A novel scaffold long-acting selective estrogen receptor antagonist and degrader with superior preclinical profile against ER+ breast cancer.

Breast cancer is one of the most common malignant tumors in women worldwide, with the majority of cases showing expression of estrogen receptors (ERs). Although drugs targeting ER have significantly improved survival rates in ER-positive patients, drug resistance remains an unmet clinical need. Fulvestrant, which overcomes selective estrogen receptor modulator (SERM) and AI (aromatase inhibitor) resistance, is currently the only long-acting selective estrogen receptor degrader (SERD) approved for both first and second-line settings. However, it fails to achieve satisfactory efficacy due to its poor solubility. Therefore, we designed and synthesized a series of novel scaffold (THC) derivatives, identifying their activities as ER antagonists and degraders. G-5b, the optimal compound, exhibited binding, antagonistic, degradation or anti-proliferative activities comparable to fulvestrant in ER+ wild type and mutants breast cancer cells. Notably, G-5b showed considerably improved stability and solubility. Research into the underlying mechanism indicated that G-5b engaged the proteasome pathway to degrade ER, subsequently inhibiting the ER signaling pathway and leading to the induction of apoptosis and cell cycle arrest events. Furthermore, G-5b displayed superior in vivo pharmacokinetics and pharmacodynamics properties, coupled with a favorable safety profile in the MCF-7 tamoxifen-resistant (MCF-7/TR) tumor xenograft model. Collectively, G-5b has emerged as a highly promising lead compound, offering potent antagonistic and degradation activities, positioning it as a novel long-acting SERD worthy of further refinement and optimization.

A c-MET-Targeted Topical Fluorescent Probe cMBP-ICG Improves Oral Squamous Cell Carcinoma Detection in Humans.

INTRODUCTION: The postoperative survival of oral squamous cell carcinoma (SCC) relies on precise detection and complete resection of original tumors. The mucosal extension of the tumor is evaluated visually during surgery, but small and flat foci are difficult to detect. Real-time fluorescence imaging may improve detection of tumor margins. MATERIALS AND METHODS: In the current study, a peptide-based near-infrared (NIR) fluorescence dye, c-MET-binding peptide-indocyanine green (cMBP-ICG), which specifically targets tumor via c-MET binding, was synthetized. A prospective pilot clinical trial then was conducted with oral SCC patients and intraoperatively to assess the feasibility of cMBP-ICG used to detect tumors margins. Fluorescence was histologically correlated to determine sensitivity and specificity. RESULTS: The immunohistochemistry (IHC) results demonstrated increased c-Met expression in oral SCC compared with normal mucosa. Tumor-to-background ratios ranged from 2.71 ± 0.7 to 3.11 ± 1.2 in different concentration groups. From 10 patients with oral SCC, 60 specimens were collected from tumor margins. The sensitivity and specificity of discriminative value derived from cMBP-ICG application in humans were respectively 100% and 75%. CONCLUSIONS: Topical application of cMBP-ICG is feasible and safe for optimizing intraoperative visualization and tumor margin detection in oral SCC patients, which could clinically increase the probability of complete resections and improve oncologic outcomes.

The preparation and characterisation of tasteless core-shell clarithromycin microcapsules.

This study aims to fabricate core-shell clarithromycin (CAM) microcapsules to cover up the bitter taste of CAM by spray drying with aqueous polymer dispersion. Water dispersion of Eudragit EPO and Surelease® were innovatively used to encapsulate CAM into microcapsules via a one-step spray-drying method. The inlet air temperature, airflow rate, CAM-polymer ratio, and particle size of CAM were optimised based on drug content and T6% (the time taken for the drug to release equal to 6% w/w). The powder properties were assessed by measuring particle size and microstructure using SEM, FT-IR, and PXRD. Furthermore, selected batch was assessed for their drug content, encapsulation efficiency, in vitro release, bitterness, and stability studies. EPO-Surelease® (1: 4) microcapsules had an average diameter (D50) of 37.69 ± 3.61 µm with a span of 2.395. The drug contents and encapsulation efficiency of EPO-Surelease®(1:4) were 10.89% and 63.7%, respectively. EPO-Surelease® (1:4) microcapsules prepared by spray drying with aqueous polymer dispersion can effectively mask the bitter taste of CAM.

Characterization of nimodipine amorphous nanopowder prepared by quenching cooling combined with wet milling and spray drying.

Currently, reducing particle size or preparing drugs into amorphous forms are widely used methods to improve the solubility and dissolution rate of insoluble drugs. The purpose of this study was to prepare nimodipine amorphous nanopowder (NMD-NAP) using nimodipine (NMD) as a model drug to increase the solubility and dissolution rate of insoluble drugs by the combined effect of reducing the particle size and preparing the drug into an amorphous form. The NMD-NAP was successfully prepared by quenching cooling combined with wet milling and spray drying. The prepared NMD-NAP was shown to have good redispersibility by particle size analysis. The shapeof NMD-NAP was characterized by SEM and AFM, showing a spherical or spheroidal structure. The results of PLM, DSC, XRD, and FT-IR indicated that the drug existed in an amorphous form. The dissolution study showed that the dissolution rate of NMD in NMD-NAP was improved about 5 times that of pure NMD and 3 times that of nimodipine nanocrystalline (NMD-NC), indicating the combination of nano size and amorphous form produced a synergistic effect that could significantly increase the dissolution rate of NMD. Due to the significantly improved solubility and good industrial feasibility of the prepared NMD-NAP, the preparation of insoluble drugs into amorphous nanopowders is an effective method to improve the solubility of insoluble drugs and has good application prospects.

Utility of apparent diffusion coefficient histogram analysis in differentiating benign and malignant palate lesions.

OBJECTIVES: To explore the ability of conventional MRI and histogram analysis of apparent diffusion coefficient (ADC) for differentiating between malignant and benign palatal lesions. MATERIALS AND METHODS: A retrospective analysis was performed on MRI images of 86 patients with palatal lesions confirmed by histopathology between January 2015 and December 2018. Each lesion was evaluated based on the conventional MRI characteristics, including size, location, morphology, inner texture, enhancement, capsule, bone destruction, and nerve invasion. ADC histogram analysis was fitted to a bimodal Gaussian distribution mixture curve. Nine histogram analysis parameters were extracted from ADC maps and were compared between malignant and benign palatal lesions. Statistical analysis was performed to assess the differential performance of each parameter individually and combined. RESULTS: On conventional MRI, the capsule structure and nerve invasion were useful characteristics for the differential diagnosis of palatal lesions. Histogram analysis showed significant differences between the groups in terms of mean ADC values of the lower curve and overall curve of the bimodal histogram, as well as ADC10 and ADC50. The optimal diagnostic threshold of ADC value was ADC50 = 1.17 × 10-3 mm2/s (area under curve [AUC] = 0.934, sensitivity = 93.0 %, specificity = 86.2 %). The combination of conventional MRI and ADC values yielded the best predictive performance, with an AUC of 0.949, and an increase in sensitivity from 80.7 % to 96.5 % and specificity from 58.6 % to 82.8 %, compared to conventional MRI. CONCLUSIONS: Histogram analysis of DWI combined with conventional MRI allows accurate differentiation between benign and malignant palatal lesions.

Resources allocation optimization algorithm based on the comprehensive utility in edge computing applications.

In the mobile edge computing environment, aiming at the problems of few classifications of resource nodes and low resource utilization in the process of multi-user and multi-server resource allocation, a resource optimization algorithm based on comprehensive utility is proposed. First, the algorithm improves the Naive Bayes algorithm, obtains the conditional probabilities of job types based on the established Naive Bayes formula and calculates the posterior probabilities of different job types under specific conditions. Second, the classification method of resource service nodes is designed. According to the resource utilization rate of the CPU and I/O, the resource service nodes are divided into CPU main resources and I/O main resources. Finally, the resource allocation based on comprehensive utility is considered. According to three factors, resource location, task priority and network transmission cost, the matching computing resource nodes are allocated to the job, and the optimal solution of matching job and resource nodes is obtained by the weighted bipartite graph method. The experimental results show that, compared with similar resource optimization algorithms, this method can effectively classify job types and resource service nodes, reduce resource occupancy rate and improve resource utilization rate.

Rod-shaped nintedanib nanocrystals improved oral bioavailability through multiple intestinal absorption pathways.

Nintedanib (BIBF) is a biopharmaceutical classification system II (BCS II) drug that has a good therapeutic effect for the treatment of nonsmall cell lung cancer; however, it shows poor oral bioavailability due to low dissolution and intestinal absorption. This study aims to fabricate rod-shaped nanocrystals to enhance oral bioavailability by improving the dissolution and absorption of BIBF in the intestine. By prescription screening, BIBF nanocrystals (BIBF-NCs) with a particle size of 325.30 ± 1.03 nm and zeta potential of 32.70 ± 1.24 mV were fabricated by an antisolvent precipitation-ultrasound approach with a stabilizer of sodium carboxyl methyl cellulose (CMC-Na). BIBF-NCs exhibited a rod-shaped morphology by transmission electron microscopy (TEM). The results of powder X-ray diffraction (PXRD) and differential scanning calorimetry (DSC) showed that the crystal form of BIBF in BIBF-NCs was altered. The BIBF-NCs remarkably improved the saturation solubility and dissolution of BIBF compared with BIBF powder. According to the results of in situ single-pass intestinal perfusion (SPIP), BIBF-NCs showed improved absorption and membrane permeability, with Ka and Papp values in the jejunum of 0.21 ± 0.01 min-1 and (4.34 ± 0.11) × 10-4 cm/min, respectively. Further, the Ka and Papp values of BIBF-NCs were all reduced significantly after the addition of inhibitors colchicine, chlorpromazine and indomethacin, which demonstrated that BIBF-NCs could be absorbed by endocytosis mediated by caveolae and clathrin and micropinocytosis in the intestine. The cell evaluation results showed that BIBF-NCs could be taken up by macrophages and transported from Caco-2 monolayers. The in vivo pharmacokinetic results showed that the bioavailability of the BIBF-NCs was 2.51-fold higher than that of the BIBF solution (BIBF-Sol) after oral administration with a longer Tmax (4.50 ± 1.00 h vs. 2.60 ± 1.92 h). In summary, rod-shaped BIBF-NCs could significantly improve oral bioavailability through multiple intestinal absorption pathways.

Dynamic computation offloading algorithm based on particle swarm optimization with a mutation operator in multi-access edge computing.

The current computation offloading algorithm for the mobile cloud ignores the selection of offloading opportunities and does not consider the uninstall frequency, resource waste, and energy efficiency reduction of the user's offloading success probability. Therefore, in this study, a dynamic computation offloading algorithm based on particle swarm optimization with a mutation operator in a multi-access edge computing environment is proposed (DCO-PSOMO). According to the CPU utilization and the memory utilization rate of the mobile terminal, this method can dynamically obtain the overload time by using a strong, locally weighted regression method. After detecting the overload time, the probability of successful downloading is predicted by the mobile user's dwell time and edge computing communication range, and the offloading is either conducted immediately or delayed. A computation offloading model was established via the use of the response time and energy consumption of the mobile terminal. Additionally, the optimal computing offloading algorithm was designed via the use of a particle swarm with a mutation operator. Finally, the DCO-PSOMO algorithm was compared with the JOCAP, ECOMC and ESRLR algorithms, and the experimental results demonstrated that the DCO-PSOMO offloading method can effectively reduce the offloading cost and terminal energy consumption, and improves the success probability of offloading and the user's QoS.

A Novel Eyes Topical Drug Delivery System: CsA-LNC for the Treatment of DED.

PURPOSE: The objective of the present work was to prepare safe and effective Ciclosporin A Lipid nanocapsule (CsA-LNC) eye-drops for the treatment of DED. METHODS: The phase-inversion method was used to prepared different sizes CsA-LNC. CsA biodistribution in ocular after topical administration in rabbits was analyzed by a validated UPLC-MS/MS method. The efficacy of CsA-LNCs (25 nm, 50 nm, 85 nm) was evaluated using the tear breakup time, fluorescein staining, tear production, inflammatory cytokines and histopathology tests. The safety of CsA-LNCs was study by the score of ocular irritation and histological examination study. RESULTS: CsA-LNCs(20-100 nm) were successfully prepared, An in vivo PK study showed significant improvement of the bioavailability (4.20-fold (25 nm), 2.15-fold (50 nm) and 2.33-fold (85 nm)) in bulbar conjunctiva, and great permeability was observed in the cornea for CsA-LNCs compared with CsA emulsion. An in vivo PD study showed that CsA-LNCs have great efficacy for DED, and the effect was improved over CsA emulsion. CsA-LNCs were safe and not cause significant irritation to the eyes surface of rabbits. CONCLUSION: This work has demonstrated CsA-LNCs, in particular small sizes CsA-LNC, are safe and effective with promising potential to treat DED. Grapical abstract.

Nanostructured lipid carriers as oral delivery systems for improving oral bioavailability of nintedanib by promoting intestinal absorption.

The aim of this study was to fabricate nanostructured lipid carriers, NLCs, of nintedanib (BIBF) to improve its oral bioavailability. Two types of NLCs loaded with BIBF (BIBF-NLCs-1 and BIBF-NLCs-2) were prepared by the melt-emulsification technique. BIBF-NLCs-1 and BIBF-NLCs-2 showed nanoscale particle sizes of 142.70 ± 0.85 nm and 7.99 ± 0.06 nm, and both were positive zeta potential. Study on Caco-2 cells showed that BIBF-NLCs-1 exhibited distinct advantages at the cytological level. The oral bioavailability of BIBF-NLCs-1 and BIBF-NLCs-2 was extremely improved 3.13-fold and 2.39-fold respectively compared with BIBF solution (BIBF-Sol). And in vivo anti-tumor efficiency study in mice bearing LLC lung tumor indicated that BIBF-NLCs-1 and BIBF-NLCs-2 had excellent tumor inhibition. Besides, the two NLCs did not increase the risk of liver damage and can even reduce the incidence of gastrointestinal irritation of BIBF to some extent. In summary, NLCs are a potential oral delivery system to improve the bioavailability of BIBF by promoting intestinal absorption.