Cytotoxic Efficacy Research Articles

Synthesis, DPPH Radical Scavenging, Cytotoxic Activity, and Apoptosis Induction Efficacy of Novel Thiazoles and Bis-thiazoles.

Heterocyclic materials-containing thiazoles exhibited incredible importance in pharmaceutical chemistry and drug design due to their extensive biological properties. Synthesis of thiazoles and bis-thiazoles from the reaction of 2-((6-Nitrobenzo[ d][1,3]dioxol-5-yl)methylene)hydrazine-1-carbothioamide with hydrazonoyl chlorides in dioxane and in the existence of triethylamine as basic catalyst. The antioxidant, in vitro antiproliferative, and cytotoxicity efficacy of thiazoles and bis-thiazoles were measured. In this work, novel series of 5-methyl-2-(2-(-(6-nitrobenzo[d][1,3]dioxol-5-yl)methylene) hydrazinyl)-4-(aryldiazenyl)thiazoles (4a-f) were prepared via the reaction of hydrazonoyl chlorides 2a-f with 2-((6-nitrobenzo[d][1,3]dioxol-5-yl)methylene)hydrazine-1-carbothioamide (1) in dioxane and employing triethylamine as basic catalyst. Following the same procedure, bisthiazoles (6, 8, and 10) have been synthesized by utilizing bis-hydrazonoyl chlorides (5, 7, and 9) and carbothioamide 1 in a molar ratio (1:2), respectively. The distinctive features in the structure of isolated products were elucidated by spectroscopic tools and elemental analyses. The antioxidant, in vitro anti-proliferative, cytotoxicity, and anti-cancer efficacy of thiazoles and bis-thiazoles were evaluated. Compounds 4d and 4f were the most potent antioxidant agents. Gene expression of apoptosis markers and fragmentation assay of DNA were assessed to explore the biochemical mechanism of synthesized products. Thiazoles significantly inhibited cell growth and proliferation more than bis-thiazoles. They induced apoptosis through induction of apoptotic gene expression P53 and downregulation of antiapoptotic gene expression Bcl-2. Moreover, they induced fragmentation of DNA in cancer cells, indicating that they could be employed as anticancer agents by inhibiting tumor growth and progression and can be considered effective compounds in the strategy of anti-cancer agents' discovery. Synthesis, DPPH Radical Scavenging, Cytotoxic activity, and Apoptosis Induction Efficacy based on Novel Thiazoles and Bis-thiazoles.

Novel Triazolo[4,3-a]pyrazines as Potential MmpL3 Inhibitors: Design, Synthesis, Antitubercular Evaluation and Molecular Docking Studies

A series of biologically active novel triazolo[4,3-a]pyrazines (5a-f) were synthesized and characterized by spectroscopic techniques. The synthesized compounds 5a-f were evaluated for their in vitro anti-tubercular (anti-TB) activity against drug-sensitive Mtb H37Rv (ATCC 27294) strain as well as two drug-resistant Mtb strains viz. Mtb H37Rv ATCC 35822 (INH-resistant) and Mtb H37Rv ATCC 35837 (ETH-resistant). The synthesized compounds 5a-f displayed good to moderate anti-TB activity against drug-sensitive, INH-resistant and ETH-resistant Mtb H37Rv strains. Among all the compounds tested, compound 5c was found to be significantly potent. It inhibited the growth of drug-sensitive, INH-resistant and ETH-resistant Mtb H37Rv strains with MIC values 0.59 ± 0.11 µM, 20.83 ± 0.67 µM and 15.37 ± 0.14 µM, respectively. Moreover, compounds 5a-f were also tested for their cytotoxic efficacy against the mammalian Vero cell line at a maximum concentration of 50 µM. Molecular docking experiments of compounds 5a-f with the mycobacterial membrane protein large 3 (MmpL3) were performed to justify the biological activity and provide insight into the possible mechanism of action and binding mode of compounds. In silico predictions were used to validate compound toxicity descriptors, drug scores and drug-likeness properties.

Development of B7-H3 targeted CAR-T cells for renal cell carcinoma therapy: in vitro and in vivo efficacy.

This study aims to develop chimeric antigen receptor (CAR)-T cells specifically targeting B7-H3-expressing renal cell carcinoma (RCC) and to evaluate the feasibility of B7-H3 CAR-T therapy for RCC. We analyzed B7-H3 expression in RCC using bioinformatics approaches and confirmed it in tissues and cell lines through immunohistochemical staining and Western blot analysis. A lentiviral vector containing a B7-H3 specific CAR was constructed and transfected into human T cells, with CAR expression verified by flow cytometry. Cytotoxic efficacy was evaluated in co-culture experiments, measuring the production of interferon-gamma (IFN-γ), interleukin-2 (IL-2), granzyme B, and lactate dehydrogenase (LDH) release. Xenograft models in nude mice were used to evaluate tumor growth inhibition by B7-H3 CAR-T cells. B7-H3 was significantly expressed in RCC and associated with poor prognosis. Elevated levels of B7-H3 expression were validated in both RCC tissues and cell lines. A B7-H3-specific CAR-T cell was developed, achieving a CAR transduction efficiency of 39.85%, as assessed by flow cytometry. In vitro co-culture assays demonstrated that the CAR-T cells exhibited substantial cytotoxic activity against RCC cell lines, with this activity positively correlating with the effector-to-target ratio. Furthermore, the secretion levels of IFN-γ, IL-2, granzyme B, and LDH were significantly increased compared to the control groups. In vivo experiments further confirmed that B7-H3 CAR-T cells significantly inhibited tumor growth. The current study suggests that B7-H3 CAR-T cells exhibit significant efficacy in targeting and eliminating RCC cells, indicating a promising cellular immunotherapy approach for RCC treatment.

Magnesium-Doped Hydroxyapatite Nanofibers for Medicine Applications: Characterization, Antimicrobial Activity, and Cytotoxicity Study.

Magnesium-doped hydroxyapatite (HAp-Mg) nanofibers show promise for medical applications due to their structural similarity to bone minerals and enhanced biological properties, such as improved biocompatibility and antimicrobial activity. This study synthesized HAp-Mg nanofibers using a microwave-assisted hydrothermal method (MAHM) to evaluate their cytotoxicity, biocompatibility, and antimicrobial efficacy compared to commercial hydroxyapatite (HAp). Characterization through X-ray diffraction (XRD), scanning electron microscopy (SEM), Transmission Electron Microscopy (TEM), energy-dispersive X-ray spectroscopy (EDS), and Fourier transform infrared spectroscopy (FTIR) confirmed the successful incorporation of magnesium, producing high-purity, crystalline nanofibers with hexagonal morphology. Rietveld refinement showed slight lattice parameter shortening, indicating Mg2+ ion integration. Cell viability assays (MTT and AlamarBlue) revealed a significant increase in fibroblast proliferation with 2% and 5% HAp-Mg concentrations compared to controls (p < 0.05), demonstrating non-cytotoxicity and enhanced biocompatibility. Antimicrobial tests (disk diffusion method, 100 µg/mL) showed that HAp-Mg had strong antibacterial effects against Gram-positive and Gram-negative bacteria and moderate antifungal activity against Candida albicans. In contrast, commercial HAp showed no antimicrobial effects. These results suggest HAp-Mg nanofibers have significant advantages as biomaterials for medical applications, particularly in preventing implant-related infections and supporting further clinical development.

Discovery of a potent PARP1 PROTAC as a chemosensitizer for the treatment of colorectal cancer

Given the vulnerability of colorectal cancer (CRC) patients could not obtain a sustained benefit from chemotherapy, combination therapy is frequently employed as a treatment strategy. Targeting PARP1 blockade exhibit specific toxicity towards tumor cells with BRCA1 or BRCA2 mutations through synthetic lethality. This study focuses on developing a series of potent PROTACs targeting PARP1 in order to enhance the sensitivity of CRC cells with BRCA1 or BRCA2 mutations to chemotherapy. Compound C6, obtained based on precise structural optimization of the linker, has been shown to effectively degrade PARP1 with a DC50 value of 58.14 nM. Furthermore, C6 significantly increased the cytotoxic efficacy of SN-38, an active metabolite of Irinotecan, in BRCA-mutated CRC cells, achieving a favorable combination index (CI) of 0.487. In conclusion, this research underscores the potential benefits of employing a combination therapy that utilizes PAPRP1 degrader C6 alongside Irinotecan for CRC patients harboring BRCA mutations in CRC.

Enhanced adsorption, anticancer and antibacterial potentials of Pontederia crassipes L. extract mediated ecofriendly synthesized ZnO/biochar nanohybrid

This current study presents a green synthesis approach of ZnO, biochar and ZnO/biochar nanostructures using leaves of Pontederia crassipes L. The green fabricated nanomaterials were investigated using different characterization techniques, including as XRD, UV–Vis, TEM, FE-SEM, EDX, BET/BJH, and FTIR. The fabricated nanomaterials were well crystallized with an average crystallite size of 40 nm (ZnO), 43 nm (biochar), and 48 nm (ZnO/biochar). A coomassie brilliant blue G250 (CBB) and methylene blue (MB) removal study was conducted to optimizing (optimize) the influence of operating factors on the adsorption efficiency. Employing a ZnO/biochar 98 % and 99 % adsorption efficiencies were reached in an optimum condition for CCB and MB, respectively. Adopting ZnO/biochar heterostructure as an anticancer for MCF-7 human breast cancer cells was also evaluated. The MTT assay revealed that ZnO/biochar samples exhibit a promise in vitro cytotoxic efficacy against the MCF-7 cell line with IC50 being 79.82 μg /mL. In addition, antimicrobial activity of ZnO/biochar nanoparticles was evaluated on Gram-negative and Gram-positive bacteria. Escherichia coli (E. coli) and Staphylococcus aureus (S. aureus) were used as test microorganisms. The results revealed that the ZnO/biochar possesses an antibacterial inhibition zone of 11 and 9 mm on E. coli, and S. aureus, respectively.

Alternating Donor-Acceptor Ladder-Type Heteroarene for Efficient Photothermal Conversion via Boosting Non-Radiative Decay.

The development of novel ladder-type conjugated molecules is crucial for advancing supramolecular chemistry and material science. In this study, we report a straightforward synthesis of new alternating donor-acceptor (D-A) ladder-type heteroarene, FCDTDPP, and demonstrate its application as photothermal agent for imaging and cancer therapy. FCDTDPP is constructed by vinylene bridge between cyclopentadithiophene (D) and diketopyrrolopyrrole (A) through intramolecular Friedel-Crafts type reaction. FCDTDPP exhibits unique combination of good molecular planarity, efficient intra/inter-molecular mixed D-A interactions, and local aromaticity. These features collectively contribute to its broad and intense absorptions with narrow bandgap in red band of the spectra, coupled with multiple vibrational absorption feature, thereby enhancing non-radiative decay process and resulting in efficient photothermal conversion property. FCDTDPP and its nanoparticles (NPs) exhibit superior photothermal conversion performance and stability under 660 nm laser irradiation. Moreover, in vitro studies reveal that FCDTDPP NPs possess excellent biocompatibility, low cytotoxicity, and robust photothermal therapeutic efficacy, a finding further corroborated by preliminary in vivo experiments in tumor-bearing mice. This work charts a novel course for the molecular engineering of organic photothermal conversion systems, propelling relevant research forward.

Alternating Donor‐Acceptor Ladder‐Type Heteroarene for Efficient Photothermal Conversion via Boosting Non‐Radiative Decay

The development of novel ladder‐type conjugated molecules is crucial for advancing supramolecular chemistry and material science. In this study, we report a straightforward synthesis of new alternating donor‐acceptor (D‐A) ladder‐type heteroarene, FCDTDPP, and demonstrate its application as photothermal agent for imaging and cancer therapy. FCDTDPP is constructed by vinylene bridge between cyclopentadithiophene (D) and diketopyrrolopyrrole (A) through intramolecular Friedel‐Crafts type reaction. FCDTDPP exhibits unique combination of good molecular planarity, efficient intra/inter‐molecular mixed D‐A interactions, and local aromaticity. These features collectively contribute to its broad and intense absorptions with narrow bandgap in red band of the spectra, coupled with multiple vibrational absorption feature, thereby enhancing non‐radiative decay process and resulting in efficient photothermal conversion property. FCDTDPP and its nanoparticles (NPs) exhibit superior photothermal conversion performance and stability under 660 nm laser irradiation. Moreover, in vitro studies reveal that FCDTDPP NPs possess excellent biocompatibility, low cytotoxicity, and robust photothermal therapeutic efficacy, a finding further corroborated by preliminary in vivo experiments in tumor‐bearing mice. This work charts a novel course for the molecular engineering of organic photothermal conversion systems, propelling relevant research forward.

DDEL-16. MICROMESH FOR REVAMPING THE ‘COLD’ TUMOR MICROENVIRONMENT IN GLIOBLASTOMA IMMUNOTHERAPY

Abstract High-grade gliomas have poor prognoses with limited treatment options, typically maximal safe resection and adjuvant radiochemotherapy. Novel therapies often face challenges due to low brain penetrance and poor bioavailability. To address these issues, a conformable, compartmentalized polymeric implant called microMESH has been developed. microMESH provides localized, sustained release of drugs, small inhibitors, antibodies, and nanomedicines, enabling novel therapeutic combinations. When applied to the tumor margins, microMESH adheres to the tissue, releasing its therapeutic cargo over weeks and reducing systemic toxicity. Its biocompatibility, cytotoxicity, and anti-tumor efficacy were tested on murine cancer cells (CT-2A) and orthotopic glioblastoma syngeneic models. Exposing primary bone marrow-derived monocytes (BMDM) to CT-2A conditioned medium increased the expression of anti-inflammatory cytokines (IL-10 and IL-4) by 2 times without significantly affecting the pro-inflammatory cytokines (TNF-α, IL-1β, and IL-6), indicating that CT-2A cells tend to establish an immunosuppressive ‘cold’ tumor microenvironment. Next, the co-incubation of CT-2A cells with BMDM followed by the administration of the immune checkpoint inhibitor aCD47 resulted in a cancer cell viability drop by 50% already at 50 μg/ml aCD47 after 1 day. Additionally, pre-treatment with docetaxel (DTXL) further decreased cell viability, suggesting a synergism between aCD47 and the chemotherapeutic drug. Flow cytometry showed that 50 nM DTXL at 3 days post-incubation was responsible for a strong translocation of the ‘immunogenic dell death’ protein calreticulin on the cell membrane, potentially explaining the synergism. Over 2 months, the intracranially deployed microMESH biodegraded without inducing any toxic effect. In orthotopic CT-2A tumors, aCD47/DTXL–microMESH (0.75 mg/kg, single intracranial application) showed a 40-day survival compared to 22 days for iv DTXL (3 mg/kg qod), 24 days for ip aCD47 (5 mg/kg qod), and 18 days for untreated mice. microMESH helped identify and enabled novel combination therapies directly at the tumor bed, demonstrating superior efficacy over systemic therapies.

Enhanced anticancer effect of thymidylate synthase dimer disrupters by promoting intracellular accumulation.

Thymidylate synthase (TS) plays a crucial role in cellular growth, proliferation, DNA synthesis, and repair, thus gaining attention for targeted therapies in cancer. TS overexpression and the altered pharmacokinetics of anti-TS drugs are among the most prominent causes of cellular resistance. Decreased drug influx and/or efficient efflux result in reduced drug access to the intracellular targets. In this study, we have evaluated and demonstrated the increased cytotoxic efficacy of novel TS dimer disrupters (Ddis) in the presence of specific inhibitors of drug efflux protein pumps in ovarian and colon cancer cells, suggesting that these compounds are substrates of the cellular drug extruders. A second strategy adopted to favor intracellular accumulation was to employ, as a drug delivery system, a molecular tool able to help less lipophilic compounds to cross the cell membrane. The Ddis were delivered through the SAINT-Protein transfection agent. The observed cell-killing effects agreed with the reduction of TS protein level and cell cycle perturbation. Overall, this preclinical study suggests that the innovative TS dimer disrupters can be optimized by increasing their intracellular accumulation by both inhibiting their outflow and/or enhancing cellular uptake.

Asciminib stands out as the superior tyrosine kinase inhibitor to combine with anti-CD20 monoclonal antibodies for the treatment of CD20+ Philadelphia-positive B-cell precursor acute lymphoblastic leukemia in preclinical models.

Philadelphia chromosome-positive B-cell precursor acute lymphoblastic leukemia (Ph+ BCP-ALL) is a high-risk subtype of acute lymphoblastic leukemia characterized by the presence of the BCR::ABL1 fusion gene. Tyrosine kinase inhibitors (TKI) combined with chemotherapy are established as the first-line treatment. Additionally, rituximab, an anti-CD20 monoclonal antibody is administered to adult BCP-ALL patients with ≥20% CD20+ blasts. In this study, we observed a marked prevalence of CD20 expression in patients diagnosed with Ph+ BCP-ALL, indicating a potential widespread clinical application of rituximab in combination with TKI. Consequently, we examined the influence of TKI on the antitumor effectiveness of anti-CD20 monoclonal antibodies by evaluating levels of CD20 on the cell surface and conducting in vitro functional assays. All tested TKI were found to uniformly downregulate CD20 on leukemic cells, diminishing the efficacy of rituximab-mediated complement- dependent cytotoxicity. Interestingly, these TKI displayed varied effects on natural killer (NK) cell-mediated antibody- dependent cytotoxicity and macrophage phagocytic function. While asciminib demonstrated no inhibition of effector cell functions, dasatinib notably suppressed the anti-CD20-monoclonal antibody-mediated NK cell cytotoxicity and macrophage phagocytosis of BCP-ALL cells. Dasatinib and ponatinib also decreased NK cell degranulation in vitro. Importantly, oral administration of dasatinib, but not asciminib, compromised NK cell activity in patients' blood, as determined by an ex vivo degranulation assay. Our results indicate that asciminib might be preferred over other TKI for combination therapy with anti-CD20 monoclonal antibodies.

Eco-friendly fabrication of ZnO nanocomposites using Lepidium didymium and polymer-assisted CTAB/PEG: A multifunctional approach for enhanced biomedical applications

This work illustrates the environmentally benign fabrication of zinc oxide (ZnO) nanoparticles using Lepidium didymium to enhance their effectiveness in various biological applications. The use of extracts from the plant as reactive constituents in nanoparticle fabrication presents a cost-effective, scalable, and eco-friendly methodology, wherein plant-based substances serve as stabilizing and reducing agents. Apart from this polymer which acts as the surfactant is capped with the green synthesized ZnO. In this study,green ZnO was synthesized byutilizing CTAB and PEG, as a polymeric surfactantwhich led to a notable reduction in nanoparticle size and increased stability. Stearic hindrance, which keeps NPs stable, is caused bya mechanism in which polymeric chains build a strong covalent bondwith their neighboring chains. X-ray diffraction (XRD), Ultraviolet–visible spectroscopy, Fourier transform infrared spectroscopy (FTIR), and Scanning Electron Microscopy (FESEM) were utilized and this helps to analyze the synthesized ZnO and its nanocomposites produced through environmentally friendly methods. The assessed ZnO nanoparticles demonstrated versatility in biomedical applications, as indicated by their evaluation for antibacterial, anti-inflammatory, anticancer, and characteristics that promote wound healing. The cytotoxic efficacy of green-synthesized ZnO nanocomposites on the HepG2 cell line was assessed utilizing the MTT assay method. The analysis produced the subsequent IC50 value: The concentrations of 69.91 μg/mL for green synthesized ZnO and 83.05 μg/mL for CTAB-assisted ZnO nanocomposite indicate detrimental effects on the evolution of the HepG2 cell line. The efficacy of the green-synthesized zinc oxide nanoparticles and ZnO nanocomposite for wound healing were assessed on L929 cells, with cipladine as a reference standard. This study highlights the effectiveness and sustainability of green fabrication methods in producing functional nanomaterials for various healthcare applications.

New Chalcone-Derived Molecule for the Topical Regulation of Hyperpigmentation and Skin Aging.

Background/Objectives: Skin hyperpigmentation is a biological process that results in an excessive production of melanin and is highly regulated by several mechanisms, tyrosinase being one of the key enzymes involved. Current reported inhibitors lack clinical efficacy, show toxic side effects, have poor bioavailability, or low formulation compatibility. The aim of this study was to design a new effective tyrosinase inhibitor for topical hyperpigmentation and anti-aging treatments. Methods: Homology modeling was used to build the tridimensional structure of human tyrosinase, and virtual docking was used to predict molecule-enzyme binding modes. The tyrosinase activity of the designed and synthesized compounds was assessed and water solubility was determined by HPLC. Cell assays were performed to determine melanin content, cytotoxicity, wound healing, anti-glycation, antioxidation, and autophagy efficacy. Gene expression and miRNA levels were quantified by qPCR and chromatin accessibility by ATAC-Seq. Human reconstructed epidermis was used to test the depigmenting efficacy as well as the skin irritation potential. Results: The 3D structure of human tyrosinase was designed and validated. The new molecule could effectively inhibit human tyrosinase and melanin synthesis in 2D monocultures and a 3D epidermis model. Two melanogenesis-related miRNAs were increased in treated cells. Anti-glycation, antioxidant, mitochondria protection, autophagy activation, and wound healing properties were also observed, with special emphasis on epigenetics. Conclusions: The designed molecule is a potential candidate to be used as a depigmenting and anti-aging agent, with suitable properties to be introduced in final product formulations for dermatology or cosmetics treatments.

Synergistic Chemo-Immunotherapy Using pH-Responsive Nanoparticles in Breast Cancer Treatment: In Vitro and In Vivo Studies.

Recent research underscores the pivotal role of the heterogeneous multicellular interactome within the tumor microenvironment (TME) in tumor progression and survival. Tumor-associated macrophages (TAMs), among other nonmalignant cells in the TME, promote an immunosuppressive environment, fostering tumor cell survival, proliferation, and resistance. Hence, combining chemotherapy with immunomodulatory agents to transition TAMs to an immunostimulatory phenotype holds immense therapeutic potential. The present study focuses on developing tumor-responsive nanoparticles (NPs) for combined chemo-immunotherapy using resiquimod (RSQ), a TLR 7/8 agonist as an immunomodulator, and paclitaxel (PTX) as chemotherapeutics. A pH-responsive NP known as PHNP, tailored with a star-shaped PLGA conjugated with poly histidine, was engineered to selectively deliver a consistent ratio of PTX and RSQ directly to the tumor site. In vitro studies demonstrate enhanced drug release at pH 6.4, increased penetration in tumor spheroids, and increased cytotoxic efficacy against breast cancer cells. Furthermore, PHNPs activate macrophages for antitumor activity. In vivo studies demonstrated a notable rise in plasma AUC and improved delivery of drugs to the tumor using PHNPs, resulting in enhanced effectiveness against tumor growth in a mouse orthotopic breast cancer model. Notably, PHNP treatment elevated intratumoral ROS and apoptosis levels and inhibited lung metastasis. Overall, this study underscores the potential of the PTX and RSQ combination as a prospective combined chemo-immunotherapeutic modality.

Targeted PHA Microsphere-Loaded Triple-Drug System with Sustained Drug Release for Synergistic Chemotherapy and Gene Therapy.

The combination of paclitaxel (PTX) with other chemotherapy drugs (e.g., gemcitabine, GEM) or genetic drugs (e.g., siRNA) has been shown to enhance therapeutic efficacy against tumors, reduce individual drug dosages, and prevent drug resistance associated with single-drug treatments. However, the varying solubility of chemotherapy drugs and genetic drugs presents a challenge in co-delivering these agents. In this study, nanoparticles loaded with PTX were prepared using the biodegradable polymer material poly(3-hydroxybutyrate-co-3-hydroxyhexanoate) (PHBHHx). These nanoparticles were surface-modified with target proteins (Affibody molecules) and RALA cationic peptides to create core-shell structured microspheres with targeted and cationic functionalization. A three-drug co-delivery system (PTX@PHBHHx-ARP/siRNAGEM) were developed by electrostatically adsorbing siRNA chains containing GEM onto the microsphere surface. The encapsulation efficiency of PTX in the nanodrug was found to be 81.02%, with a drug loading of 5.09%. The chemogene adsorption capacity of siRNAGEM was determined to be 97.3%. Morphological and size characterization of the nanodrug revealed that PTX@PHBHHx-ARP/siRNAGEM is a rough-surfaced microsphere with a particle size of approximately 150 nm. This nanodrug exhibited targeting capabilities toward BT474 cells with HER2 overexpression while showing limited targeting ability toward MCF-7 cells with low HER2 expression. Results from the MTT assay demonstrated that PTX@PHBHHx-ARP/siRNAGEM exhibits high cytotoxicity and excellent combination therapy efficacy compared to physically mixed PTX/GEM/siRNA. Additionally, Western blot analysis confirmed that siRNA-mediated reduction of Bcl-2 expression significantly enhanced cell apoptosis mediated by PTX or GEM in tumor cells, thereby increasing cell sensitivity to PTX and GEM. This study presents a novel targeted nanosystem for the co-delivery of chemotherapy drugs and genetic drugs.

Anti-Oxidant and Anti-Cancerous Properties of Pyrus pashia (Buch. -Ham.Ex D.Don) Against KB-3-1 Cancer Cell Lines In Vitro

Background: Oral cancer is the fastest-growing cancer in men. Many medicinal approaches are tried step-wise for cancers. Homeopathy and Ayurveda are contributing much to cure cancers without side effects. Plants having antioxidant properties are now being utilized with different solvents to extract different chemical compounds to cure cancer. Objective: The current study aimed to examine the anti-cancer and antioxidant properties of acetone extract of Pyrus pashia (PP-AE) fruit against KB-3-1 cancer cell lines. Materials and Methods: The extract's total phenolic content was determined using a folin-ciocalteu reagent. The DPPH, ABTS, and H2O2 assay were used to measure the free radical scavenging activity of the PP-AE. The MTT assay was used to evaluate the cytotoxic efficacy of the PP-AE against KB-3-1 cancer cell lines at various concentrations. Results: Based on the observations, the total phenolic content was present in the PP-AE of fruit and all free radical scavenging assays have shown remarkable IC50 values. Conclusion: According to the current study, acetone extract of Pyrus pashia fruit significantly possesses antioxidant and anti-cancer properties against oral (KB-3-1) cancer cell lines. This effect may be used in the future to analyze particular chemical compounds in extract, capable of minimizing the growth of oral cancer cells.

Hyaluronic acid/lactoferrin–coated polydatin/PLGA nanoparticles for active targeting of CD44 receptors in lung cancer

Traditional chemotherapeutic drugs lack optimal efficacy and invoke severe adverse effects in cancer patients. Polydatin (PD), a phytomedicine, has gradually gained attention due to its antitumor activity. However, its low solubility and poor bioavailability are still cornerstone issues. The present study aimed to fabricate and develop hyaluronic acid/lactoferrin–double coated PD/PLGA nanoparticles via a layer-by-layer self-assembly technique for active targeting of CD44 receptors in lung cancer. Different molecular weights (M.wt.) of HA (32 and 110 kDa) were exploited to study the relationship between the HA M.wt. and the NPs targeting efficacy. The optimized formulations were fully characterized. Their cytotoxicity and cellular uptake were investigated against A549 cell line by CCK-8 kit and fluorescence imaging, respectively. Finally, HA110/Lf-coated PD/PLGA NPs (F9) were subjected to a competitive inhibition study to prove internalization through CD44 overexpressed receptors. The results verified the fabrication of F9 with a particle size of 174.87 ± 3.97 nm and a zeta potential of −24.37 ± 1.19 mV as well as spherical NPs architecture. Importantly, it provoked enhanced cytotoxicity (IC50 = 0.57 ± 0.02 µg/mL) and superior cellular uptake efficacy. To conclude, the current investigation lays the foundation for the prospective therapeutic avenue of F9 for active targeting of CD44 receptors in lung cancer.

Rosuvastatin Flexible Chitosomes: Development, In Vitro Evaluation and Enhancement of Anticancer Efficacy Against HepG2 and MCF7 Cell Lines.

Rosuvastatin (ROS), a statin drug with promising anticancer properties has a low bioavailability of approximately 20% due to lipophilicity and first-pass metabolism. This study aimed to enhance ROS anticancer efficacy through loading into flexible chitosomes. The chitosomes were prepared starting from negatively charged liposomes through electrostatic interactions with chitosan. The conversion of zeta potential from negative to positive confirmed the successful formation of chitosomes. The chitosan coating increased the particle size and zeta potential, which ranged from 202.0 ± 1.7nm to 504.7 ± 25.0nm and from - 44.9 ± 3.0 mV to 50.1 ± 2.6 mV, respectively. Chitosan and drug concentrations had an important influence on the chitosome properties. The optimum chitosome formulation was used to prepare ROS-loaded flexible chitosomes using different concentrations of four edge activators. The type and concentration of edge activator influenced the particle size, drug entrapment efficiency, and drug release rate of the flexible chitosomes. Flexible chitosomes significantly increased drug permeation through rat abdominal skin compared to control transferosomes and drug solution. The optimal ROS flexible chitosomes containing sodium deoxycholate as an edge activator had a 2.23-fold increase in ROS cytotoxic efficacy against MCF7 cells and a 1.84-fold increase against HepG2 cells. These results underscore the potential of flexible chitosomes for enhancing ROS anticancer efficacy.

SMAD4 enhances the cytotoxic efficacy of human NK cells against colorectal cancer cells via the m6A reader YTHDF2.

Colorectal cancer (CRC) ranks as the third most prevalent malignant neoplasm in terms of both morbidity and mortality. Within the tumor microenvironment (TME) of CRC, the diminished presence and diminished cytotoxic function of natural killer (NK) cells serve as important factors driving the advancement of CRC; however, the precise regulatory mechanisms governing this phenomenon remain incompletely understood. Consequently, the identification of novel, potential anti-CRC targets associated with NK cells emerges as a pressing and paramount concern warranting immediate attention. We examined the regulatory mechanism of SMAD4-mediated NK cell cytotoxicity on CRC by utilizing various experimental techniques, such as qRT-PCR, flow cytometry. Our findings revealed that the expression of SMAD4 is decreased in NK cells within the TME of human CRC. Furthermore, we observed that enforced upregulation of SMAD4 resulted in enhanced cytotoxicity of NK cells towards CRC cells. Furthermore, our research has revealed that YTHDF2 functions as a downstream effector of SMAD4, playing a crucial role in the control of transcription and translation of m6A-modified RNA. Moreover, our investigation demonstrated that increased expression of SMAD4 promoted the activating receptor NKG2D by elevating levels of YTHDF2. Ultimately, the SMAD4-YTHDF2 regulatory axis significantly enhanced the cytotoxicity of NK cells against human CRC cells. Our study unveils a novel mechanism through which SMAD4 modulates the cytotoxicity of NK cells towards CRC cells, suggesting that SMAD4 may hold promise as a potential therapeutic target for NK cell therapy in CRC.

Biomimetic Single-Atom Nanozyme for Dual Starvation-Enhanced Breast Cancer Immunotherapy.

Cold exposure (CE) therapy is an innovative and cost-efficient cancer treatment that activates brown adipose tissue to compete for glucose uptake, leading to metabolic starvation in tumors. Exploring the combined antitumor mechanisms of CE and traditional therapies (such as nanocatalysis) is exciting and promising. In this study, a platelet membrane biomimetic single-atom nanozyme (SAEs) nanodrug (PFB) carrying bis-2-(5-phenylacetamido-1, 2, 4-thiadiazol-2-yl) ethyl sulfide (BPTES) is developed for use in cancer CE therapy. Owing to the platelet membrane modification, PFB can effectively target tumors. Upon entering cancer cells, the dual starvation effect induced by CE treatment and BPTES can significantly diminish intracellular glucose and ATP levels, resulting in a substantial reduction in cellular (glutathione) GSH, which can enhance the cytotoxic efficacy of reactive oxygen species generated by SAEs. This strategy not only boosts ROS production in tumors, but also strengthens immune responses, particularly by increasing memory T-cell abundance and suppressing distant tumor growth and tumor metastasis. Compared with SAEs therapy alone, this combined approach offers superior benefits for tumor immunotherapy. This study achieves a combination of CE and nanomedicines for the first time, providing new ideas for future nanomedicine combination therapy modalities.