Transferrin-conjugated UiO-66 metal organic frameworks loaded with doxorubicin and indocyanine green: A multimodal nanoplatform for chemo-photothermal-photodynamic approach in cancer management.

Stimuli-responsive nanoplatforms have been popular in controlled drug delivery research because of their ability to differentiate the tumor microenvironment from the normal tissue environment in a spatiotemporally controllable manner. The synergistic therapeutic approach of combining cancer chemotherapy with photothermal tumor ablation has improved the therapeutic efficacy of cancer therapeutics. In this study, a UiO-66 metal organic framework (MOF)-based system loaded with doxorubicin (DOX), surface decorated with the photothermal agents indocyanine green (ICG) and polydopamine (PDA), and conjugated with transferrin (TF) was successfully designed to operate as a responsive system to pH changes, featuring photothermal capabilities and target specificity for the purpose of treating breast cancer. The synthesized nanoplatform benefits from its uniform size, excellent DOX encapsulation efficiency (91.66 %), and efficient pH/NIR-mediated controlled release of the drug. In vitro photothermal studies indicate excellent photothermal stability of the formulation even after 6 on-off cycles of NIR irradiation. The in vitro cytotoxicity assessment using an NIR laser (808 nm) revealed that the DOX-loaded functionalized UiO-66 nanocarriers had outstanding inhibitory effects on 4T1 cells because of synergistic chemo-photo therapies, with no substantial toxicity by the carriers. In addition, cellular uptake evaluations revealed that UiO-DOX-ICG@PDA-TF could specifically target 4T1 cells on the basis of receptor-mediated internalization of transferrin receptors. Additionally, in vivo toxicity studies in Wistar rats indicated no signs of significant toxicity. The UiO-based nanoformulations effectively inhibited and destroyed cancer cells under 808 nm laser irradiation because of their minimal toxicity, strong biocompatibility, and outstanding synergistic chemo/photothermal/photodynamic treatment.

Nano-Innovations in Cancer Therapy: The Unparalleled Potential of MXene Conjugates.

MXenes are two-dimensional transition metal carbides, nitrides, and carbonitrides that have become important materials in nanotechnology because of their remarkable mechanical, electrical, and thermal characteristics. This review emphasizes how crucial MXene conjugates are for several biomedical applications, especially in the field of cancer. These two-dimensional (2D) nanoconjugates with photothermal, chemotherapeutic, and photodynamic activities have demonstrated promise for highly effective and noninvasive anticancer therapy. MXene conjugates, with their distinctive optical capabilities, have been employed for bioimaging and biosensing, and their excellent light-to-heat conversion efficiency makes them perfect biocompatible and notably proficient nanoscale agents for photothermal applications. The synthesis and characterization of MXenes provide a framework for an in-depth understanding of various fabrication techniques and their importance in the customized formation of MXene conjugates. The following sections explore MXene-based conjugates for nanotheranostics and demonstrate their enormous potential for biomedical applications. Nanoconjugates, such as polymers, metals, graphene, hydrogels, biomimetics, quantum dots, and radio conjugates, exhibit unique properties that can be used for various therapeutic and diagnostic applications in the field of cancer nanotheranostics. An additional layer of understanding into the safety concerns of MXene nanoconjugates is provided by detailing their toxicity viewpoints. Furthermore, the review concludes by addressing the opportunities and challenges in the clinical translation of MXene-based nanoconjugates, emphasizing their potential in real-world medical practices.

Moving pharmacoepigenetics tools for depression toward clinical use.

BACKGROUND: Major depressive disorder (MDD) is a leading cause of disability worldwide, and over half of patients do not achieve symptom remission following an initial antidepressant course. Despite evidence implicating a strong genetic basis for the pathophysiology of MDD, there are no adequately validated biomarkers of treatment response routinely used in clinical practice. Pharmacoepigenetics is an emerging field that has the potential to combine both genetic and environmental information into treatment selection and further the goal of precision psychiatry. However, this field is in its infancy compared to the more established pharmacogenetics approaches. METHODS: We prepared a narrative review using literature searches of studies in English pertaining to pharmacoepigenetics and treatment of depressive disorders conducted in PubMed, Google Scholar, PsychINFO, and Ovid Medicine from inception through January 2019. We reviewed studies of DNA methylation and histone modifications in both humans and animal models of depression. RESULTS: Emerging evidence from human and animal work suggests a key role for epigenetic marks, including DNA methylation and histone modifications, in the prediction of antidepressant response. The challenges of heterogeneity of patient characteristics and loci studied as well as lack of replication that have impacted the field of pharmacogenetics also pose challenges to the development of pharmacoepigenetic tools. Additionally, given the tissue specific nature of epigenetic marks as well as their susceptibility to change in response to environmental factors and aging, pharmacoepigenetic tools face additional challenges to their development. LIMITATIONS: This is a narrative and not systematic review of the literature on the pharmacoepigenetics of antidepressant response. We highlight key studies pertaining to pharmacoepigenetics and treatment of depressive disorders in humans and depressive-like behaviors in animal models, regardless of sample size or methodology. While we discuss DNA methylation and histone modifications, we do not cover microRNAs, which have been reviewed elsewhere recently. CONCLUSIONS: Utilization of genome-wide approaches and reproducible epigenetic assays, careful selection of the tissue assessed, and integration of genetic and clinical information into pharmacoepigenetic tools will improve the likelihood of developing clinically useful tests.

Novel insights into the dynamics behavior of glucagon-like peptide-1 receptor with its small molecule agonists.

The glucagon-like peptide-1 receptor (GLP-1R) is a well-known target of therapeutics industries for the treatment of various metabolic diseases like type 2 diabetes and obesity. The structural-functional relationships of small molecule agonists and GLP-1R are yet to be understood. Therefore, an attempt was made on structurally known GLP-1R agonists (Compound 1, Compound 2, Compound A, Compound B, and (S)-8) to study their interaction with the extracellular domain of GLP-1R. In this study, we explored the dynamics, intrinsic stability, and binding mechanisms of these molecules through computational modeling, docking, molecular dynamics (MD) simulations and molecular mechanics Poisson-Boltzmann surface area (MM/PBSA) binding free energy estimation. Molecular docking study depicted that hydrophobic interaction (pi-pi stacking) plays a crucial role in maintaining the stability of the complex, which was also supported by intermolecular analysis from MD simulation study. Principal component analysis suggested that the terminal ends along with the turns/loops connecting adjacent helix and strands exhibit a comparatively higher movement of main chain atoms in most of the complexes. MM/PBSA binding free energy study revealed that non-polar solvation (van der Waals and electrostatic) energy subsidizes significantly to the total binding energy, and the polar solvation energy opposes the binding agonists to GLP-1R. Overall, we provide structural features information about GLP-1R complexes that would be conducive for the discovery of new GLP-1R agonists in the future for the treatment of various metabolic diseases. Communicated by Ramaswamy H. Sarma.

Effects of escitalopram on attentional bias to cocaine-related stimuli and inhibitory control in cocaine-dependent subjects.

Key characteristics of cocaine dependence include attentional bias to cocaine cues and impaired inhibitory control. Studies suggest that serotonin modulates both cocaine cue reactivity and inhibitory control. We investigated effects of the selective serotonin reuptake inhibitor escitalopram on cocaine cue reactivity and inhibitory processes in cocaine-dependent subjects. In a double-blind placebo-controlled design, cocaine-dependent subjects received placebo (n=12) or escitalopram (n=11; 10 mg on days 1-3, 20 mg on days 4-24 and 10 mg on days 25-28) orally, once daily for 4 weeks. The cocaine Stroop and immediate memory task (IMT) were administered at baseline, days 1, 4, 11, 18 and 25 after placebo or escitalopram initiation. There were no significant between-group differences in baseline performance on the cocaine Stroop task or the IMT. On day 1 (acute phase), escitalopram produced a significantly greater decrease from baseline than placebo in attentional bias measured by cocaine Stroop task 5 hours post-dose. No significant changes from baseline in attentional bias were observed on subsequent test days (chronic phase). Inhibitory control as measured by IMT commission error rate was not significantly different between two groups in either the acute or chronic phase. Consistent with preclinical data, serotonin-modulating drugs like escitalopram may have acute effects on cocaine cue reactivity in human cocaine users.