ELK3-SERPINE1-PCBP2 axis promotes gefitinib resistance in lung cancer by inhibiting ferroptosis.

Acidifying agents impact erlotinib and gefitinib pharmacokinetic parameters and elevate liver enzymes in Wistar rats

RELAY+: Final Overall Survival With Ramucirumab Plus Gefitinib in Patients With Untreated EGFR-Mutated Metastatic NSCLC

Non-small cell lung cancer (NSCLC) is one of the leading causes of cancer-related deaths, remaining a significant challenge in terms of early detection, effective treatment, and improving patient survival rates. In this study, we investigated the anticancer mechanism of rubiarbonol B (Ru-B) and its derivative 3-O-acetylrubiarbonol B (ARu-B), a pentacyclic terpenoid in gefitinib (GEF)-sensitive and -resistant NSCLC HCC827 cells. Concentration- and time-dependent cytotoxicity was observed for both Ru-B and ARu-B. The in vitro kinase assay showed that ARu-B treatment inhibited epidermal growth factor receptor (EGFR), mesenchymal-epithelial transition (MET), and AKT1, and their phosphorylation in HCC827 cells. A molecular docking model suggested that ARu-B could interact with EGFR and MET in different ways, either by binding to the ATP pocket or the substrate pocket. ARu-B induced reactive oxygen species (ROS) generation and cell cycle arrest. The induction of apoptosis through caspase activation was confirmed by preventing cytotoxicity with Z-VAD-FMK pretreatment. Taken together, ARu-B inhibited the growth of both GEF-sensitive and GEF-resistant NSCLC cells by targeting EGFR, MET, and AKT and inducing ROS generation and caspase activation. Further studies on ARu-B can improve the treatment of chemotherapy-resistant NSCLC through the development of effective ARu-B-based anticancer agents.

Ultra-fast detoxification pathways of anti-cancer drug (Gefitinib) via high-entropy engineering driving catalysis.

The current study investigates the therapeutic potential of paclitaxel (PX) co-loaded with imatinib (IMT), IMT with protamine (PT), and gefitinib (GF) nanoparticle (NP) formulations against triple-negative breast cancer (TNBC) to overcome drug resistance. Building upon our previous work where the SR-F-I (PX-IMT-PLGA NPs), SR-F-I (coated) as PX-IMT-PT-PLGA-NPs, and SR-F-II (PX-GF-PLGA NPs) formulations were optimized and evaluated in both MCF-7 and MCF-7/ADR cells, we extended our investigation to MDA-MB-231 TNBC cells and in vivo animal model. Comparative in vitro cytotoxicity studies demonstrated that SR-F formulations, especially SR-F-I (coated) and SR-F-II, significantly enhanced drug delivery and cell death compared to free PX and combination conventional drug solutions. Confocal imaging confirmed improved NP internalization, correlating with increased cytotoxic efficacy. In vivo, SR-F formulations exhibited reduced tumor growth volumes, lower prostaglandin-2 (PGs-2) levels, and diminished tumor markers (tumor necrosis factor-alpha; TNF-α and breast cancer Antigen 15-3; CA 15-3), indicating reduced inflammation and tumor burden. Histopathological evaluations of SR-F formulations revealed improved tissue repair and organized fibrosis in mammary tissue. Our findings thus highlight the superior potential of co-loaded polymeric NPs in targeted cancer therapy, with an enhanced safety profile, therapeutic outcomes, and modulation of systemic inflammation. The co-loaded formulation of PX with IMT and GF presents a promising strategy for advancing breast cancer treatment.

Alchemical free energy-based optimization of quinazoline derivatives as potent EGFR inhibitors with cytotoxic activity.

Abstract Glycyrrhizic acid (GCA), also referred to as glycyrrhizin, is a triterpene saponin produced by Glycyrrhiza glabra. GCA has many pharmacological actions, like anti‐inflammatory, antioxidant, and anti‐tumor effects. GCA is generally used as a targeting molecule against protein kinase c alpha (PKC‐α), which is also overly expressed in non‐small cell lung cancer (NSCLC). In this research work, a self‐targeted and self‐assembled nanomicelles system is successfully developed using GCA for the delivery of gefitinib (GEF) for the treatment of lung cancer. The lipid molecule, stearylamine (SA) is conjugated to the GCA to synthesize amphiphilic glycyrrhizic acid‐stearylamine (GCA‐SA) conjugate. The GCA‐SA conjugate is characterized and its critical micelle concentration is determined (100 µg mL−1). GEF‐loaded GCA‐SA nanomicelles (GNM) are prepared using the solvent evaporation method and their physicochemical properties are thoroughly investigated. The nanomicelles demonstrate high drug encapsulation efficiency (85%), amorphous drug dispersion, and improved dissolution behavior compared to the free drug. The cytotoxicity studies reveal the high therapeutic efficacy of GNM compared to free GEF, with minimal toxicity observed in the blank nanomicelles group against A549 cells. Overall, these findings suggest that the developed nanocarrier holds great promise for improving the efficacy and selectivity of anti‐cancer agents in the treatment of lung cancer.

Objective The aim of this study was to investigate the mechanism of Qingjieyifei Miao Fang (QJYFMF) in combination with gefitinib (GE) against non-small cell lung cancer (NSCLC). Methods Network pharmacology was used to identify the key targets and signaling pathways of QJYFMF in the treatment of NSCLC. Both in vitro (A549 cell culture model) and in vivo (mouse lung cancer xenograft model) models were established. The therapeutic effects of QJYFMF on NSCLC were evaluated using CCK-8, flow cytometry, wound healing, and transwell assays. The expression of key proteins in the PTEN/PI3 K/AKT signaling pathway was assessed by Western blot and qRT-PCR. Results A total of 98 active components and 901 targets of QJYFMF were identified, with the majority involved in the PI3K-AKT, MAPK, and apoptosis signaling pathways. Compared with the control group, QJYFMF significantly inhibited A549 cell proliferation, promoted apoptosis, and reduced cell migration and invasion abilities. In vivo , the transplanted tumor volume and weight were reduced, while the protein expression levels of PTEN, caspase-9, and BAD were increased. Additionally, the levels of PI3 K/p-PI3 K, AKT/p-AKT, p-caspase-9, and p-BAD were decreased, and the mRNA expression levels of BAD and caspase-9 were increased. The combination of GE and QJYFMF showed greater efficacy. Conclusion QJYFMF significantly inhibited NSCLC proliferation, migration, and invasion while promoting apoptosis. The combination of GE and QJYFMF enhances the therapeutic effects of GE, potentially through the modulation of the PTEN/PI3 K/AKT signaling pathway.

Gefitinib (GFN) is an Epithelial Growth Factor Receptor (EGFR) inhibitor, and Food and Drug Administration (FDA) has approved medication to treat lung cancer. However, this investigation aimed to produce and characterize Gefitinib (GFN)-loaded chitosan and soy lecithin nanoparticles (NPs) modified with D-α-tocopheryl polyethylene glycol 1000 succinate mono ester (TPGS) and assess their therapeutic potential against HepG2 liver cell lines. Chitosan, a cationic polymer with biocompatible and biodegradable properties, was combined with soy lecithin to develop the NPs loaded with GFN using a self-organizing ionic interaction methodology. The entrapment efficiency and drug loading were found to be 59.04±4.63 to 87.37±3.82% and 33.46±3.76 to 49.50±4.35%, respectively, and results indicated the encapsulation of GEN in NPs. The pH of the formulations was observed between 4.48-4.62. Additionally, all the prepared NPs showed the size and PDI range of 89.2±15.9 nm to 799.2±35.8 nm and 0.179±0.065 to 0.455±0.097, respectively. The FTIR bands in optimized formulation (GFN-NP1) indicated that the drug might be contained within the NP's core. The SEM photograph revealed the spherical shape of NPs. The kinetic release model demonstrated the combination of diffusion and erosion mechanisms. The IC50 value of GFN and GFN-NP1 formulation against the HepG2 cell lines were determined and found to be 63.22±3.36 μg/ml and 45.80±2.53 μg/ml, respectively. DAPI and PI staining agents were used to detect nuclear morphology. It was observed that the optimized GFN-NP1 formulation successfully internalized and inhibited the growth of HepG2 cells. Hence, it can be concluded that the prepared NPs can be a new therapeutic option for treating liver cancer.

Gefitinib (GB), an oral tyrosine kinase inhibitor suffers major setbacks in clinical application due to limited aqueous solubility leading to poor oral bioavailability. Nanosuspension serves as a promising formulation strategy to overcome the above-mentioned drawbacks. Hence, the present study involves the development of gefitinib nanosuspension (GB-NS) using High-pressure homogenization (HPH) to increase its aqueous solubility and maximize oral bioavailability. GB-NS was optimized by utilizing thequality-by-design strategy to optimize independent variables such as homogenization pressure,drug-to-stabilizer ratio, and number of cycles. Lecithin was found to stabilize the nanosuspension with optimal particle size, PDI, and zeta potential of 157 ± 18.77nm, 0.296 ± 0.040, and -33.25 respectively. Intriguingly, a drug-to-stabilizer ratio significantly influenced (p < 0.005) particle size and PDI, establishing its crucial role in optimization. The morphological characterization by SEM of GB-NS revealed a rod-shaped structure. Thereafter, the thermal and powder X-ray analysis depicted the crystalline nature of gefitinib in GB-NS. Additionally, GB-NS exhibited enhanced saturation solubility (~ 2.4- and ~ 3.4-fold) and dissolution rate (~ 2.5- and ~ 3.5-fold) compared to pure GB in 0.1 N HCl and PBS 6.8 respectively. GB-NS remained stable under both storage conditions ( 25°C and 4°C). Finally, the pharmacokinetic study depicted aconsiderable increase in Cmax (~ 2.84-fold) and AUC(0-t) (~ 3.87-fold) of GB-NS when compared to free GB. Therefore, developed formulations showed a competent solution for enhancing theoral bioavailability of poor water-soluble drugs.

The exploration of novel carriers for cancer treatments is on the rise, as drugs are often hindered by ineffective delivery. In the present study, Mesoporous silica nano scaffolds were developed by a novel heat assisted hydrolysis (HAH) technique, and were functionalized using PLGA. These carriers were further loaded with nanosized Gefitinib (GTB). The surface properties of MSNs (GTB-PEG-PLGA-MSN) were enhanced using 1-oleoyl-2-hydroxy-sn-glycero-3-phosphocholine (SPC3). The MSNs were characterized for pore volume, particle size, zeta potential (ZP), surface area, entrapment efficiency (%EE), and drug content. The in vitro drug release kinetics, cytotoxicity analysis, and in vivo biodistribution studies were performed in optimized MSN using Albino Wistar rats. The result shows an increase in surface area, pore volume, %EE, and drug loading in MSN. In vitro cytotoxicity of optimized F5-GTB-PEG-PLGA-SPC3-MSN demonstrated a higher antitumor activity (43.84 ± 0.63%, p < 0.05) in comparison to free drug. A higher GTB was detected in the liver (29,415 ± 126 ng) indicating significant biodistribution (p > 0.05). The in vitro studies in the MCF-7 cell line signify an increase in cell viability demonstrating its efficacy in breast cancer. Optimized F5-GTB-PEG-PLGA-SPC3-MSN offers improved cellular uptake, biodistribution, and higher antitumor suppression with less toxicity. To conclude, the HAH technique produced stable MSNs, and PLGA-SPC3 functionalized MSN nano scaffolds could be an ideal carrier for cancer drug delivery.

Personalized treatment strategies have greatly improved the efficacy of anticancer drugs. Nanocarriers, especially liposomes, function as excellent platform for the delivery of both hydrophilic and hydrophobic agents. iRGD is a peptide composed of 9-amino acid denoted as (iRGDP), enhances selective and intratumoral delivery of anticancer drugs. Trastuzumab (TMAB), mainly targets HER2-positive advanced stage breast cancer is an FDA-approved monoclonal antibody. Gefitinib (GEB) is an anticancer drug, effective against metastatic breast cancer (MBC), while Lycorine hydrochloride (LCOH), a naturally derived compound, possess both anti-inflammatory and anticancer properties. This research is mainly emphasizing on the preparation of GEB and LCOH-entrapped TPGS-COOH coated-liposomes, camouflaged with an antibody (TMAB) and cyclic peptide (iRGDP) for targeted delivery in MBC therapy. The developed multifunctional liposomes were studied for extensive in vitro cell line studies on MCF-7 cells. The half-maximum inhibitory concentration (IC-50) values of GEB and LCOH co-loaded single functionalized liposome (SFL) (iRGDP-LiP, and TMAB-LiP) and dual-functionalized liposome (DFL) (iRGDP-TMAB-LiP) on MCF-7 cells were 1.04 ± 0.023 μg/mL, 0.71 ± 0.018 μg/mL, and 0.56 ± 0.028 μg/mL, respectively. Inverted confocal laser scanning microscopy (ICLSM) revealed enhanced cellular internalization in SFL and DFL-treated groups tagged with coumarin-6 and rhodamine-B dye as compared to conventional liposome. The scratch assay revealed a marked reduction in cell migration, while DAPI staining confirmed enhanced nuclear condensation (NC) and nuclear fragmentation (NF) in SFL and DFL-treated groups. Moreover, flow cytometry demonstrated enhanced early and late apoptosis in SFL and DFL groups. These findings indicate that GEB and LCOH co-loaded multifunctional liposome holds promise as a multifaceted therapeutic approach for MBC therapy.

Hepatocellular carcinoma (HCC) is a health problem due to multi-drug resistance (MDR). Codelivery of multiple oncotherapy in one cargo as chimeric cancer therapy (CCT) is suggested as a solution for MDR. This study aims to engineer chitosan-coated nanostructure lipid carriers (NLCs) loaded with gefitinib (GF) and simvastatin (SV) as CCT for HCC. Both GF and SV-loaded nanostructure lipids carriers (GFSVNLC) and chitosan-capped GF and SV-loaded nanostructure lipids carriers (CGFSVNLC) formulations were assembled by top-down techniques. Moreover, particle size (PS), zeta potential (ZP), and polydispersity index (PDI) were measured by Zetasizer. The biosafety of GFSVNLC preparations was investigated by using erythrocytes as a biological model. The cytotoxic, and apoptotic effects of the prepared GFSVNLCs were investigated using HepG2 cell lines as a substitute model for HCC. The effect of GF, SV, and NLC composition on JNK3, HDAC6, and telomerase was studied using molecular docking simulation (MDS). The present results revealed that the obtained GFSVNLC and CGFSVNLC have nanosized and consistent, CS coating shifts anionic ZP of GFSVNLC into CGFSVNLC with cationic ZP. Moreover, both formulations are biocompatible as indicated by their gentle effect on erythrocyte hemolysis. The treatment of HepG2 cells with GFSVNLC, and CGFSVNLC induced marked cell death compared to other groups with a decrease of IC50. Equally, the percentage of the apoptotic HepG2 cells was increased upon treatment of the cells with GFSV, GFSVNLC, and CGFSVNLC compared to the control group. Additionally, GF, SV, stearic acid (SA), and oleic acid (OA) modulate the activity of JNK3, HDAC6, and telomerase. This study suggests CGFSVNLC achieves codelivery, selective targeting, and enhancing the synergistic effect of GF and SV for inducing HepG2 cell death. Mechanistically, CGFSVNLC inhibits key cascades implicated in MDR and HepG2 cell survival. CGFSVNLC is promising for overcoming drug resistance mechanisms and improving therapeutic outcomes against HepG2 cells.

The aim of research is to enhance the solubility of crystalline gefitinib (GF), a poorly water-soluble drug, by developing drug delivery systems using chitosan oligosaccharide (COS) particle engineering. Fabrication utilizes ionic gelation followed by spray drying. The preliminary evaluations such as Uv-Vis, FTIR, DSC followed by advanced techniques like SEM and invitro drug release characteristics was performed along with solubility study. The spray-dried particles measured a mean diameter of 3.18 ± 0.5 microns, %EE as well as load w/w improved from 63.25 ± 2.1% and 37.98 ± 1.5% w/w (COS nanoparticles) to 78.15 ± 2.6% and 45.34 ± 1.6% w/w (engineered microparticles), respectively. The zeta potential and in vitro studies demonstrated 41 ± 3.5 mV and 92 ± 2.1% (w/w) release suggest long-term stability and prolonged release. This novel engineering approach effectively enhances GF solubility and surface characteristics, offering promising potential for improving delivery characteristics.

Aninnovative methodology is proposedfor quantifying Gefitinib(GFT) using an electrochemical sensor constructed from a composite of graphene quantum dots (GQDs) and gold nanoparticles (AuNPs). GQDs were synthesized from graphite, preserving graphene's large surface area and excellent electron transfer capabilities while enhancing dispersibility. The combination of GQDs with AuNPs resulted in an AuNPs@GQDs composite, which was used to construct the sensor. The synthesized nanomaterials were characterized using scanning electron microscopy (SEM) and transmission electron microscopy (TEM), and the electrochemical performance of the sensor was evaluated via cyclic voltammetry (CV) and differential pulse voltammetry (DPV). Under optimized conditions, the sensor displayed a linear calibration curve for GFT detection within the range 0.01 to 10.0 µM, with a limit of detection (LOD) of 0.005 µM (S/N = 3). The sensor demonstrated excellent anti-interference properties and stability in tests using pharmaceutical formulations and plasma samples. Compared to chromatographic methods, the sensor exhibited similaraccuracy and recovery. Its easy fabrication and high sensitivity make it a promising tool for pharmaceutical analysis and clinical therapeutic drug monitoring.

Regulating the physical and chemical properties of gefitinib and its positional isomer through salt formation

Comparison of efficacy of gefitinib and osimertinib for untreated EGFR mutation-positive non-small-cell lung cancer in patients with poor performance status

Non-small cell lung cancer (NSCLC) remains a significant challenge, as it is one of the leading causes of cancer-related deaths, and the development of resistance to anticancer therapy makes it difficult to treat. In this study, we investigated the anticancer mechanism of deoxybouvardin (DB), a cyclic hexapeptide, in gefitinib (GEF)-sensitive and -resistant NSCLC HCC827 cells. DB inhibited the viability and growth of HCC827 cells in a concentration- and time-dependent manner. In vitro kinase assay showed DB inhibited epidermal growth factor receptor (EGFR), mesenchymal–epithelial transition (MET), and AKT, and their phosphorylation was suppressed in HCC827 cells treated with DB. A molecular docking model suggested that DB interacts with these kinases in the ATP-binding pockets. DB induces ROS generation and cell cycle arrest. DB treatment of HCC827 cells leads to mitochondrial membrane depolarization. The induction of apoptosis through caspase activation was confirmed by Z-VAD-FMK treatment. Taken together, DB inhibited the growth of both GEF-sensitive and GEF-resistant NSCLC cells by targeting EGFR, MET, and AKT and inducing ROS generation and caspase activation. Further studies on DB can improve the treatment of chemotherapy-resistant NSCLC through the development of effective DB-based anticancer agents.

Human epidermal growth factor receptor-2 (HER2)-positive breast cancer metastasis remains the primary cause of mortality among women globally. Targeted therapies have revolutionized treatment efficacy, with Trastuzumab (Trast), a monoclonal antibody, targeting HER2-positive advanced breast cancer. The tumor-homing peptide iRGD enhances the intratumoral accumulation and penetration of therapeutic agents. Liposomes serve as versatile nanocarriers for both hydrophilic and hydrophobic drugs. Gefitinib (GFB) is a potential anticancer drug against HER2-positive breast cancer, while Lycorine hydrochloride (LCH) is a natural compound with anticancer and anti-inflammatory properties. This study developed TPGS-COOH-coated liposomes co-loaded with GFB and LCH, prepared by the solvent injection method, and surface-functionalized with Trast and iRGD. The dual surface-decorated liposomes (DSDLs) were characterized for their particle size (PS), polydispersity index (PDI), zeta potential (ZP), surface chemistry, surface morphology, and their crystallinity during in-vitro drug release, drug encapsulation, and in-vitro cell line studies on SK-BR-3 and MDA-MB-231 breast cancer cells. The half-maximum inhibitory concentration (IC-50) values of single decorated liposomes (SDLs), iRGD-LP, and Trast-LP, as well as DSDLs (iRGD-Trast-LP) on SK-BR-3 cells, were 6.10 ± 0.42, 4.98 ± 0.36, and 4.34 ± 0.32 μg/mL, respectively. Moreover, the IC-50 values of SDLs and DSDLs on MDA-MB-231 cells were 15.12 ± 0.68, 13.09 ± 0.59, and 11.08 ± 0.48 μg/mL, respectively. Cellular uptake studies using confocal laser scanning microscopy (CLSM) showed that iRGD and Trast functionalization significantly enhanced cellular uptake in both cell lines. The wound-healing assay demonstrated a significant reduction in SDL and DSDL-treated MDA-MB-231 cell migration compared to the control. Additionally, the blood compatibility study showed minimal hemolysis (less than 5% RBC lysis), indicating good biocompatibility and biosafety. Overall, these findings suggest that TPGS-COOH-coated, GFB and LCH co-loaded, dual-ligand (iRGD and Trast) functionalized, multifunctional liposomes could be a promising therapeutic strategy for treating HER2-positive metastatic breast cancer.