Current Medicinal Chemistry - Volume 27, Issue 41, 2020

Upper respiratory tract infections include inflammations of the nose, sinuses (sinusitis), pharynx (tonsillitis, pharyngitis) and larynx (laryngitis) with bacteria or viruses as the main cause of these conditions. Due to their repetitive nature, chronic respiratory infections represent a global problem which is often a result of improper treatment. If not treated adequately, these conditions may have serious consequences. On the other hand, mis - and overuse of antibiotics has reduced their efficiency and accelerated the development of resistant bacterial strains, which further complicates the treatment of infections. This literature review will focus on current knowledge regarding medicinal plants and mushrooms which have been traditionally used in the treatment of infections caused by chronic sinusitis and tonsillitis commonly linked to bacteria - Staphylococcus aureus, Streptococcus pneumoniae, Streptococcus pyogenes, Fusobacterium nucleatum, Haemophilus influenzae and Moraxella catarrhalis. The present literature overview might be considered as a starting point for the development of novel, natural antimicrobial products with potential practical use in the treatment of chronic tonsillitis and sinusitis.

Background: The genus Achillea L. is rich in bioactive sesquiterpenes and flavonoids; most of the studied species exhibit several biological activities and are used as emmenagogue, wound healing and analgesic agents. Some species are also used in local folklore medicine. Objective: Following a literature survey, we discuss the anti-cancer properties of Achillea species, taking into consideration ethnopharmacological data on their use in traditional medicine for the treatment of cancer. In addition, we screened extracts and isolated secondary metabolites from A. coarctata for cytotoxicity, upon information based on local traditional medicine. The plant was collected in Kozani (Northern Greece), where it is locally used for treating gastrointestinal disorders, including stomach cancer. Methods: A selection of the relevant data was performed through a search in PubMed, Scopus, Google Scholar and Science Direct databases. In addition, extracts and isolated compounds from A. coarctata were tested for their in vitro activity against the human cancer cell lines MCF-7 and HeLa. Conclusion: The genus Achillea L. is a valuable source of bioactive secondary metabolites. The most significant outcome of the investigation of medicinal plants is the documentation and the assessment of the traditional information and its use and perspectives in the light of modern pharmacology.

Bioactive compounds derived from mushrooms have been shown to present promising potential as cosmeceutical or nutricosmetic ingredients. Scientific data reviewed herein showed that extracts prepared from medicinal and edible mushrooms and their individual metabolites presented antiinflammatory, antioxidant, photoprotective, antimicrobial, anti-tyrosinase, anti-elastase, and anticollagenase activities. These metabolites can be utilised as ingredients to suppress the severity of Inflammatory Skin Diseases, offer photoprotection to the skin, and correct Hyperpigmentation. However, studies regarding the molecular mechanism behind the mentioned bioactivities are still lacking. Challenges associated with the use of mushroom extracts and their associated metabolites as cosmeceutical and nutricosmetic ingredients include several steps from the fruiting bodies to the final product: extraction optimization, estimation of the efficacy and safety claims, the use of micro and nanocarriers to allow for controlled release and the pros and cons associated with the use of extracts vs individual compounds. This systematic review highlights that mushrooms contain diverse biomolecules that can be sustainably used in the development of nutricosmetic and cosmeceutical formulations. Reports regarding stability, compatibility, and safety assessment, but also toxicological studies are still needed to be considered. Furthermore, some of the constraints and limitations hindering the development of this type of ingredients still require long-term studies to achieve major breakthroughs.

Liver cancer/Hepatocellular Carcinoma (HCC) is a leading cause of cancer death and represents an important cause of mortality worldwide. Several biomarkers are overexpressed in liver cancer, such as Glypican 3 (GPC3) and Epidermal Growth Factor Receptor (EGFR). These biomarkers play important roles in the progression of tumors and could serve as imaging and therapeutic targets for this disease. Peptides with adequate stability, receptor binding properties, and biokinetic behavior have been intensively studied for liver cancer imaging. A great variety of them have been radiolabeled with clinically relevant radionuclides for liver cancer diagnosis, and many are promising imaging and therapeutic candidates for clinical translation. Herein, we summarize the advancement of radiolabeled peptides for the targeted imaging of liver cancer.

Breast cancer is the most common cancer in women worldwide. Due to the heterogeneous nature of breast cancer, the optimal treatment and expected response for each patient may not necessarily be universal. Molecular imaging techniques could play an important role in the early detection and targeted therapy evaluation of breast cancer. This review focuses on the development of peptides labeled with SPECT and PET radionuclides for breast cancer imaging. We summarized the current status of radiolabeled peptides for different receptors in breast cancer. The characteristics of radionuclides and major techniques for peptide labeling are also briefly discussed.

Receptor-targeted image-guided Radionuclide Therapy (TRT) is increasingly recognized as a promising approach to cancer treatment. In particular, the potential for clinical translation of receptor-targeted alpha-particle therapy is receiving considerable attention as an approach that can improve outcomes for cancer patients. Higher Linear-energy Transfer (LET) of alpha-particles (compared to beta particles) for this purpose results in an increased incidence of double-strand DNA breaks and improved-localized cancer-cell damage. Recent clinical studies provide compelling evidence that alpha-TRT has the potential to deliver a significantly more potent anti-cancer effect compared with beta-TRT. Generator-produced ²¹²Pb (which decays to alpha emitters ²¹²Bi and ²¹²Po) is a particularly promising radionuclide for receptor-targeted alpha-particle therapy. A second attractive feature that distinguishes ²¹²Pb alpha-TRT from other available radionuclides is the possibility to employ elementallymatched isotope ²⁰³Pb as an imaging surrogate in place of the therapeutic radionuclide. As direct non-invasive measurement of alpha-particle emissions cannot be conducted using current medical scanner technology, the imaging surrogate allows for a pharmacologically-inactive determination of the pharmacokinetics and biodistribution of TRT candidate ligands in advance of treatment. Thus, elementally-matched ²⁰³Pb labeled radiopharmaceuticals can be used to identify patients who may benefit from ²¹²Pb alpha-TRT and apply appropriate dosimetry and treatment planning in advance of the therapy. In this review, we provide a brief history on the use of these isotopes for cancer therapy; describe the decay and chemical characteristics of ²⁰³/²¹²Pb for their use in cancer theranostics and methodologies applied for production and purification of these isotopes for radiopharmaceutical production. In addition, a medical physics and dosimetry perspective is provided that highlights the potential of ²¹²Pb for alpha-TRT and the expected safety for ²⁰³Pb surrogate imaging. Recent and current preclinical and clinical studies are presented. The sum of the findings herein and observations presented provide evidence that the ²⁰³Pb/²¹²Pb theranostic pair has a promising future for use in radiopharmaceutical theranostic therapies for cancer.

Protein interactions are the basis for the biological functioning of human beings. However, many of these interactions are also responsible for diseases, including cancer. Synthetic inhibitors of protein interactions based on small molecules are widely investigated in medicinal chemistry. The development of radiolabeled protein-inhibitor peptides for molecular imaging and targeted therapy with quickstep towards clinical translation is an interesting and active research field in the radiopharmaceutical sciences. In this article, recent achievements concerning the design, translational research and theranostic applications of structurally-modified small radiopeptides, such as prostate-specific membrane antigen (PSMA) inhibitors, fibroblast activation protein (FAP) inhibitors and antagonists of chemokine-4 receptor ligands (CXCR-4-L), with high affinity for cancer-associated target proteins, are reviewed and discussed.

This review describes the usefulness of in silico design approaches in the design of new radiopharmaceuticals, especially peptide-based radiotracers (including peptidomimetics). Although not part of the standard arsenal utilized during radiopharmaceutical design, the use of in silico strategies is steadily increasing in the field of radiochemistry as it contributes to a more rational and scientific approach. The development of new peptide-based radiopharmaceuticals as well as a short introduction to suitable computational approaches are provided in this review. The first section comprises a concise overview of the three most useful computeraided drug design strategies used, namely i) a Ligand-based Approach (LBDD) using pharmacophore modelling, ii) a Structure-based Design Approach (SBDD) using molecular docking strategies and iii) Absorption-Distribution-Metabolism-Excretion-Toxicity (ADMET) predictions. The second section summarizes the challenges connected to these computer-aided techniques and discusses successful applications of in silico radiopharmaceutical design in peptide-based radiopharmaceutical development, thereby improving the clinical procedure in Nuclear Medicine. Finally, the advances and future potential of in silico modelling as a design strategy is highlighted.

Apoptosis is a regulated cell death induced by extrinsic and intrinsic stimulants. Tracking of apoptosis provides an opportunity for the assessment of cardiovascular and neurodegenerative diseases as well as monitoring of cancer therapy at early stages. There are some key mediators in apoptosis cascade, which could be considered as specific targets for delivering imaging or therapeutic agents. The targeted radioisotope-based imaging agents are able to sensitively detect the physiological signal pathways which make them suitable for apoptosis imaging at a single-cell level. Radiopeptides take advantage of both the high sensitivity of nuclear imaging modalities and favorable features of peptide scaffolds. The aim of this study is to review the characteristics of those radiopeptides targeting apoptosis with different mechanisms.

Background: Radionuclide molecular imaging of Gastrin-Releasing Peptide Receptor (GRPR) expression promises unparalleled opportunities for visualizing subtle prostate tumors, which due to small size, adjacent benign tissue, or a challenging location would otherwise remain undetected by conventional imaging. Achieving high imaging contrast is essential for this purpose and the molecular design of any probe for molecular imaging of prostate cancer should be aimed at obtaining as high tumor-to-organ ratios as possible. Objective: This short review summarizes the key imaging modalities currently used in prostate cancer, with a special focus on radionuclide molecular imaging. Emphasis is laid mainly on the issue of radiometals labeling chemistry and its influence on the targeting properties and biodistribution of radiolabeled GRPR antagonists for imaging of disseminated prostate cancer. Methods: A comprehensive literature search of the PubMed/MEDLINE, and Scopus library databases was conducted to find relevant articles. Results: The combination of radionuclide, chelator and required labeling chemistry was shown to have a significant influence on the stability, binding affinity and internalization rate, off-target interaction with normal tissues and blood proteins, interaction with enzymes, activity uptake and retention in excretory organs and activity uptake in tumors of radiolabeled bombesin antagonistic analogues. Conclusion: Labeling chemistry has a very strong impact on the biodistribution profile of GRPRtargeting peptide based imaging probes and needs to be considered when designing a targeting probe for high contrast molecular imaging. Taking into account the complexity of in vivo interactions, it is not currently possible to accurately predict the optimal labeling approach. Therefore, a detailed in vivo characterization and optimization is essential for the rational design of imaging agents.

A wide variety of radiolabeled peptide analogs for specific targeting of cholecystokinin- 2 receptors (CCK2R) has been developed in the last decades. Peptide probes based on the natural ligands Minigastrin (MG) and Cholecystokinin (CCK) have a high potential for molecular imaging and targeted radiotherapy of different human tumors, such as Medullary Thyroid Carcinoma (MTC) and Small Cell Lung Cancer (SCLC). MG analogs with high persistent uptake in CCK2R expressing tumors have been preferably used for the development of radiolabeled peptide analogs. The clinical translation of CCK2R targeting has been prevented due to high kidney uptake or low metabolic stability of the different radiopeptides developed. Great efforts in radiopharmaceutical development have been undertaken to overcome these limitations. Various modifications in the linear peptide sequence of MG have been introduced mainly with the aim to reduce kidney retention. Furthermore, improved tumor uptake could be obtained by in situ stabilization of the radiopeptide against enzymatic degradation through coinjection of peptidase inhibitors. Recent developments focusing on the stabilization of the Cterminal receptor binding sequence (Trp-Met-Asp-Phe-NH2) have led to new radiolabeled MG analogs with highly improved tumor uptake and tumor-to-kidney ratio. In this review, all the different aspects in the radiopharmaceutical development of CCK2R targeting peptide probes are covered, giving also an overview on the clinical investigations performed so far. The recent development of radiolabeled MG analogs, which are highly stabilized against enzymatic degradation in vivo, promises to have a high impact on the clinical management of patients with CCK2R expressing tumors in the near future.