Interaction of Radiopharmaceuticals with Somatostatin Receptor 2 Revealed by Molecular Dynamics Simulations

The development of drugs targeting somatostatin receptor 2 (SSTR2), generally overexpressed in neuroendocrine tumors, is focus of intense research. A few molecules in conjugation with radionuclides are in clinical use for both diagnostic and therapeutic purposes. These radiopharmaceuticals are composed of a somatostatin analogue biovector conjugated to a chelator moiety bearing the radionuclide. To date, despite valuable efforts, a detailed molecular-level description of the interaction of radiopharmaceuticals in complex with SSTR2 has not yet been accomplished. Therefore, in this work, we carefully analyzed the key dynamical features and detailed molecular interactions of SSTR2 in complex with six radiopharmaceutical compounds selected among the few already in use (64Cu/68Ga-DOTATATE, 68Ga-DOTATOC, 64Cu-SARTATE) and some in clinical development (68Ga-DOTANOC, 64Cu-TETATATE). Through molecular dynamics simulations and exploiting recently available structures of SSTR2, we explored the influence of the different portions of the compounds (peptide, radionuclide, and chelator) in the interaction with the receptor. We identified the most stable binding modes and found distinct interaction patterns characterizing the six compounds. We thus unveiled detailed molecular interactions crucial for the recognition of this class of radiopharmaceuticals. The microscopically well-founded analysis presented in this study provides guidelines for the design of new potent ligands targeting SSTR2

Essential Oils Loaded in Nanosystems: A Developing Strategy for a Successful Therapeutic Approach

Essential oils are complex blends of a variety of volatile molecules such as terpenoids, phenol-derived aromatic components, and aliphatic components having a strong interest in pharmaceutical, sanitary, cosmetic, agricultural, and food industries. Since the middle ages, essential oils have been widely used for bactericidal, virucidal, fungicidal, antiparasitical, insecticidal, and other medicinal properties such as analgesic, sedative, anti-inflammatory, spasmolytic, and locally anaesthetic remedies. In this review their nanoencapsulation in drug delivery systems has been proposed for their capability of decreasing volatility, improving the stability, water solubility, and efficacy of essential oil-based formulations, by maintenance of therapeutic efficacy. Two categories of nanocarriers can be proposed: polymeric nanoparticulate formulations, extensively studied with significant improvement of the essential oil antimicrobial activity, and lipid carriers, including liposomes, solid lipid nanoparticles, nanostructured lipid particles, and nano- and microemulsions. Furthermore, molecular complexes such as cyclodextrin inclusion complexes also represent a valid strategy to increase water solubility and stability and bioavailability and decrease volatility of essential oils

Molecular simulations of SSTR2 dynamics and interaction with ligands

The cyclic peptide hormone somatostatin regulates physiological processes involved in growth and metabolism, through its binding to G-protein coupled somatostatin receptors. The isoform 2 (SSTR2) is of particular relevance for the therapy of neuroendocrine tumours for which different analogues to somatostatin are currently in clinical use. We present an extensive and systematic computational study on the dynamics of SSTR2 in three different states: active agonist-bound, inactive antagonist-bound and apo inactive. We exploited the recent burst of SSTR2 experimental structures to perform μs-long multi-copy molecular dynamics simulations to sample conformational changes of the receptor and rationalize its binding to different ligands (the agonists somatostatin and octreotide, and the antagonist CYN154806). Our findings suggest that the apo form is more flexible compared to the holo ones, and confirm that the extracellular loop 2 closes upon the agonist octreotide but not upon the antagonist CYN154806. Based on interaction fingerprint analyses and free energy calculations, we found that all peptides similarly interact with residues buried into the binding pocket. Conversely, specific patterns of interactions are found with residues located in the external portion of the pocket, at the basis of the extracellular loops, particularly distinguishing the agonists from the antagonist. This study will help in the design of new somatostatin-based compounds for theranostics of neuroendocrine tumours

Risk Factors of Right Ventricular Dysfunction and Adverse Cardiac Events in Patients with Repaired Tetralogy of Fallot

Aim: This study evaluates the risk factors associated with right ventricular (RV) dilation and dysfunction leading to pulmonary valve replacement (PVR) or adverse cardiac events in repaired Tetralogy of Fallot (rToF) patients. Methods: Data from all rToF patients who underwent magnetic resonance imaging (MRI) evaluation at our hospital between February 2007 and September 2020 were collected. Results: Three hundred and forty-two patients (60% males, 42% older than 18 years), with a median age of 16 years (IQR 13–24) at the time of MRI, were included. All patients underwent complete repair at a median age of 8 months (IQR 5–16), while palliation was performed in 56 patients (16%). One hundred and forty-four patients (42%) subsequently received pulmonary valve replacement (PVR). At the multivariate analysis, male gender was an independent predictor for significant RV dilation, RV and left ventricular (LV) dysfunction. Transventricular ventricular septal defect (VSD) closure and previous palliation significantly affected LV function and RV size, respectively. Male gender and the transventricular VSD closure were independent predictors for PVR. Conclusions: Male gender and surgical history (palliation, VSD closure approach) significantly affected the long-term outcomes in rToF patients and should be taken into consideration in the follow-up management and in PVR timing in this patient population

Flavonoids Loaded in Nanocarriers: An Opportunity to Increase Oral Bioavailability and Bioefficacy"

Flavonoids are among the biggest group of polyphenols, widely distributed in plant-based foods. A plethora of evidence supports the health benefits and value of flavonoids can play in the physiological function treatment and in the prevention of disease particularly in the prevention of degenerative conditions including cancers, cardiovascular and neurodegenerative diseases. Hence, flavonoids represent the active constituents of many dietary supplements and herbal remedies, as well as there is an increasing interest in this class of polyphenols as functional ingredients of beverages, food grains and dairy products. Conversely, various studies have also shown that flavonoids have some drawbacks after oral administration such as stability, bioavailability and bioefficacy. This article reviews the current status of novel nanodelivery systems including nanospheres, nanocaspsules, micro- and nanoemulsions, micelles, solid lipid nanoparticles and nanostructured lipid capsules, successfully developed for overcoming the delivery challenges of flavonoids

Essential oils loaded in nanosystems: a developing strategy for a successful therapeutic approach,” Evidence-Based Complementary and Alternative Medicine, vol

Essential oils are complex blends of a variety of volatile molecules such as terpenoids, phenol-derived aromatic components, and aliphatic components having a strong interest in pharmaceutical, sanitary, cosmetic, agricultural, and food industries. Since the middle ages, essential oils have been widely used for bactericidal, virucidal, fungicidal, antiparasitical, insecticidal, and other medicinal properties such as analgesic, sedative, anti-inflammatory, spasmolytic, and locally anaesthetic remedies. In this review their nanoencapsulation in drug delivery systems has been proposed for their capability of decreasing volatility, improving the stability, water solubility, and efficacy of essential oil-based formulations, by maintenance of therapeutic efficacy. Two categories of nanocarriers can be proposed: polymeric nanoparticulate formulations, extensively studied with significant improvement of the essential oil antimicrobial activity, and lipid carriers, including liposomes, solid lipid nanoparticles, nanostructured lipid particles, and nano-and microemulsions. Furthermore, molecular complexes such as cyclodextrin inclusion complexes also represent a valid strategy to increase water solubility and stability and bioavailability and decrease volatility of essential oils

Interaction of Radiopharmaceuticals with Somatostatin Receptor 2 Revealed by Molecular Dynamics Simulations

The development of drugs targeting somatostatin receptor 2 (SSTR2), generally overexpressed in neuroendocrine tumors, is focus of intense research. A few molecules in conjugation with radionuclides are in clinical use for both diagnostic and therapeutic purposes. These radiopharmaceuticals are composed of a somatostatin analogue biovector conjugated to a chelator moiety bearing the radionuclide. To date, despite valuable efforts, a detailed molecular-level description of the interaction of radiopharmaceuticals in complex with SSTR2 has not yet been accomplished. Therefore, in this work, we carefully analyzed the key dynamical features and detailed molecular interactions of SSTR2 in complex with six radiopharmaceutical compounds selected among the few already in use (64Cu/68Ga-DOTATATE, 68Ga-DOTATOC, 64Cu-SARTATE) and some in clinical development (68Ga-DOTANOC, 64Cu-TETATATE). Through molecular dynamics simulations and exploiting recently available structures of SSTR2, we explored the influence of the different portions of the compounds (peptide, radionuclide, and chelator) in the interaction with the receptor. We identified the most stable binding modes and found distinct interaction patterns characterizing the six compounds. We thus unveiled detailed molecular interactions crucial for the recognition of this class of radiopharmaceuticals. The microscopically well-founded analysis presented in this study provides guidelines for the design of new potent ligands targeting SSTR2

Andrographolide-loaded nanoparticles for brain delivery: formulation, charcterization and in vitro permeability using hCMEC/D3 cell line

Andrographolide (AG) is a major diterpenoid of the Asian medicinal plant Andrographis paniculata which has shown exciting pharmacological potential for the treatment of inflammation-related pathologies including neurodegenerative disorders. Conversely, the low bioavailability of AG still represents a limiting factor for its use. To overcome these limitations, AG was loaded into human serum albumin based nanoparticles (HSA NPs) and poly ethylcyanoacrylate nanoparticles (PECA NPs). HSA NPs were prepared by thermal (HSAT AG NPs) and chemical cross-linking (HSAC AG NPs), while PECA AG NPs were produced by emulsion-polymerization. NPs were characterized in terms of size, zeta (ζ)-potential, polydispersity, and release studies of AG. In addition, the ability of free AG and AG-loaded in PECA and HSAT NPs to cross the blood-brain barrier (BBB) was assessed using an in vitro BBB model based on human cerebral microvascular endothelial cell line (hCMEC/D3). For BBB drug permeability assays, a quantitative UPLC-MS/MS method for AG in Ringer HEPES buffer was developed and validated according to international regulatory guidelines for industry. Free AG did not permeate the BBB model, as also predicted by in silico studies. HSAT NPs improved by two-fold the permeation of AG while maintaining the integrity of the cell layer, while PECA NPs temporarily disrupted BBB integrity