Pier Cesare Capponi

In recent years, advancements in imaging techniques have contributed to a gradual yet promising reduction in colorectal cancer-related mortality. Among these, positron emission tomography (PET), particularly in combination with computed tomography using 2-deoxy-2-[fluorine-18]fluoro-D-glucose ([¹⁸F]FDG), has emerged as a valuable non-invasive diagnostic tool. However, the application of [¹⁸F]FDG-PET in colorectal cancer remains limited because of the radiotracer's pharmacokinetics and metabolic characteristics. As a result, [¹⁸F]FDG-PET is not routinely recommended for the initial diagnosis or staging of colorectal cancer but is primarily used for assessing treatment response and disease surveillance. Additionally, colorectal cancer imaging with [¹⁸F]FDG presents challenges related to false-positive results caused by radiotracer uptake in non-malignant conditions such as inflammatory bowel disease, polyps, Crohn's disease, and colitis. This inability to reliably distinguish between benign and malignant lesions remains a significant limitation in colorectal cancer imaging. To overcome these challenges, ongoing research is focused on the development of novel radiotracers capable of improving the specificity and accuracy of PET imaging in colorectal cancer. New radiolabeled probes are being investigated, including natural molecules, inflammatory markers, and target-specific immune elements, labeled with [¹⁸F], [⁶⁸Ga], [¹¹C], and [⁶⁴Cu], which have shown potential in preclinical studies. Among emerging radiopharmaceuticals for colorectal cancer, only [⁶⁸Ga]Ga-HNI01 and [⁶⁸Ga]Ga-FAPI-04 have advanced to preliminary clinical evaluation phases. Despite promising initial diagnostic performance, these investigations remain limited in scale and scope, necessitating further rigorous, large-scale clinical trials to validate efficacy and safety. All these advancements could significantly enhance colorectal cancer detection and characterization, leading to earlier diagnoses and better patient outcomes.

Natural products often provide a pool of pharmacologically relevant precursors for the development of various drug-related molecules. In this review, the research performed on some radiolabeled chalcone derivatives characterized by the presence of the α-β unsaturated carbonyl functional group as potential radiotracers for the imaging of β-amyloids plaques will be summarized. Chalcones’ structural modifications and chemical approaches which allow their radiolabeling with the most common SPECT (Single Photon Emission Computed Tomography) and PET (Positron Emission Tomography) radionuclides will be described, as well as the state of the art regarding their in vitro binding affinity and in vivo biodistribution and pharmacokinetics in preclinical studies. Moreover, an explanation of the rationale behind their potential utilization as probes for Alzheimer’s disease in nuclear medicine applications will be provided.

Curcumin is known for its therapeutic properties; among these, antioxidant, anti-inflammatory and anti-cancer ones stand out. Besides, curcumin metal complexes have shown widespread application in medicine and can be exploited as lead structures for developing metal-based drugs. Unfortunately, curcumin is poorly bioavailable, mainly due to its instability in physiological conditions; this weakness is tightly connected to the presence of the β-diketo moiety undergoing tautomeric equilibrium. Stability and metal-chelating ability can be tuned by modulating the electronic effects and steric hindrance close to the β-diketo moiety; in addition, formation of a metal complex shifts the tautomeric equilibrium towards the β-keto–enol form and increases stability in biological media. Among the metals used in clinical therapy, gallium nitrate has shown to have significant antitumor activity against non-Hodgkin lymphoma and bladder cancer, thus indicating that gallium-based drugs have potential for further development as antineoplastic agents with improved therapeutic activity. Curcuminoids have demonstrated high affinity for gallium(III), allowing the formation of stable positively charged M:L 1:2 β-diketonate complexes that benefit from the therapeutic activity of both the metal and the ligand. Seven new curcumin derivatives were synthesized and completely characterized. The new derivatives retain the solvent-dependent keto–enol tautomerism, with the prevalence of the diketo form in aqueous solution. Enhanced stability in simulated physiological conditions was observed in comparison to the lead compound curcumin. The presence of Ga³⁺ anticipates the dissociation of the enolic proton, allowing chelate complex formation, and simultaneously it shifts the tautomeric equilibrium towards the keto–enol form. A complete ¹H/¹³C NMR and UV–Vis study was performed to define the metal-to-ligand stoichiometry ratio and the overall stability constants. In addition, we demonstrated that some of the derivatives have increased antiproliferative activity on colon cancer cells compared to curcumin and antioxidant properties. On the whole, the synthesized curcumin-based molecules may act as new gallium(III) chelators with improved stability with respect to curcumin and could open interesting perspectives for the development of novel therapeutic agents for cancer.

L-ascorbic acid, is a well-known molecule, sometimes used as antioxidant for skin care. Nonetheless, few studies have taken in account its utility as topical treatment for non-melanoma skin vancer. Non-melanoma skin cancer includes basal cell carcinoma and squamous cell carcinoma and is widespread worldwide with an increasing incidence. The purpose of this paper is to analyze the characteristics of L-ascorbic acid topical formulation, its percutaneous absorption and biochemical mechanism, focusing on its anti-cancer properties. In particular, it will be described how the pH and the concentration of the formulation are able to influence its distribution in the skin and tissues. We will report, the current knowledge on the pharmacokinetic aspects of L-ascorbic acid that allows us to reconsider it in the light of its ability to act as a prodrug and as an anticancer agent. Lastly, a short review with the aim to find any evidence of a possible clinical use of L-ascorbic acid for the treatment of non-melanoma skin cancer was made.

Clinical use of topical ascorbic acid solution could have both the role as an adjunct to consolidated therapies and as an alternative to them, for the treatment of BCC and SCC of the skin.

MiRNAs are single stranded RNAs of 18–22 nucleotides. They are promising diagnostic and prognostic markers for several pathologies including tumors, neurodegenerative, cardiovascular and autoimmune diseases. In the present work the development and characterization of anti-miRNA radiolabeled probes based on peptide nucleic acids (PNAs) for potential non-invasive molecular imaging in vivo of giant cell arteritis are described. MiR-146a and miR-146b-5p were selected as targets because they have been found up-regulated in this disease. Anti-miR and scramble PNAs were synthesized and linked to carboxyfluorescein or DOTA. DOTA-anti-miR PNAs were then labelled with copper-64 (⁶⁴Cu) to function as non-invasive molecular imaging tools. The affinity of the probes for the targets was assessed in vitro by circular dichroism and melting temperature. Differential uptake of fluorescein and ⁶⁴Cu labeled anti-miRNA probes was tested on BCPAP and A549 cell lines, expressing different levels of miR-146a and -146b-5p. The experiments showed that the anti-miR-146a PNAs were more effective than the anti-miR-146b-5p PNAs. Anti-miR-146a PNAs could bind both miR-146a and miR-146b-5p. The uptake of fluorescein and ⁶⁴Cu labeled anti-miR-146a PNAs was higher than that of the negative control scramble PNAs in miRNA expressing cells in vitro. ⁶⁴Cu-anti-miR-146a PNAs might be further investigated for non-invasive PET imaging of miR-146 overexpressing diseases.

Colorectal cancer is the third most commonly occurring cancer in men and the second most commonly occurring cancer in women worldwide. We have recently reported that curcuminoid complexes labelled with gallium-68 have demonstrated preferential uptake in HT29 colorectal cancer and K562 lymphoma cell lines compared to normal human lymphocytes. In the present study, we report a new gallium-68-labelled curcumin derivative (⁶⁸Ga-DOTA-C21) and its initial validation as marker for early detection of colorectal cancer. The precursor and non-radioactive complexes were synthesized and deeply characterized by analytical methods then the curcuminoid was radiolabelled with gallium-68. The in vitro stability, cell uptake, internalization and efflux properties of the probe were studied in HT29 cells, and the in vivo targeting ability and biodistribution were investigated in mice bearing HT29 subcutaneous tumour model. ⁶⁸Ga-DOTA-C21 exhibits decent stability (57 ± 3% after 120 min of incubation) in physiological media and a curcumin-mediated cellular accumulation in colorectal cancer cell line (121 ± 4 KBq of radiotracer per mg of protein within 60 min of incubation). In HT29 tumour-bearing mice, the tumour uptake of ⁶⁸Ga-DOTA-C21 is 3.57 ± 0.3% of the injected dose per gram of tissue after 90 min post injection with a tumour to muscle ratio of 2.2 ± 0.2. High amount of activity (12.73 ± 1.9% ID/g) is recorded in blood and significant uptake of the radiotracer occurs in the intestine (13.56 ± 3.3% ID/g), lungs (8.42 ± 0.8% ID/g), liver (5.81 ± 0.5% ID/g) and heart (4.70 ± 0.4% ID/g). Further studies are needed to understand the mechanism of accumulation and clearance; however, ⁶⁸Ga-DOTA-C21 provides a productive base-structure to develop further radiotracers for imaging of colorectal cancer.