Solubility determination, dissolution properties and solid transformation of resmetirom (form A) in heptane and seven alcohols.

In this work, the solubility of resmetirom (form A) was initially measured in heptane and seven alcohol solvents by gravimetric methods. Then, the transformation temperature between form A and ethanol solvate was determined at 333.76 K. Subsequently, some commonly used models were applied to fit the solubility data, and it was found that the modified Apelblat equation and the Jouyban-Acree-van't Hoff (J-A-V) model achieved the highest correlation accuracy for those in mono-solvents and heptane + propanol, respectively. And the average relative deviation (ARD) values of models were less than 0.5%, indicating a good agreement with the experimental results. Additionally, through density functional theory calculation and the analysis of solvent parameters, it was observed that hydrogen-bonding played primary roles in the dissolution process of resmetirom. The multiple factors such as the polarity of solvent, active site interaction, the molecular size and free volume all affect the solubility of resmetirom. Furthermore, by comparing the experimental and simulated infrared spectra of form A and two alcohol solvates, five characteristic bands were selected for quantification. Partial least squares regression (PLSR), a multivariate statistical analysis method, was used to extract quantitative information. The quantitative analysis model was established based on specific wavelength intervals, which were associated with inter-molecular interactions. Combined with PLSR, a new high-precision quantitative method was established to study the solid transformation process between form A and solvates. From 303.15 to 323.15 K, the rate of transformation from form A to methanol solvate or ethanol solvate was decreased with increasing temperature, revealing that the transformation process was driven by the solubility difference between form A and solvates under the studied conditions. This research will definitely afford necessary solubility data and solvent selection for the design of the crystallization process of resmetirom (form A) in industry, and provide basic data for the production of resmetirom (form A) in the pharmaceutical industry.

Direct Crystallization Resolution of Racemates Enhanced by Chiral Nanorods: Experimental, Statistical, and Quantum Mechanics/Molecular Dynamics Simulation Studies.

Three chiral nanorods of C14-l-Thea, C14-l-Phe, and C14-d-Phe were first synthesized and utilized as heterogeneous nucleants to enhance the resolution of racemic Asp via direct crystallization. Through the statistical analysis from 320 batches of nucleation experiments, we found that the apparent appearance diversity of two enantiomeric crystals of Asp existed in 80 homogeneous experiments without chiral nanorods. However, in 240 heterogeneous experiments with 4.0 wt % chiral nanorods of solute mass added, the appearance of those nuclei with the same chirality as the nanorods was apparently promoted, and that with the opposite chirality was totally inhibited. Under a supersaturation level of 1.08, the maximum ee of the initial nuclei was as high as 23.51%. When the cooling rate was 0.025 K/min, the ee of the product was up to 76.85% with a yield of 14.41%. Furthermore, the simulation results from quantum mechanics (QM) and molecular dynamics (MD) revealed that the higher chiral recognition ability of C14-l-Thea compared to C14-l-Phe that originated from the interaction difference between C14-l-Thea and Asp enantiomers was larger than that between C14-l-Phe and Asp enantiomers. Moreover, the constructed nanorods exhibited good stability and recyclability.

Using Amphiphilic Polymer Micelles as the Templates of Antisolvent Crystallization to Produce Drug Nanocrystals.

Biocompatible and biodegradable amphiphilic polymeric micelles (PLA-CMCS-g-OA) were prepared by surface grafting of oleic acid and polylactic acid onto carboxymethyl chitosan and were used as templates for the crystallization of camptothecin. The camptothecin (CPT) nanocrystals prepared by the novel micelle-templated antisolvent crystallization (mt-ASC) method demonstrated higher crystallinity, narrower particle size distribution, and slower release characteristic than those prepared by conventional antisolvent crystallization (c-ASC) using a high initial concentration and fast addition rate. In particular, the CPT release behavior of mt-ASC products in phosphate buffer solutions presented a pH-responsive characteristic with the increasing release rate of CPT under lower pH conditions. This work confirmed that amphiphilic nanomicelle-templated crystallization was an effective method for preparing drug nanocrystals.

"All-in-One" Theranostic Agent with Seven Functions Based on Bi-Doped Metal Chalcogenide Nanoflowers.

Most of the existing single-component nanostructures cannot provide comprehensive diagnostic information, and their treatment strategies always have to combine other therapeutics as a complementary for effective biomedical application. Here, we adopted a facile approach to design a theranostic nanoflower (NF) with robust efficacy for comprehensive tumor diagnosis and quadruple synergistic cancer therapy. The NF is equipped with a metallic hybrid of several functional elements and flower-like superstructures and thus shows excellent in vitro and in vivo theranostic performance. It shows high X-ray attenuation coefficiency for the Bi element, strong near-infrared (NIR) plasmon absorbance and singlet oxygen (1O2) generation ability for the Mo element, and great photothermal conversion efficiency (54.7%) because of enhanced photoabsorption of the petal structure. Moreover, the NF realizes a very high doxorubicin-loading efficiency (90.0%) and bimodal pH/NIR-responsive drug release, posing a promise as a controlled drug carrier. The NF also shows excellent performance at trimodal magnetic resonance/X-ray computed tomography/photoacoustic imaging for comprehensive tumor diagnosis. To our best knowledge, it is the first time that integrating at least seven functions into one biomedical nanomaterial for well-rounded tumor theranostics has been reported. This "all-in-one" NF opens a new perspective in developing novel and efficient multifunctional nanotheranostics.

Amperometric sensor for dopamine based on surface-graphenization pencil graphite electrode prepared by in-situ electrochemical delamination.

A surface-graphenized pencil graphite electrode (SGPGE) served as an amperometric sensor for dopamine (DA). It was prepared through a one-step in-situ electrochemical graphene delamination. The graphite particles on the outer surface of the pencil graphite electrode (PGE) were delaminated by controlling the electrochemical delaminating conditions such as the applied anodic voltage and polarization duration, as well as the kind of electrolytes. The best conditions were identified by scanning electron microscopy, Raman spectra, cyclic voltammetry and differential pulse voltammetry (DPV). As a result, the electrode was endowed with an optimum combination of graphene delamination efficiency and electrochemical activity. The electrochemical treatment activates the surface sensing sites and improves the sensing performance. The NaOH-teated anodically graphenized electrode was used to sense dopamine by DPV. The best oxidation voltage of dopamine is at around 0.17 V (vs. SCE). The electrode respondsy to dopamine in the ranges of 0.15 to 45 µM, the detection limit is 8.2 nM (S/N = 3), and the sensitivity is 20.81 µA µM-1 cm-2. In real human urine samples, the sensor exhibited detection recoveries of 97.4-98.8% and low relative standard deviations of 3.49-3.92%. Graphical abstract Schematic presentation of a surface-graphenized pencil graphite electrode (SGPGE) for detecting dopamine. It was prepared by a one-step in situ electrochemical graphene delamination.

Facile assembling of novel polypyrrole nanocomposites theranostic agent for magnetic resonance and computed tomography imaging guided efficient photothermal ablation of tumors.

Multifunctional nanocomposites for image-guided cancer therapy are highly desired in clinical application. Herein, a novel theranostic agent based on gold and ferroferric oxide nanoparticles coating polypyrrole particles (PPy@Fe3O4/Au nanocomposites) for computed tomography (CT) and magnetic resonance (MR) imaging guided photothermal therapy was successfully assembled by a very facile electrostatic adsorption method. PPy@Fe3O4/Au nanocomposites exhibit good biocompatibility in vitro and in vivo. Because of high r2 relaxivity of Fe3O4 and high X-ray attenuation ability of Au, the PPy@Fe3O4/Au nanocomposites exhibited desirable CT and MR imaging performance, which provide more comprehensive and accurate diagnostic information. Moreover, PPy@Fe3O4/Au nanocomposites can efficiently kill cancer cells by hyperthermia with the guiding of CT and MR imaging, even completely ablate tumours. Hence, the electrostatic adsorption assembled PPy@Fe3O4/Au nanocomposites have great potential in clinical application for diagnosing and treating tumour in the future.

One-step assembly of CuMo2S3 nanocrystals for the synergistic effect of photothermal therapy and photodynamic therapy.

In this study, we fabricated a novel PVP conjugated CuMo2S3 nanocrystal, which can be used as an efficient photosensitizer. The CuMo2S3 nanocrystals were synthesized via a facile one-pot reflux method and exhibited high biocompatibility, strong NIR absorbance, low cytotoxicity, high stability, high photothermal conversion efficiency, and effective generation of reactive oxygen species (ROS). Moreover, the combined treatments of photodynamic therapy (PDT) and photothermal therapy (PTT) generated by the CuMo2S3 nanocrystals under NIR irradiation drastically inhibited tumor growth. Thus, CuMo2S3 nanocrystals have a great potential for synergistic effect of PDT and PTT.

Se@SiO2-FA-CuS nanocomposites for targeted delivery of DOX and nano selenium in synergistic combination of chemo-photothermal therapy.

In this study, a versatile tumor-targeted and multi-stimuli-responsive drug delivery vehicle (Se particle@porous silica-folic acid-copper sulfide/doxorubicin (Se@SiO2-FA-CuS/DOX)) was fabricated for combined photothermal therapy with chemotherapy in cancer treatment. Due to excellent targeting ability, the Se@SiO2-FA-CuS/DOX nanocomposites actively accumulated in tumor tissues and thus provided photothermal therapy under NIR irradiation and chemotherapy through the release of DOX and Se. Owing to the synergistic effect of chemotherapy (Se and DOX) and photothermal therapy, the Se@SiO2-FA-CuS/DOX nanocomposites could efficiently inhibit cancer cells both in vitro and in vivo and even completely eliminate tumors. Moreover, as the toxicity of DOX could be reduced by Se, the treatment using Se@SiO2-FA-CuS/DOX nanocomposites exhibited no appreciable adverse reactions. Thus, the Se@SiO2-FA-CuS/DOX nanocomposites have great potential as a multifunctional nanoplatform in future clinical applications.

A novel theranostic agent based on porous bismuth nanosphere for CT imaging-guided combined chemo-photothermal therapy and radiotherapy.

In recent years, multifunctional bio-nanomaterials applied as theranostic agents in cancer diagnosis and therapy have attracted great attention due to their powerful functionality. Here, for the first time, we develop a novel theranostic agent based on porous bismuth (pBi) nanospheres for tumor imaging and combined chemotherapy, photothermal therapy (PTT) and radiotherapy (RT). The pBi nanospheres have good biocompatibility due to a polyvinylpyrrolidone (PVP) coating, and have a high photothermal conversion efficiency (η = 48.5%) for PTT. The pBi nanospheres could be used as a radiosensitizer to trigger X-ray deposition and acted as an excellent computed tomography (CT) imaging contrast agent owing to the Bi content. The pBi nanospheres can also be used as a carrier for drug delivery due to their porous structures. Moreover, the thermal effect of the as-produced PTT substantially enhanced the release of doxorubicin (DOX) for chemotherapy, resulting in a synergistic therapeutic effect for complete tumor removal. Meanwhile, treatment with pBi/DOX nanospheres caused no obvious toxicity. Therefore, these multi-functional pBi nanospheres, fabricated by a unique method, have a great promise for application in CT imaging-guided synergetic cancer therapy.