Current Pharmaceutical Design - Volume 26, Issue 31, 2020

Prostate cancer is the most prevalent type of cancer and the second cause of death in men worldwide. Various diagnostic and treatment procedures are available for this type of malignancy, but High-grade or locally advanced prostate cancers showed the potential to develop to lethal phase that can be causing dead. Therefore, new approaches are needed to prolong patients’ survival and to improve their quality of life. Precision medicine is a novel emerging field that plays an essential role in identifying new sub-classifications of diseases and in providing guidance in treatment that is based on individual multi-omics data. Multi-omics approaches include the use of genomics, transcriptomics, proteomics, metabolomics, epigenomics and phenomics data to unravel the complexity of a disease-associated biological network, to predict prognostic biomarkers, and to identify new targeted drugs for individual cancer patients. We review the impact of multi-omics data in the framework of systems biology in the era of precision medicine, emphasising the combination of molecular imaging modalities with highthroughput techniques and the new treatments that target metabolic pathways involved in prostate cancer.

A novel approach to current radiopharmaceutical study design to document the efficiency of 177Lu- PSMA-radioligand therapy of metastatic prostate cancer is described in a proposed prospective, real-time, realworld audit of a large patient population worldwide. The NIGHTCAP (National Investigators Global Harmonisation Theragnostics of Cancer of Prostate) Study will establish real-world evidence (RWE) of overall survival (OS) and quality of life (QoL) in patients undergoing routine 177Lu-PSMA-radioligand therapy on harmonised compassionate patient-usage protocols throughout the world. Such long-term efficiency data will be contrasted with the short-term randomised controlled trial (RCT) assessments of efficacy predicated upon surrogate markers of survival outcomes, such as progression-free survival (PFS). The shortcomings of RCT evaluation of the clinical benefit of new anticancer agents are detailed in this review, which advocates RWE to determine efficiency. The real-time monitoring of QoL in the NIGHTCAP Study is independent of questionnaires, language differences, or oncologist bias, and relies upon individual patient self-assessment by choice of one of five emoji which best reflects their mood each day.

The optimum selection of the appropriate radiolabelled probe for the right target and the right patient is the foundation of theranostics in personalised medicine. In nuclear medicine, this process is realised through the appropriate choice of radiopharmaceuticals based on molecular biomarkers regarding molecular imaging. Theranostics is developing a strategy that can be used to implement accepted tools for individual molecular targeting, including diagnostics, and advances in genomic molecular knowledge, which has led to identifying theranostics biomaterials that have the potency to diagnose and treat malignancies. Today, numerous studies have reported on the discovery and execution of these radiotracers in personalised medicine. In this review, we presented our point of view of the most important theranostics agents that can be used to treat several types of malignancies. Molecular targeted radionuclide treatment methods based on theranostics are excellent paradigms of the relationship between molecular imaging and therapy that has been used to provide individualised or personalised patient care. Toward that end, a precise planned prospective examination of theranostics must be done to compare this approach to more standard therapies.

This review of radioactive iodide treatment (RAIT) extends from historical origins to its modern utilization in differentiated thyroid cancer (DTC). The principles embedded in the radiotheragnostics (RTGs) paradigm are detailed. The diverse approaches in current practice are addressed, and this broad variability represents a major weakness that erodes our specialty’s trust-based relationship with patients and referring physicians. The currently developing inter-specialty collaboration should be hailed as a positive change. It promises to clarify the target-based terminology for RAIT. It defines RAIT of post total thyroidectomy (PTT), presumably benign thyroid as ‘remnant ablation’ (RA). ‘Adjuvant treatment’ (AT) referrers to RAIT of suspected microscopic DTC that is inherently occult on diagnostic imaging. RAIT directed at DTC lesion(s) overtly seen on diagnostic imaging is termed ‘treatment of known disease’ (TKD). It was recently recognized that a ‘recurrent’ DTC is actually occult residual DTC in the majority of cases. Thyroglobulin with remnant uptake concord (TRUC) method (aka Tulchinsky method) was developed to validate that a benign remnant in the post-thyroidectomy neck bed, as quantified by the RAI uptake, is concordant with a measured thyroglobulin (Tg) level at the time of the initial post-thyroidectomy evaluation. It allows recognition of occult residual DTC contribution to post-thyroidectomy Tg. Case examples demonstrate the application of the TRUC method for a logical selection of a specific RAIT category, using imaging-guided identification and management of RAI-avid versus RAI-nonavid residual DTC, i.e. the radiotheragnostics paradigm.

Background: Nanoparticle imaging and tracking the release of the loaded material from the nanoparticle system have attracted significant attention in recent years. If the release of the loaded molecules could be monitored reliably in vivo, it would speed up the development of drug delivery systems remarkably. Methods: Here, we test a system that uses indocyanine green (ICG) as a fluorescent agent for studying release kinetics in vitro and in vivo from the lipid iron nanoparticle delivery system. The ICG spectral properties like its concentration dependence, sensitivity and the fluctuation of the absorption and emission wavelengths can be utilized for gathering information about the change of the ICG surrounding. Results: We have found that the absorption, fluorescence, and photoacoustic spectra of ICG in lipid iron nanoparticles differ from the spectra of ICG in pure water and plasma. We followed the ICG containing liposomal nanoparticle uptake into squamous carcinoma cells (SCC) by fluorescence microscopy and the in vivo uptake into SCC tumors in an orthotopic xenograft nude mouse model under a surgical microscope. Conclusion: Absorption and emission properties of ICG in the different solvent environment, like in plasma and human serum albumin, differ from those in aqueous solution. Photoacoustic spectral imaging confirmed a peak shift towards longer wavelengths and an intensity increase of ICG when bound to the lipids. The SCC cells showed that the ICG containing liposomes bind to the cell surface but are not internalized in the SCC-9 cells after 60 minutes of incubation. We also showed here that ICG containing liposomal nanoparticles can be traced under a surgical camera in vivo in orthotopic SCC xenografts in mice.

Background: Occult metastases are common in patients with oral squamous cell carcinoma (OSCC) which is why elective neck dissection, adjuvant radiotherapy or watchful waiting have been treatment options after surgical removal of the primary tumour. Sentinel lymph node biopsy (SLNB) has lately emerged as a novel possibility in treatment planning. Objectives: To establish a reliable and clinically useful protocol for SLNB in staging/elective neck dissection in oral cancer. Methods: Fourteen consecutive patients with T1-T2 N0 oral cancer were enrolled when scheduled for elective neck dissection. Results: This study outlines various techniques for improving SLNB in head and neck cancer. After evaluation, a combination of techniques was found to constitute a reliable, clinically adaptable work concept. The suggested procedure starts with the pre-surgical injection of radioactive technetium 99Tcm carried on tilmanocept (Lymphoseek ®) at the tumour site. The radioactivity in the lymph node is then visualized preoperatively with Single Photon Emission Computed Tomography (SPECT/CT). Intraoperatively, indocyanine green (ICG) is injected and a sentinel node is visualized with near-infrared light. To support the sentinel node detection, the surgeon uses a hand-held gamma detection probe. This approach results in a reproducible and reliable detection of sentinel nodes. Conclusion: This paper presents a novel protocol for the identification of the sentinel node in the head and neck region. The protocol additionally enables the use of flow cytometry analysis of resected lymph nodes.

Background: The purpose of our study was to find a novel targeted imaging and drug delivery vehicle for inflammatory bowel disease (IBD). IBD is a common and troublesome disease that still lacks effective therapy and imaging options. As an attempt to improve the disease treatment, we tested αMSH for the targeting of nanoliposomes to IBD sites. αMSH, an endogenous tridecapeptide, binds to the melanocortin-1 receptor (MC1-R) and has anti-inflammatory and immunomodulating effects. MC1-R is found on macrophages, neutrophils and the renal tubule system. We formulated and tested a liposomal nanoparticle involving αMSH in order to achieve a specific targeting to the inflamed intestines. Methods: NDP-αMSH peptide conjugated to Alexa Fluor™ 680 was linked to the liposomal membrane via NSuccinyl PE and additionally loaded into the lumen of the liposomes. Liposomes without the αMSH-conjugate and free NDP-αMSH were used as a control. The liposomes were also loaded with ICG to track them. The liposomes were tested in DSS treated mice, which had received DSS via drinking water order to develop a model IBD. Inflammation severity was assessed by the Disease Activity Index (DAI) score and ex vivo histological CD68 staining of samples taken from different parts of the intestine. The liposome targeting was analyzed by analyzing the ICG and ALEXA 680 fluorescence in the intestine compared to the biodistribution. Results: NPD-αMSH was successfully labeled with Alexa and retained its biological activity. Liposomes were identified in expected regions in the inflamed bowel regions and in the kidneys, where MC1-R is abundant. In vivo liposome targeting correlated with the macrophage concentration at the site of the inflammation supporting the active targeting of the liposomes through αMSH. The liposomal αMSH was well tolerated by animals. Conclusion: This study opens up the possibility to further develop an αMSH targeted theranostic delivery to different clinically relevant applications in IBD inflammation but also opens possibilities for use in other inflammations like lung inflammation in Covid 19.

The low water solubility and low bioavailability of natural bioactive substances such as polyphenols and flavonoids, either in pure form or extracts, are a major concern in the pharmaceutical field and even on the food development sector. Although encapsulation has demonstrated success in addressing these drawbacks, it is important to evaluate the antioxidant activity of the encapsulated compounds. This article reviews the encapsulation of bioactive compounds from natural sources focusing their antioxidant activity after encapsulation. Attention is given to the methods and wall materials used, and the antioxidant activity methodologies (classical in vitro techniques such as DPPH, ORAC, FRAP and others, as well as in vivo/ex vivo tests to evaluate endogenous antioxidant enzymes or oxidative stress) applied to assess the antioxidant capacity are also comprehensively summarized.

There is an increasing number of therapeutic agents being developed for the treatment of pulmonary artery hypertension (PAH) which is a condition characterized by raised pulmonary artery pressure and right heart failure. Despite our better understanding of the pathophysiology of PAH, the treatment outcomes are still suboptimal. There is growing evidence suggesting the role of increases in the levels of aldosterone, which is a mineralocorticoid hormone, in the pathophysiology of PAH; however, the extent to which hyperaldosteronism is associated with PAH in patients is unclear. There are also a few studies assessing the effects of mineralocorticoid receptor antagonists (MRA) in PAH. MRAs are a recognized treatment for heart failure and hypertension. In this review, we focus on the relationship between aldosterone level in patients with PAH and right ventricular failure and the effect of MRAs on the PAH severity.

Background: Schizophrenia belongs to mental illnesses affecting 1% of the worldwide population. Its therapy is still unmet; thus, researchers aimed to develop new pharmacological molecules which can improve its management. Methods: Moreover, the current typical and atypical antipsychotics should be formulated in more efficacious systems that can deliver the drug in the brain with as few side effects as possible. Further, the development of long-acting efficient drug delivery systems could be significant in minimizing frequent dosing which is nonpreferred to schizophrenics. Results: Herein, authors focused on current developments of antipsychotic medications used in schizophrenia management. Various studies, which include the use of first and second-generation antipsychotics, were analyzed according to their efficacy. In fact, in this review, oral, injectable, transdermal and intranasal formulations entrapped antipsychotics are presented to be valuable guidance for scientists to formulate more effective drug delivery systems for schizophrenic patients. Conclusion: This review aimed to assist researchers working on schizophrenia management by summarizing current medications and newly synthesized drug delivery systems recently found in the literature.

Background: Psychotic states related to psychostimulant misuse in patients with hepatitis C virus infection may complicate acceptance and reaction to antiviral treatment. This observation equally applies to the widely used ribavirin therapy. Objective: We examined psychomotor and body weight gain responses to low ribavirin doses after cessation of intermittent amphetamine treatment in adult rats to assess its role in neurobehavioral outcome during psychostimulant withdrawal. Method: The model of amphetamine-induced (1.5 mg/kg/day, i.p., 7 consecutive days) motor sensitization and affected body weight gain was established in adult male Wistar rats. Then, additional cohort of amphetaminesensitized rats was subjected to saline (0.9% NaCl; 1 mL/kg/day; i.p.) or ribavirin (10, 20 and 30 mg/kg/day, i.p.) treatment for 7 consecutive days. Animals’ motor activity in a novel environment was monitored after the 1st and the 7th saline/ribavirin injection. Body weight gain was calculated as appropriate. Determination and quantification of ribavirin in the brain tissue were performed also. Results: The 1st application of ribavirin to amphetamine-sensitized rats affected/decreased their novelty-induced motor activity only at a dose of 30 mg/kg. After the 7th application, ribavirin 30 mg/kg/day still decreased, while 10 and 20 mg/kg/day increased novelty-induced motor activity. These behavioral effects coincided with the time required to reach maximum ribavirin concentration in the brain. Body weight gain during withdrawal was not influenced by any of the doses tested. Conclusion: Ribavirin displays central effects that in repeated treatment, depending on the applied dose, could significantly influence psychomotor response but not body weight gain during psychostimulant/amphetamine withdrawal.

Background: Plant lectins have shown promising biological activities in the central nervous system (CNS). Objective: This study evaluated the effect of DAL, a lectin isolated from the seeds of the Dioclea altissima species, having binding affinity to D-glucose or D-mannose residues, on mice behavior. Methods: Mice (n=6/group) were treated (i.p.) with DAL (0.25, 0.5 or 1 mg/kg) or vehicle and subjected to several tests (open field/OFT, marble-burying/MBT, hole-board/HBT, elevated plus maze/PMT, tail suspension/ TST, forced swimming/FST or rotarod/RRT). Pizotifen, cyproheptadine, flumazenil, L-NAME, 7-NI, Larginine or yohimbine were administered 15 min before DAL (0.5 mg/kg) and the animals were evaluated on PMT. It was also verified whether the DAL effect depended on its structural integrity and ability to interact with carbohydrates. Results: The results showed there were no neurobehavioral changes in the mice at the RRT, FST and locomotion in the OFT. DAL (0.25, 0.5 or 1 mg/kg) increased the behavior of grooming and rearing in the OFT, head dips in the HBT, pedalling in the TST and decreased the number of marbles hidden in the MBT. In the PMT, DAL (0.25, 0.5 and 1 mg/kg) and Diazepam increased the frequency of entries in the open arms and the time of permanence in the open arms without affecting the locomotor activity. The effect of DAL was dependent on carbohydrate interaction and protein structure integrity and it prevented by pizotifen, cyproheptadine, flumazenil, L-NAME and 7-NI, but not by L-arginine or yohimbine. Conclusion: DAL was found to have an anxiolytic-like effect mediated by the 5-HT and GABAergic receptors and NO pathway.