Preclinical and clinical evaluation of German-sourced ONC201 for the treatment of H3K27M-mutant diffuse intrinsic pontine glioma.

BACKGROUND: Diffuse intrinsic pontine glioma (DIPG) is a fatal childhood brainstem tumor for which radiation is the only treatment. Case studies report a clinical response to ONC201 for patients with H3K27M-mutant gliomas. Oncoceutics (ONC201) is only available in the United States and Japan; however, in Germany, DIPG patients can be prescribed and dispensed a locally produced compound-ONC201 German-sourced ONC201 (GsONC201). Pediatric oncologists face the dilemma of supporting the administration of GsONC201 as conjecture surrounds its authenticity. Therefore, we compared GsONC201 to original ONC201 manufactured by Oncoceutics Inc. METHODS: Authenticity of GsONC201 was determined by high-resolution mass spectrometry and nuclear magnetic resonance spectroscopy. Biological activity was shown via assessment of on-target effects, in vitro growth, proliferation, and apoptosis analysis. Patient-derived xenograft mouse models were used to assess plasma and brain tissue pharmacokinetics, pharmacodynamics, and overall survival (OS). The clinical experience of 28 H3K27M+ mutant DIPG patients who received GsONC201 (2017-2020) was analyzed. RESULTS: GsONC201 harbored the authentic structure, however, was formulated as a free base rather than the dihydrochloride salt used in clinical trials. GsONC201 in vitro and in vivo efficacy and drug bioavailability studies showed no difference compared to Oncoceutics ONC201. Patients treated with GsONC201 (n = 28) showed a median OS of 18 months (P = .0007). GsONC201 patients who underwent reirradiation showed a median OS of 22 months compared to 12 months for GsONC201 patients who did not (P = .012). CONCLUSIONS: This study confirms the biological activity of GsONC201 and documents the OS of patients who received the drug; however, GsONC201 was never used as a monotherapy.

Considerations for using optical clearing techniques for 3D imaging of nanoparticle biodistribution.

A key consideration in the clinical translation of nanomedicines is determining their in vivo biodistribution in preclinical studies, which is important for predicting and correlating therapeutic efficacy and safety. There are a number of techniques available for analyzing the in vivo biodistribution of nanoparticles, with each having its own advantages and limitations. However, conventional techniques are limited by their inability to image the three-dimensional (3D) association of nanoparticles with cells, vasculature and other biological structures in whole organs at a subcellular level. Recently, optical clearing techniques have been used to evaluate the biodistribution of nanoparticles by 3D organ imaging. Optical clearing is a procedure that is increasingly being used to improve the imaging of biological tissues, whereby light scattering substances are removed to better match the refractive indices of different tissue layers. The use of optical clearing techniques has the potential to transform the way we evaluate the biodistribution of new and existing nanomedicines, as it allows the visualization of the interaction of nanoparticles with the biological environment in intact tissues. This review will compare the main optical clearing techniques and will address the considerations for the use of these techniques to evaluate nanoparticle biodistribution.

Can Hemp Help? Low-THC Cannabis and Non-THC Cannabinoids for the Treatment of Cancer.

Cannabis has been used to relieve the symptoms of disease for thousands of years. However, social and political biases have limited effective interrogation of the potential benefits of cannabis and polarised public opinion. Further, the medicinal and clinical utility of cannabis is limited by the psychotropic side effects of ∆9-tetrahydrocannabinol (∆9-THC). Evidence is emerging for the therapeutic benefits of cannabis in the treatment of neurological and neurodegenerative diseases, with potential efficacy as an analgesic and antiemetic for the management of cancer-related pain and treatment-related nausea and vomiting, respectively. An increasing number of preclinical studies have established that ∆9-THC can inhibit the growth and proliferation of cancerous cells through the modulation of cannabinoid receptors (CB1R and CB2R), but clinical confirmation remains lacking. In parallel, the anti-cancer properties of non-THC cannabinoids, such as cannabidiol (CBD), are linked to the modulation of non-CB1R/CB2R G-protein-coupled receptors, neurotransmitter receptors, and ligand-regulated transcription factors, which together modulate oncogenic signalling and redox homeostasis. Additional evidence has also demonstrated the anti-inflammatory properties of cannabinoids, and this may prove relevant in the context of peritumoural oedema and the tumour immune microenvironment. This review aims to document the emerging mechanisms of anti-cancer actions of non-THC cannabinoids.

Advantages and Limitations of Current Techniques for Analyzing the Biodistribution of Nanoparticles.

Nanomedicines are typically submicrometer-sized carrier materials (nanoparticles) encapsulating therapeutic and/or imaging compounds that are used for the prevention, diagnosis and treatment of diseases. They are increasingly being used to overcome biological barriers in the body to improve the way we deliver compounds to specific tissues and organs. Nanomedicine technology aims to improve the balance between the efficacy and the toxicity of therapeutic compounds. Nanoparticles, one of the key technologies of nanomedicine, can exhibit a combination of physical, chemical and biological characteristics that determine their in vivo behavior. A key component in the translational assessment of nanomedicines is determining the biodistribution of the nanoparticles following in vivo administration in animals and humans. There are a range of techniques available for evaluating nanoparticle biodistribution, including histology, electron microscopy, liquid scintillation counting (LSC), indirectly measuring drug concentrations, in vivo optical imaging, computed tomography (CT), magnetic resonance imaging (MRI), and nuclear medicine imaging. Each technique has its own advantages and limitations, as well as capabilities for assessing real-time, whole-organ and cellular accumulation. This review will address the principles and methodology of each technique and their advantages and limitations for evaluating in vivo biodistribution of nanoparticles.

Advantages and Limitations of Current Imaging Techniques for Characterizing Liposome Morphology.

There are currently a number of imaging techniques available for evaluating the morphology of liposomes and other nanoparticles, with each having its own advantages and disadvantages that should be considered when interpreting data. Controlling and validating the morphology of nanoparticles is of key importance for the effective clinical translation of liposomal formulations. There are a number of physical characteristics of liposomes that determine their in vivo behavior, including size, surface characteristics, lamellarity, and homogeneity. Despite the great importance of the morphology of nanoparticles, it is generally not well-characterized and is difficult to control. Appropriate imaging techniques provide important details regarding the morphological characteristics of nanoparticles, and should be used in conjunction with other methods to assess physicochemical parameters. In this review, we will discuss the advantages and limitations of available imaging techniques used to evaluate liposomal formulations.

A novel relationship between the radical-scavenging activity of flavonoids and enthalpy of formation revealed with Hartree-Fock computations and thermochemical deduction.

OBJECTIVE: The present study aims to establish the relationship between the reported radical-scavenging activities of flavonoids and some enthalpy changes that may occur during flavonoids' reactions with free radicals. METHOD: Eight flavonoids were chosen for the study on the basis of their structural merits and reported 1,1-diphenyl-2-picryl-hydrazyl scavenging activities. Enthalpy changes accompanying interconversions between selected conformations (including spin multiplicities) and homolytic dissociations were estimated. RESULTS: A novel relationship exists between the total enthalpy of reaction for the abstraction of two hydrogen atoms from flavonoids, their reported radical-scavenging activities and the enthalpy of the homolytic dissociation of hydrogen molecule (104.206 kcal mol(-1)). Only those flavonoids which could give up two hydrogen atoms with total enthalpy changes well below 104.206 kcal mol(-1) were active radical scavengers. DISCUSSION: By appealing to equilibrium dynamics, we demonstrated that, for flavonoids to be able to donate hydrogen atoms, the change in enthalpy accompanying the abstraction of two hydrogen atoms needs to be less than 104.206 kcal mol(-1). This condition does not seem to be restricted to flavonoids only but rather generally applicable to chian-breaking antioxidants. CONCLUSION: Thermodynamical relationships may be the most important factors governing the radical-scavenging reactions of flavonoids and possibly other compounds as well. Nevertheless, a more complete characterization of antioxidants would necessitate kinetic analysis.

Computation of the bond dissociation enthalpies and free energies of hydroxylic antioxidants using the ab initio Hartree-Fock method.

INTRODUCTION: A new method for calculating theoretical bond dissociation enthalpy (BDE) and bond dissociation free energy (BDFE) of hydroxylic antioxidants is forwarded. BDE and BDFE may be understood as activation energies accompanying the formation of transition states, which may undergo downhill homolytic dissociation. The new method does not involve the complete fission of O-H bonds. METHOD: Theoretical gas phase BDE values were calculated with the ab initio unrestricted Hartree-Fock (UHF) method, as changes in enthalpy between ground singlet states (GS) and triplet dissociative states (DS). Similarly, gas phase BDFEs were estimated from the corresponding changes in Gibbs free energy. The results were then compared with reliable experimental reports. RESULTS: The proposed theoretical approach of BDE and BDFE determination was tested using 10 simple phenols, 5 flavonoids, and l-ascorbic acid derivatives. The agreement between our calculated gas phase results and the adopted experimental values were generally within 0.5 kcal mol(-1), with a very few exceptions. DISCUSSION: Generally, steric interactions as well as intramolecular hydrogen bonding involving the dissociating OH group should be minimized in the GS. The DS are both electronically and vibrationally exited transition states. They have one unpaired electron on the carbon atom, which bears the homolytically dissociating OH group and are second order saddle points with a fixed

Effects of plant-derived polyphenols on TNF-alpha and nitric oxide production induced by advanced glycation endproducts.

Advanced glycation endproducts (AGEs) accumulate on protein deposits including the beta-amyloid plaques in Alzheimer's disease. AGEs interact with the "receptor for advanced glycation endproducts", and transmit their signals using intracellular reactive oxygen species as second messengers. Ultimately, AGEs induce the expression of a variety of pro-inflammatory markers including the tumor necrosis factor (TNF-alpha) and inducible nitric oxide (NO) synthase. Antioxidants that act intracellularly, including polyphenols, have been shown to scavenge these "signaling" reactive oxygen species, and thus perform in an anti-inflammatory capacity. This study tested the pure compounds apigenin and diosmetin as well as extracts from silymarin, uva ursi (bearberry) and green olive leaf for their ability to attenuate AGE-induced NO and TNF-alpha production. All five tested samples inhibited BSA-AGE-induced NO production in a dose-dependent manner. Apigenin and diosmetin were most potent, and exhibited EC(50) values approximately 10 microM. In contrast, TNF-alpha expression was only reduced by apigenin, diosmetin and silymarin; not by the bearberry and green olive leaf extracts. In addition, the silymarin and bearberry extracts caused significant cell death at concentrations >or=10 microg/mL and >or=50 microg/mL, respectively. In conclusion, we suggest that plant-derived polyphenols might offer therapeutic opportunities to delay the progression of AGE-mediated and receptor for advanced glycation endproducts-mediated neuro-inflammatory diseases including Alzheimer's disease.