Efficient Drug Research Articles

Multimodal Fusion-Based Lightweight Model for Enhanced Generalization in Drug-Target Interaction Prediction.

Predicting drug-target interactions (DTIs) with precision is a crucial challenge in the quest for efficient and cost-effective drug discovery. Existing DTI prediction models often require significant computational resources because of the intricate and exceptionally lengthy protein target sequences. This study introduces MMF-DTI, a lightweight model that uses multimodal fusion, to improve the generalizability of DTI predictions without sacrificing computational efficiency. The MMF-DTI model combines four distinct modalities: molecular sequence, molecular properties, target sequence, and target function description. This approach is noteworthy because it is the first to use natural language-based target function descriptions in predicting DTIs. The effectiveness of MMF-DTI has been confirmed through benchmark data sets, demonstrating its comparable performance in terms of generalizability, especially in scenarios with limited information about the drug or target. Remarkably, MMF-DTI accomplishes this using only half of the parameters and 17% of the VRAM compared with previous state-of-the-art models. This allows it to function even in constrained computational environments. The combination of performance and efficiency highlights the potential of multimodal data fusion in improving the overall applicability of models, providing promising opportunities for future drug discovery endeavors.

Rapid release of high-valent silver ions from water-soluble porphyrin complexes to enhance the direct killing of Methicillin-Resistant Staphylococcus aureus

The emergence of multidrug-resistant (MDR) bacteria represented by MRSA (Methicillin-resistant Staphylococcus aureus) poses a great challenge to current anti-infection treatment. It is critical to develop efficient MRSA anti-bacteria drugs and explore simple therapeutic strategies with low MDR risk. Herein, we synthesized high-valent (AgII/AgIII) water-soluble porphyrins (cationic AgTMPyP and anionic AgTMPPS) and investigated their direct bactericidal property for MRSA without photoactivation in vitro and in vivo. The cationic porphyrin AgTMPyP exhibits well oxidase-like activity and has 100% sterilizing rate at 8 μmol/L concentration. Besides, AgTMPyP can effectively destroy biofilms in vitro, mediate the polarization of macrophages from M1 to M2, and promote wound healing in vivo. Combined with DFT calculation, the related antibacterial mechanism is further discussed. High-valent silverporphyrins can maintain stable in water for at least 200 days. The moment they encounter MRSA, high-valent silver ions from AgTMPyP can be immediately released from the porphyrin ring and attack the MRSA with efficient sterilization. Together with the hemolysis, blood routine and blood biochemistry tests, it is proved that AgTMPyP can have great prospects in the direct treatment of bacterial infections in skin diseases in the future. Statement of significance: The emergence of multidrug-resistant (MDR) bacteria represented by MRSA poses a great challenge to current anti-infection treatment. It has become critical to develop efficient MRSA anti-bacteria drugs and explore simple therapeutic strategies with low MDR risk. We synthesized high-valent (AgII/AgIII) water-soluble silver porphyrins (AgTMPyP and AgTMPPS), which can be stable for long periods in aqueous solutions. AgTMPyP can directly and efficiently kill bacteria and destroy biofilms without photoactivation in vitro and in vivo. Combined with DFT calculation, the related antibacterial mechanism is further discussed. AgTMPyP is a superior antimicrobial agent with good biocompatibility and it can have great prospects in the direct treatment of bacterial infections and wound healing in the future.

Physically crosslinked chitosan/αβ–glycerophosphate hydrogels enhanced by surface-modified cyclodextrin: An efficient strategy for controlled drug release

This study reports physically crosslinked chitosan/αβ–glycerophosphate (CS/GP) hydrogels containing surface-modified cyclodextrin for efficient controlled drug release. Highly water-soluble β–cyclodextrin-grafted L–serine (CD–g–Ser) compounds were synthesized, and employed as an effective carrier of berberine hydrochloride (Ber) for CS/GP hydrogels. Various characterizations, including gelation time determination, scanning electron microscopy, and viscosity measurement, indicated that the introduction of CD–g–Ser led to increased crosslinking degree, improved temperature sensitivity, and shortened sol–gel phase transition time of the hydrogel. Meanwhile, the sustained release ability for Ber was achieved due to the hydrophobic association between cyclodextrin and Ber. It was observed that within 4 h, the hydrogel containing CD–g–Ser released 40 % of Ber, while the CS/GP hydrogel without CD–g–Ser released 65 % of Ber. Furthermore, in vitro bacteriostasis experiments confirmed the drug-loaded hydrogel had an excellent antibacterial effect against E. coli and S. aureus (diameter of the inhibition zone up to (16.4 and 34.7) mm, respectively), low hemolysis rate (<2 %), and high cell viability (>90 %). The findings indicate that the physical crosslinked CS hydrogel can be used as a new drug delivery system, and its excellent antibacterial effect makes it a potential wound dressing candidate.

Unlocking the Microbial Potential of Intercalated Calcium-aluminum Layered Double Hydroxide-palmitic Acid

Introduction: An efficient and coherent drug delivery system is imperative in detouring a repetitive administration of high doses of the drug to achieve an effective therapeutic effect. This study, therefore, aims to synthesize the nanocomposite (CAPA) utilizing the layered double hydroxide as a drug carrier that can safeguard the medicine and improve its bioavailability while minimizing the adverse impact on the biological process. Method: The Calcium-aluminum Layered Double Hydroxide (CAL) was synthesized via the coprecipitation method followed by integrating palmitic acid (PA) drug into that host employing a similar approach. The successful intercalation was assessed utilizing X-ray diffraction (PXRD) analysis and Fourier transform infrared spectroscopy (FTIR). The characterization of the material was evaluated by using a thermogravimetric-derivative thermogravimetric analysis (TGA-DTG) and accelerated surface area and porosity (ASAP) analyzer. Result: The increment of basal spacing of CAPA (15.21Å) synthesized in this study implies the retainment of PA in the interlayer space of CAL. The FTIR spectra of CAPA, with the elimination of the nitrate ion peak at 1359.87 cm-1 and the appearance of carboxylate ion at 1643.17 cm-1, hint at the existence of PA in the host layer. The surface area of CAPA exhibited a value of 19.8 m2g-1, bigger than that of hosts, while its pore size is within the micropores range. Conclusion: The TGA analysis revealed that the thermal stability of PA was improved following the intercalation process due to the decomposition of the PA core that occurs at 260°C. The antimicrobial activity proposes that the synthesized CAPA can retain the drug's activity against S. aureus, emphasizing the ability of CAL as a potential drug delivery vehicle for PA.

A Critical Appraisal of Functionalized 2-Dimensional Carbon-Based Nanomaterials for Drug Delivery Applications.

The development of an efficient and innovative drug delivery system is essential to improve the pharmacological parameters of the medicinal compound or drug. The technique or manner used to improve the pharmacological parameters plays a crucial role in the delivery system. In the current scenario, various drug delivery systems are available where nanotechnology has firmly established itself in the field of drug delivery. One of the most prevalent elements is carbon with its allotropic modifications such as graphene-based nanomaterials, carbon nanotubes, carbon dots, and carbon fullerenes, these nanomaterials offer notable physiochemical and biochemical properties for the delivery applications due to their smaller size, surface area, and ability to interact with the cells or tissues. The exceptional physicochemical properties of carbon-based 2D nanomaterials, such as graphene and carbon nanotubes, make them attractive candidates for drug delivery systems. These nanomaterials offer a large surface area, high drug loading capacity, and tunable surface chemistry, enabling efficient encapsulation, controlled release, and targeted delivery of therapeutic agents. These properties of the nanomaterials can be exploited for drug delivery applications, like assisting the target delivery of drugs and aiding combination molecular imaging. This review emphasizes on the recent patents on 2D carbon-based nanomaterial and their role in drug delivery systems. Carbon-based 2D nanomaterials present a wealth of opportunities for advanced drug delivery systems. Their exceptional properties and versatility offers great potential in improving therapeutic efficacy, minimizing side effects, and enabling personalized medicine and the recent patents on 2D nanomaterial.

Preparation and Characterization of Nanostructured Lipid Carriers (NLCs) Containing Glycyrrhiza glabra Extract for the Treatment of Skin Hyperpigmentation.

This study aimed to prepare, characterize, and in vitro and in vivo evaluate a novel nanostructured lipid carriers (NLCs) formulation containing two fractions of Glycyrrhiza glabra L. (licorice) extract for the treatment of hyperpigmentation. Two fractions, one enriched with glabridin (FEG) and the other enriched with liquiritin (FEL), were obtained by partitioning the methanol (MeOH) extract of licorice roots with ethyl acetate (EtOAc) and partitioning the EtOAc fraction with butanol (n-BuOH) and water. The quantities of glabridin (Glab) and liquiritin (LQ) in the fractions were determined by high-performance liquid chromatography (HPLC). FEG and FEL were loaded in different NLC formulations, and surface characterization and long-term stability were studied using Dynamic Light Scattering (DLS). The best formulation was chosen for further surface characterization, including Transmission Electron Microscopy (TEM), Differential Scanning Calorimetry (DSC), and Fouriertransform infrared (FTIR) spectroscopy. Moreover, entrapment efficiency percentage (EE%), in vitro drug release, in vivo skin penetration, cytotoxicity on B16F10 melanoma cells, effect on melanin production, and anti- tyrosinase activity were tested for the selected formulation. Based on HPLC results, FEG contained 34.501 mg/g of Glab, and FEL contained 31.714 mg/g of LQ. Among 20 different formulations, NLC 20 (LG-NLCs) showed desirable DLS results with a Z-average size of 185.3 ± 1.08 nm, polydispersity index (PDI) of 0.229 ± 0.35, and zeta potential of -16.2 ± 1.13 mV. It indicated good spherical shape, high EE% (79.01% for Glab and 69.27% for LQ), two-stage release pattern (an initial burst release followed by sustained release), efficient in vivo skin penetration, and strong anti-tyrosinase activity. LG-NLCs had acceptable physiochemical stability for up to 9 months and were non-cytotoxic. The LG-NLC formulation has revealed desirable surface characterization, good physiochemical stability, efficient drug release pattern and in vivo penetration, and high EE%. Therefore, it can be a suitable nanosystem for the delivery of licorice extract in the treatment of hyperpigmentation.

Enhanced antitumor activity of lapatinib against triple-negative breast cancer via loading in human serum albumin

Triple-negative breast cancer (TNBC) presents significant treatment challenges due to its aggressive nature. Human serum albumin (HSA) is a promising drug delivery platform, offering high binding capacity, biocompatibility, and reduced toxicity. Lapatinib (LAP), a tyrosine kinase inhibitor for TNBC, is hindered by poor water solubility and toxicity. To address these issues, LAP was encapsulated within HSA (HSA-LAP), and its structural, drug release, and therapeutic properties were evaluated in cellular and animal TNBC models. HSA-LAP demonstrated efficient drug loading and pH-dependent tumor-targeted release, favoring acidic tumor microenvironments. Structural and microscopic studies confirmed LAP binding to HSA, with only minor structural and no significant morphological changes observed. In 4 T1 breast cancer cells, HSA-LAP exhibited superior anti-proliferative, pro-apoptotic, and anti-migratory effects compared to free LAP, which were further amplified when combined with VGB3, a VEGFR1/2-targeting peptide, indicating an effective dual-targeting strategy for TNBC. In vivo, HSA-LAP showed greater tumor inhibition and improved survival rates, especially in combination with VGB3 through apoptosis induction. Biodistribution studies using technetium-99 m (99mTc) labeling revealed enhanced tumor targeting. These findings highlight the potential of HSA as a delivery vehicle for LAP, particularly in combination with anti-angiogenic agents like VGB3, offering a promising therapeutic strategy for TNBC.

Enhanced transcytosis and therapeutic efficacy of paclitaxel nanoparticles: Pyridylboronic acid modification and sialic acid targeting

Efficient drug delivery and deeper penetration into tumors have become a primary focus of anti-tumor nanomedicine. In this study, pyridylboronic acid (BPA), as a targeting ligand for sialic acid, which is highly expressed on the surface of tumor cells, was conjugated with DSPE-PEG2k-NH2 to synthesize DSPE-PEG2k-BPA and used to encapsulate PTX. The resultant PTX@DSPE-PEG2k-BPA nanoparticles (DPB NPs) showed a mean particle size of 189.0 ± 3.5 nm, with a high drug loading content of 48.75 % and a rod-like morphology. In contrast to PTX@DSPE-mPEG2k nanoparticles (DP NPs), DPB NPs displayed enhanced cellular uptake and targetability to 4T1 tumor cells. Interestingly, BPA modification could also enhance transcytosis through the endoplasmic reticulum-Golgi pathway, thus improving penetration and accumulation of nanoparticles in tumors. An in vivo study on 4T1 tumor-bearing mice demonstrated that DPB NPs achieved a faster and more accumulation in tumors than DP NPs after intravenous administration, led to significantly improved therapeutic efficacy with a higher tumor inhibition rate (74.27 % vs 50.58 %, p < 0.01). In conclusion, the modification of BPA presents a strategy for the development of drug delivery systems that exhibit dual functionalities: active targeting and transcytosis.

Therapeutic co-assemblies for synergistic NSCLC treatment through dual topoisomerase I and tubulin inhibitors

Camptothecin (CPT) and podophyllotoxin (PPT) function as topoisomerase (TOP) I and tubulin inhibitors, respectively, with potent anticancer effects in a variety of cancers. Despite its promise, the clinical applicability of the combination of CPT and PPT faces challenges, including potential side effect and limited therapeutic efficacy. In this study, we designed co-assembly nanomedicines with the different weight (w/w) ratios of amphiphilic Evans blue conjugated CPT prodrug (EB-ss-CPT) and PPT molecules, denoted as ECT Nano. The co-assembly of EB-ss-CPT and PPT without other excipients has nearly 100% drug loading efficiency and high drug loading content of PPT of up to 74.29 ± 0.90 wt%. Notably, the ECT Nano (1:2) equipped with the ability to inhibit TOP I activity and tubulin polymerization, which provided a highly efficient strategy to improve synergistic efficacy and decrease side toxicity in non-small cell lung cancer mouse model. This work represents a step forward to the development of practical applications for dual TOP I and tubulin inhibitors and especially hopeful to the rational design of combination nanomedicine for therapeutic purposes.

Development of a doxepin-loaded chitosan nanogel as an innovative nano platform for oral mucositis treatment

Oral mucositis is a prevalent complication in patients undergoing chemotherapy. This study aimed to develop and characterize a doxepin-loaded chitosan nanogel (DX-CN) as a topical treatment option. DX-CN and chitosan nanogel (CN) were synthesized using ionic gelation and characterized by Fourier transform infrared spectroscopy (FTIR) and field emission scanning electron microscopy (FESEM). FTRI confirmed the spectral compatibility of DX-CN. The nanogels exhibited spherical morphology. Particle sizes were 322.7 nm for DX-CN and 302.8 nm for CN. Polydispersity indices (PdI) were 0.732 for DX-CN and 0.51 for CN. Zeta potentials (ZP) were +52.7 mV for DX-CN and +52.8 mV for CN. In vitro assays included drug loading capacity (96.2 % for DX-CN), drug release profile (83.39 % cumulative release over 10 h), cytotoxicity, and antioxidative effects. DX-CN exhibited significant cytocompatibility with human umbilical vein endothelial cells (HUVEC) and selective cytotoxicity against oral squamous cell carcinoma (OSCC) cells. Furthermore, DX-CN demonstrated reduced oxidative stress, as indicated by lower lipid peroxidation, lactate dehydrogenase leakage, and reactive oxygen species formation compared to doxepin alone. The findings suggest that DX-CN, with its efficient drug loading, sustained release, and targeted biocompatibility, holds promise as a therapeutic platform for the topical treatment of chemotherapy-induced oral mucositis.

Synthesis of theranostic aptamer targeted polydopamine-coated gold nanocages for chemo-photothermal therapy against melanoma

Combination therapy utilizing chemo-photothermal therapy (chemo-PTT) has demonstrated significant effectiveness in tumor ablation during preclinical investigations. Gold nanocages (AuNC), characterized by their distinctive optical properties and hollow, porous structures, have emerged as promising nanocarriers, offering excellent biocompatibility, biodegradability, and efficient drug loading with controllable release profiles. In this study, we developed an innovative nanosystem comprising thermo-sensitive polydopamine (PDA) coated gold nanocages loaded with doxorubicin (DOX), referred to as AuNC-DOX-PDA, designed for near-infrared (NIR)-triggered drug release and chemo-photothermal combination therapy. Subsequently, the Sgc-8c DNA aptamer was conjugated to the nanoparticles surface (Apt-AuNC-DOX-PDA) to facilitate targeted delivery. The DOX was encapsulated within the hollow structure of the AuNCs, achieving a loading capacity of 35.81 % ± 2.4 and a loading efficiency of 89.54 % ± 6.0. The NIR-responsive release profile of the formulation was confirmed in vitro, demonstrating effective photothermal conversion. In alignment with in vitro findings, the NIR-responsive Apt-AuNC-DOX-PDA exhibited significantly enhanced cellular toxicity in chemo-PTT compared to single-agent cancer therapies. Cytotoxicity assays conducted on the B16F0 cell line revealed notable improvements in the targeted formulation's efficacy over the non-targeted formulation. Furthermore, in B16F0 tumor-bearing mice, substantial tumor regression and improved survival rates were observed in those treated with Apt-AuNC-DOX-PDA and exposed to 808 nm laser irradiation, compared to those receiving either AuNC-DOX-PDA or Apt-AuNC-DOX-PDA without laser treatment. Additionally, the nanoplatform proved effective for computed tomography (CT) imaging. These results underscore the promising targeted theranostic potential of Apt-AuNC-DOX-PDA for both diagnostic imaging and dual chemo-PTT in melanoma treatment.

Bufonis venenum extract loaded novel cholesterol-free liposome for the treatment of hepatocellular carcinoma

BackgroundThis study aims to improve the solubility and the toxicity of Bufonis venenum, and finally enhance the therapeutic outcomes of hepatocellular carcinoma (HCC).MethodsThe cholesterol-free liposomes simultaneously encapsulate bufadienolides and indolealkylamines (Non-Cholesterol-Bufonis Venenum Extract-Liposome, Non-Chol-BVE-LP) was prepared by the thin-film evaporation technique. In vitro, the cytotoxicity, cell apoptosis study, cellular uptake and hemolysis studies were evaluated in HepG2 cells. In vivo, the biodistribution and anti-tumor activity studies were conducted in BALB/C mice with HepG2 cells.ResultsThe liposomes showed good size distribution, encapsulation efficiency drug loading capacity and slower drug release. Non-Chol-BVE-LP had higher cytotoxicity on HepG2 cells and induced more apoptosis on HepG2 Cells compared with BVE. In addition, the liposomes could accumulate in tumor by passive targeting, thus facilitating the anti-tumor effects. In vivo, Non-Chol-BVE-LP showed equivalent anti-tumor efficacy to the first-line anti-HCC drug sorafenib.ConclusionThe study provided new ideas for the development and clinical application of Bufonis venenum related formulation and offered new drug for the treatment of HCC.

Backstage Heroes—Yeast in COVID-19 Research

The extremely rapid development of understanding and technology that led to the containment of the COVID-19 pandemic resulted from collaborative efforts in the fields of Betacoronavirus pandemicum (SARS-CoV-2) biology, pharmacology, vaccinology, and medicine. Perhaps surprisingly, much of the research was conducted using simple and efficient yeast models. In this manuscript, we describe how yeast, eukaryotic microorganisms, have been used to research this global challenge, focusing on the therapeutic potential of the studies discussed herein. Thus, we outline the role of yeast in studying viral protein interactions with the host cell proteome, including the binding of the SARS-CoV-2 virus spike protein to the human ACE2 receptor and its modulation. The production and exploration of viral antigens in yeast systems, which led to the development of two approved COVID-19 vaccines, are also detailed. Moreover, yeast platforms facilitating the discovery and production of single-domain antibodies (nanobodies) against SARS-CoV-2 are described. Methods guiding modern and efficient drug discovery are explained at length. In particular, we focus on studies designed to search for inhibitors of the main protease (Mpro), a unique target for anti-coronaviral therapies. We highlight the adaptability of the techniques used, providing opportunities for rapid modification and implementation alongside the evolution of the SARS-CoV-2 virus. Approaches introduced in yeast systems that may have universal potential application in studies of emerging viral diseases are also described.

Light-responsive antibacterial dissolving microneedles loaded with 5-aminolevulinic acid and silver nanoparticles for the treatment of acne

Acne is a chronic inflammatory disease of pilosebaceous unit, which can be aggravated by hyperkeratosis of the pilosebaceous unit, excessive secretion of sebum and the proliferation of Propionibacterium acnes (P. acnes). Traditional drug treatment methods commonly exhibit drawbacks, including bacterial resistance and poor transdermal permeability, resulting in suboptimal efficacy and recurrent infections. Herein, we designed a dual drug-loaded microneedles patch to deliver ALA and silver nanoparticles for acne treatment. The comprehensive treatment of acne is achieved by utilizing the safe and efficient advantages of 5-aminolevulinic acid (ALA) photodynamic therapy (PDT), coupled with the superior antibacterial properties of silver nanoparticles. To enhance drug permeability, dissolving microneedles (DMNs) are employed for targeted and efficient drug delivery. In vitro and in vivo experiments demonstrated that DMNs loaded with both AgNPs and ALA-PDT (ALA/AgNPs@DMNs) have significant antibacterial activity, along with superior drug loading capacity and penetration. The application of ALA/AgNPs@DMNs in treating acne-affected rats alleviates excessive epidermal keratinization, effectively inhibits bacterial growth, and significantly improves acne symptoms. This suggests that the “dissolving microneedle” formulation holds promise for the treatment and management of acne.

GraphCPP: The new state-of-the-art method for cell-penetrating peptide prediction via graph neural networks.

Cell-penetrating peptides (CPPs) are short amino acid sequences that can penetrate cell membranes and deliver molecules into cells. Several models have been developed for their discovery, yet these models often face challenges in accurately predicting membrane penetration due to the complex nature of peptide-cell interactions. Hence, there is a need for innovative approaches that can enhance predictive performance. In this study, we present the application GraphCPP, a novel graph neural network (GNN) for the prediction of membrane penetration capability of peptides. A new comprehensive dataset-dubbed CPP1708-was constructed resulting in the largest reliable database of CPPs to date. Comparative analyses with previous methods, such as MLCPP2, C2Pred, CellPPD and CellPPD-Mod, demonstrated the superior predictive performance of our model. Upon testing against other published methods, GraphCPP performs exceptionally, achieving 0.5787 Matthews correlation coefficient and 0.8459 area under the curve (AUC) values on one dataset. This means a 92.8% and 23.3% improvement in Matthews correlation coefficient and AUC measures respectively compared with the next best model. The capability of the model to effectively learn peptide representations was demonstrated through t-distributed stochastic neighbour embedding plots. Additionally, the uncertainty analysis revealed that GraphCPP maintains high confidence in predictions for peptides shorter than 40 amino acids. The source code is available at https://github.com/attilaimre99/GraphCPP. These findings indicate the potential of GNN-based models to improve CPP penetration prediction and it may contribute towards the development of more efficient drug delivery systems.

Noble Gases in Medicine: Current Status and Future Prospects

Noble gases are a valuable but overlooked source of effective and safe therapeutics. Being monoatomic and chemically inert, they nonetheless have a surprisingly wide range of biochemical and medically valuable properties. This mini review briefly summarizes these properties for the most widely used noble gases and focuses and research gaps and missed opportunities for wider use of these intriguing ‘atomic’ drugs. The main research gaps and opportunities lie firstly in the application of advanced computational modelling methods for noble gases and recent developments in accurate predictions of protein structures from sequence (AlphaFold), and secondly in the use of very efficient and selective drug delivery technologies to improve the solubility, efficacy, and delivery of noble gases to key targets, especially for the lighter, poorly soluble gases.

Identification of Potential Inhibitors of Histone Deacetylase 6 Through Virtual Screening and Molecular Dynamics Simulation Approach: Implications in Neurodegenerative Diseases.

Histone deacetylase 6 (HDAC6) plays a crucial role in neurological, inflammatory, and other diseases; thus, it has emerged as an important target for therapeutic intervention. To date, there are no FDA-approved HDAC6-targeting drugs, and most pipeline candidates suffer from poor target engagement, inadequate brain penetration, and low tolerability. There are a few HDAC6 clinical candidates for the treatment of mostly non-CNS cancers as their pharmacokinetic liabilities exclude them from targeting HDAC6-implicated neurological diseases, urging development to address these challenges. They also demonstrate off-target toxicity due to limited selectivity, leading to adverse effects in patients. Selective inhibitors have thus been the focus of development over the past decade, though no selective and potent HDAC6 inhibitor has yet been approved. This study involved an integrated virtual screening against HDAC6 using the DrugBank database to identify repurposed drugs capable of inhibiting HDAC6 activity. The primary assessment involved the determination of the ability of molecules to bind with HDAC6. Subsequently, interaction analyses and 500 ns molecular dynamics (MD) simulations followed by essential dynamics were carried out to study the conformational flexibility and stability of HDAC6 in the presence of the screened molecules, i.e., penfluridol and pimozide. The virtual screening results pinpointed penfluridol and pimozide as potential repurposed drugs against HDAC6 based on their binding efficiency and appropriate drug profiles. The docking results indicate that penfluridol and pimozide share the same binding site as the reference inhibitor with HDAC6. The MD simulation results showed that stable protein-ligand complexes of penfluridol and pimozide with HDAC6 were formed. Additionally, MMPBSA analysis revealed favorable binding free energies for all HDAC6-ligand complexes, confirming the stability of their interactions. The study implies that both penfluridol and pimozide have strong and favorable binding with HDAC6, which supports the idea of repositioning these drugs for the management of neurodegenerative disorders. However, further in-depth studies are needed to explore their efficacy and safety in biological systems.

BRD4 Degradation Enhanced Glioma Sensitivity to Temozolomide by Regulating Notch1 via Glu-Modified GSH-Responsive Nanoparticles.

Temozolomide (TMZ) serves as the principal chemotherapeutic agent for glioma; nonetheless, its therapeutic efficacy is compromised by the rapid emergence of drug resistance, the inadequate targeting of glioma cells, and significant systemic toxicity. ARV-825 may play a role in modulating drug resistance by degrading the BRD4 protein, thereby exerting anti-glioma effects. Therefore, to surmount TMZ resistance and achieve efficient and specific drug delivery, a dual-targeted glutathione (GSH)-responsive nanoparticle system (T+A@Glu-NP) is designed and synthesized for the co-delivery of ARV-825 and TMZ. As anticipated, T+A@Glu-NPs significantly enhanced penetration of the blood-brain barrier (BBB), facilitated drug uptake by glioma cells, and exhibited efficient accumulation in brain tissue. Additionally, T+A@Glu-NPs exhibited augmented efficacy against glioma both in vitro and in vivo through the induction of apoptosis, inhibition of proliferation, and cell cycle arrest. Furthermore, mechanistic exploration revealed that T+A@Glu-NPs degraded the BRD4 protein, leading to the downregulation of Notch1 gene transcription and the inhibition of the Notch1 signaling pathway, thereby augmenting the therapeutic efficacy of glioma chemotherapy. Taken together, the findings suggest that T+A@Glu-NPs represents a novel and promising therapeutic strategy for glioma chemotherapy.

Supramolecular nanomedicine targeted therapy for tumor treatment

Abstract. In recent years, the incidence of multiple myeloma (MM) has been increasing significantly and showing a trend of younger age. With the advent of new therapies, the median overall survival of patients with MM has improved, but some still relapse early or even pass away. Meanwhile, chemotherapy drugs such as Bortezomib (BTZ) used in patients bring great pain to them because of its non-targeting. Based on this, this paper explores a supramolecular nanomedicine with targeted therapeutic effect on tumors and evaluates the potential of this drug to form new supramolecular nanomedicine. The drug is a combination of BTZ, the natural polyphenol Caffeic Acid (CA), and iron ion (Fe3+), a supramolecular design that brings many advantages to cancer treatment systems, including efficient drug loading, excellent biodegradability and bio-compatibility. Studies have shown that this supramolecular nanomedicine can effectively reduce the killing effect of chemotherapy BTZ on normal cells. This kind of supramolecular nanomedicine provides a new idea for the construction of tumor targeting drugs and is also hopeful to be applied to more chemotherapy drugs.

Integrative transcriptomic analysis identifies emetine as a promising candidate for overcoming acquired resistance to ALK inhibitors in lung cancer.

Anaplastic lymphoma kinase (ALK; also known as ALK tyrosine kinase receptor) inhibitors (ALKi) are effective in treating lung cancer patients with chromosomal rearrangement of ALK. However, continuous treatment with ALKis invariably leads to acquired resistance in cancer cells. In this study, we propose an efficient strategy to suppress ALKi resistance through a meta-analysis of transcriptome data from various cell models of acquired resistance to ALKis. We systematically identified gene signatures that consistently showed altered expression during the development of resistance and conducted computational drug screening using these signatures. We identified emetine as a promising candidate compound to inhibit the growth of ALKi-resistant cells. We demonstrated that emetine exhibited effectiveness in inhibiting the growth of ALKi-resistant cells, and further interpreted its impact on the resistant signatures through drug-induced RNA-sequencing data. Our transcriptome-guided systematic approach paves the way for efficient drug discovery to overcome acquired resistance to cancer therapy.