Comparison and Analysis of Theoretical Models for Diffusion-Controlled Dissolution

Dissolution models require, at their core, an accurate diffusion model. The accuracy of the model for diffusion-dominated dissolution is particularly important with the trend toward micro- and nanoscale drug particles. Often such models are based on the concept of a “diffusion layer.” Here a framework is developed for diffusion-dominated dissolution models, and we discuss the inadequacy of classical models that are based on an unphysical constant diffusion layer thickness assumption, or do not correctly modify dissolution rate due to “confinement effects”: (1) the increase in bulk concentration from confinement of the dissolution process, (2) the modification of the flux model (the Sherwood number) by confinement. We derive the exact mathematical solution for a spherical particle in a confined fluid with impermeable boundaries. Using this solution, we analyze the accuracy of a time-dependent “infinite domain model” (IDM) and “quasi steady-state model” (QSM), both formally derived for infinite domains but which can be applied in approximate fashion to confined dissolution with proper adjustment of a concentration parameter. We show that dissolution rate is sensitive to the degree of confinement or, equivalently, to the total concentration <i>C</i>_tot. The most practical model, the QSM, is shown to be very accurate for most applications and, consequently, can be used with confidence in design-level dissolution models so long as confinement is accurately treated. The QSM predicts the ratio of diffusion layer thickness to particle radius (the Sherwood number) as a constant plus a correction that depends on the degree of confinement. The QSM also predicts that the time required for complete saturation or dissolution in diffusion-controlled dissolution experiments is singular (i.e., infinite) when total concentration equals the solubility. Using the QSM, we show that measured differences in dissolution rate in a diffusion-controlled dissolution experiment are a result of differences in the degree of confinement on the increase in bulk concentration independent of container geometry and polydisperse vs single particle dissolution. We conclude that the constant diffusion-layer thickness assumption is incorrect in principle and should be replaced by the QSM with accurate treatment of confinement in models of diffusion-controlled dissolution

DeepScaffold: A Comprehensive Tool for Scaffold-Based De Novo Drug Discovery Using Deep Learning

The ultimate goal of drug design is to find novel compounds with desirable pharmacological properties. Designing molecules retaining particular scaffolds as their core structures is an efficient way to obtain potential drug candidates. We propose a scaffold-based molecular generative model for drug discovery, which performs molecule generation based on a wide spectrum of scaffold definitions, including Bemis–Murcko scaffolds, cyclic skeletons, and scaffolds with specifications on side-chain properties. The model can generalize the learned chemical rules of adding atoms and bonds to a given scaffold. The generated compounds were evaluated by molecular docking in DRD2 targets, and the results demonstrated that this approach can be effectively applied to solve several drug design problems, including the generation of compounds containing a given scaffold and de novo drug design of potential drug candidates with specific docking scores

Lanthanide-Based Nanocomposites for Photothermal Therapy under Near-Infrared Laser: Relationship between Light and Heat, Biostability, and Reaction Temperature

In this research, typical organic/inorganic photothermal therapy (PTT) agents were designed with a combination of upconversion luminescent (UCL) or near-infrared (NIR) II imaging rare-earth nanomaterials for photo-acoustic (PA)/UCL/NIR II imaging-guided PTT under NIR laser irradiation. The results show the following: (1) The PTT effect mainly comes from NIR absorption and partly from UCL light conversion. (2) Visible UCL emission is mainly quenched by NIR absorption of the coated PTT agent and partly quenched by visible absorption, indicating that excitation may play a more important role than in the UCL emission process. (3) The biostability of the composite might be decided by the synthesis reaction temperature. Among the five inorganic/organic nanocomposites, UCNP@MnO2 is the most suitable candidate for cancer diagnosis and treatment because of its stimuli-response ability to the micro-acid environment of tumor cells and highest biostability. The composites generate heat for PTT after entering the tumor cells, and then, the visible light emission gradually regains as MnO2 is reduced to colorless Mn2+ ions, thereby illuminating the cancer cells after the therapy

Incorporating Neural Networks into the AMOEBA Polarizable Force Field

Neural network potentials (NNPs) offer significant promise to bridge the gap between the accuracy of quantum mechanics and the efficiency of molecular mechanics in molecular simulation. Most NNPs rely on the locality assumption that ensures the model’s transferability and scalability and thus lack the treatment of long-range interactions, which are essential for molecular systems in the condensed phase. Here we present an integrated hybrid model, AMOEBA+NN, which combines the AMOEBA potential for the short- and long-range noncovalent atomic interactions and an NNP to capture the remaining local covalent contributions. The AMOEBA+NN model was trained on the conformational energy of the ANI-1x data set and tested on several external data sets ranging from small molecules to tetrapeptides. The hybrid model demonstrated substantial improvements over the baseline models in term of accuracy as the molecule size increased, suggesting its potential as a next-generation approach for chemically accurate molecular simulations

Surface Plasmonic Enhanced Imaging-Guided Photothermal/Photodynamic Therapy Based on Lanthanide–Metal Nanocomposites under Single 808 nm Laser

In this research, we design the integration of Au/Ag nanocages with upconversion nanoparticles (UCNPs) as the theranostic agent under single 808 nm with enhanced imaging-guided photodynamic therapy (PDT) and photothermal therapy (PTT) properties. Different with the conventional theranostic agent, Au/Ag@UCNPs can emit higher blue emission under 808 nm laser and generate higher reactive oxygen species than that of Au@UCNPs due to higher crossed absorbance between the nanocages and UCNPs. Furthermore, the temperature change of Au/Ag@UCNPs (9.7 °C) is much higher than that of phosphate-buffered saline solution (0.6 °C) under 808 nm laser, indicating there is a low side effect to normal cells when Au/Ag@UCNPs are utilized as the photoactive agent. Finally, the in vitro and in vivo experiments show that the tumor is almost ablated totally due to high synergistic PDT and PTT effects of Au/Ag@UCNPs, revealing it could be potentially applied in the clinical theranostic field

When a Semiconductor Utilized as an NIR Laser-Responsive Photodynamic/Photothermal Theranostic Agent Integrates with Upconversion Nanoparticles

Photoactive theranostics including photodynamic therapy (PDT) hace aroused an intensive interest that combines medical diagnostics with treatment under a single irradiation laser. However, the conventional organic PDT agents usually suffer from aggregation caused by the quenching effect. In this research, we designed a core–shell–shell (CSS) UCNPs with NaGdF4 as the host, and the UCNPs could emit higher blue/green light by the energy transfer processes among Nd/Yb/Tm/Gd/Tb under 808 nm laser. When the CSS UCNPs were combined with the MnO2 semiconductor as the energy acceptor, CSS@Mn could be utilized as an effective PDT agent under a NIR laser. The temperature also increased more than 12.2 °C under the 808 nm laser, indicating the potential of synergistic photothermal therapy (PTT) and PDT. Interestingly, cells with small amounts of H2O2 could be responsive to the CSS@Mn platform. The antitumor effect was proved by the in vitro and in vivo experiments. Also, the biocompatibility, biodistribution, and excretion pathway were detected and revealed by the H&E stained pathological section and photoacoustic (PA) images. That means this platform could be potentially used as antitumor PDT/PTT agents

Gold Nanostars Combined with the Searched Antibody for Targeted Oral Squamous Cell Carcinoma Therapy

Oral squamous cell carcinoma (OSCC) is the most common cancer in the oral and maxillofacial region. Due to the special physiological and anatomical position of the oral cavity, the disease often has a significant impact on the chewing, swallowing, language, and breathing functions of patients. In recent years, with the development of medical molecular biology, molecular targeted therapy has received increasing clinical attention and has gradually become a new method for the treatment of malignant tumors. In this research, gold nanostars with a high photothermal effect combined with the searched targeted antibody were used for OSCC therapy. We use the data set in the public database and construct a gene co-expression module by weighted gene co-expression network analysis (WGCNA). It was found that the turquoise module and the midnight blue module had the greatest connection to tumorigenesis. Cytoscape software was used to analyze the important modules, and the top 10 genes of each module were selected; the survival analysis of the top 10 genes was carried out by gene expression profiling interactive analysis (GEPIA), which indicated that these genes (SERP­INH1, MMP11, ADAM12, FADS3, SLC36A2, C1QTNF7, SCRG1, and APOBEC2) have statistical significance as key genes that are related to the tumorigenesis of OSCC. Then, the anti-SERP­INH1 antibody targeted to SERP­INH1 was chosen as the inhibitor and combined with gold nanostars for photothermal assisted targeted therapy. Thus, the searched key genes can be regarded as biomarkers and therapeutic targets for further precise diagnosis

Multistage Screening Reveals 3‑Substituted Indolin-2-one Derivatives as Novel and Isoform-Selective c‑Jun N‑terminal Kinase 3 (JNK3) Inhibitors: Implications to Drug Discovery for Potential Treatment of Neurodegenerative Diseases

Alzheimer’s disease (AD) is one of the most challenging diseases around the world with no effective clinical treatment. Previous studies have suggested c-Jun N-terminal kinase 3 (JNK3) as an attractive therapeutic target for AD. Herein, we report 3-substituted indolin-2-one derivatives as the first isoform-selective JNK3 inhibitors by multistage screening. In this study, comparative structure-based virtual screening was performed, and J30-8 was identified with a half-maximal inhibitory concentration of 40 nM, which exhibited over 2500-fold isoform selectivity and marked kinome-wide selectivity. Further study indicated that 1 μM J30-8 exhibited neuroprotective activity in vitro so as to alleviate the spatial memory impairment in vivo through reducing plaque burden and inhibiting the phosphorylation of JNKs, Aβ precursor protein, and Tau protein. All of these indicated J30-8 as proved isoform-selective JNK3 inhibitors that might serve as a useful tool for further JNK3 studies with AD as well as for the development of JNK3 inhibitors for the potential treatment of neurodegenerative diseases

Multistage Screening Reveals 3‑Substituted Indolin-2-one Derivatives as Novel and Isoform-Selective c‑Jun N‑terminal Kinase 3 (JNK3) Inhibitors: Implications to Drug Discovery for Potential Treatment of Neurodegenerative Diseases

Alzheimer’s disease (AD) is one of the most challenging diseases around the world with no effective clinical treatment. Previous studies have suggested c-Jun N-terminal kinase 3 (JNK3) as an attractive therapeutic target for AD. Herein, we report 3-substituted indolin-2-one derivatives as the first isoform-selective JNK3 inhibitors by multistage screening. In this study, comparative structure-based virtual screening was performed, and J30-8 was identified with a half-maximal inhibitory concentration of 40 nM, which exhibited over 2500-fold isoform selectivity and marked kinome-wide selectivity. Further study indicated that 1 μM J30-8 exhibited neuroprotective activity in vitro so as to alleviate the spatial memory impairment in vivo through reducing plaque burden and inhibiting the phosphorylation of JNKs, Aβ precursor protein, and Tau protein. All of these indicated J30-8 as proved isoform-selective JNK3 inhibitors that might serve as a useful tool for further JNK3 studies with AD as well as for the development of JNK3 inhibitors for the potential treatment of neurodegenerative diseases