors both from in vitro/ex vivo analysis (ranging from conventional pathology to molecular biology) and in vivo analysis, where molecular imaging is showing an exponential growth and use due to technological advancements and to the new bioinformatics approaches applied to image analyses that allow the recovery of specific features in specific tumor subclones

Hydrolyzed protein formula for allergy prevention in preterm infants: follow-up analysis of a randomized, triple-blind, placebo-controlled study

Background: Allergic diseases are a major public health burden worldwide. Evidence suggests that early nutrition might play a key role in the future development of allergies and the use of hydrolyzed protein formulas have been proposed to prevent allergic disease, mainly in term infants with risk factors. Aim: To evaluate the preventive effect of a hydrolyzed protein formula vs. an intact protein formula on allergy development in preterm infants with or without risk factors. Methods: We performed a 3-year follow-up study of a previous triple-blind, placebo-controlled randomized trial. Evidence of atopic dermatitis, asthma and IgE-mediated food allergies were evaluated according to a validated parental questionnaire (Comprehensive Early Childhood Allergy Questionnaire). Food sensitization was also investigated by skin prick test at 3 years of chronological age. Results: Of the 30 subjects in the intact protein formula group and 30 in the extensively hydrolyzed formula group, respectively 18 and 16 completed the 3-year follow-up and entered the final analysis. No group differences in the incidence of atopic dermatitis, asthma, IgE-mediated food allergies, and food sensitization were found. Conclusion: Despite the small number of cases, extensively hydrolyzed protein formula seems to be ineffective in allergic diseases prevention in preterm neonates. Further adequately powered, randomized controlled trials evaluating hydrolyzed protein formula administration to prevent allergic diseases in preterm neonates are needed

Development and Evaluation of the Magnetic Properties of a New Manganese (II) Complex: A Potential MRI Contrast Agent

Magnetic resonance imaging (MRI) is a non-invasive powerful modern clinical technique that is extensively used for the high-resolution imaging of soft tissues. To obtain high-definition pictures of tissues or of the whole organism this technique is enhanced by the use of contrast agents. Gadolinium-based contrast agents have an excellent safety profile. However, over the last two decades, some specific concerns have surfaced. Mn(II) has different favorable physicochemical characteristics and a good toxicity profile, which makes it a good alternative to the Gd(III)-based MRI contrast agents currently used in clinics. Mn(II)-disubstituted symmetrical complexes containing dithiocarbamates ligands were prepared under a nitrogen atmosphere. The magnetic measurements on Mn complexes were carried out with MRI phantom measurements at 1.5 T with a clinical magnetic resonance. Relaxivity values, contrast, and stability were evaluated by appropriate sequences. Studies conducted to evaluate the properties of paramagnetic imaging in water using a clinical magnetic resonance showed that the contrast, produced by the complex [Mn(II)(L’)2] × 2H2O (L’ = 1.4-dioxa-8-azaspiro[4.5]decane-8-carbodithioate), is comparable to that produced by gadolinium complexes currently used in medicine as a paramagnetic contrast agent

The Future of Cancer Diagnosis, Treatment and Surveillance: A Systemic Review on Immunotherapy and Immuno-PET Radiotracers

Immunotherapy is an effective therapeutic option for several cancers. In the last years, the introduction of checkpoint inhibitors (ICIs) has shifted the therapeutic landscape in oncology and improved patient prognosis in a variety of neoplastic diseases. However, to date, the selection of the best patients eligible for these therapies, as well as the response assessment is still challenging. Patients are mainly stratified using an immunohistochemical analysis of the expression of antigens on biopsy specimens, such as PD-L1 and PD-1, on tumor cells, on peritumoral immune cells and/or in the tumor microenvironment (TME). Recently, the use and development of imaging biomarkers able to assess in-vivo cancer-related processes are becoming more important. Today, positron emission tomography (PET) with 2-deoxy-2-[$^{18}$F]fluoro-D-glucose ([$^{18}$F]FDG) is used routinely to evaluate tumor metabolism, and also to predict and monitor response to immunotherapy. Although highly sensitive, FDG-PET in general is rather unspecific. Novel radiopharmaceuticals (immuno-PET radiotracers), able to identify specific immune system targets, are under investigation in pre-clinical and clinical settings to better highlight all the mechanisms involved in immunotherapy. In this review, we will provide an overview of the main new immuno-PET radiotracers in development. We will also review the main players (immune cells, tumor cells and molecular targets) involved in immunotherapy. Furthermore, we report current applications and the evidence of using [$^{18}$F]FDG PET in immunotherapy, including the use of artificial intelligence (AI)