Sorafenib Research Articles

Preparation of Glutathione-Regulated Sorafenib Targeted Nanodrug Delivery System and Its Antihepatocellular Carcinoma Activity.

To enhance the therapeutic effect of sorafenib (SOR) on liver cancer, we have developed a targeted nanodrug delivery system with glutathione (GSH) downregulation functionality. The preparation process comprises the synthesis of amino-functionalized mesoporous silica nanoparticles (MSN-NH2), surface modification with ethacrynic acid (EA), loading of SOR into the pores, and final surface coating with hyaluronic acid (HA) to obtain SOR@MSN-EA@HA (SMEH) nanoparticles. SMEH nanoparticles specifically enter tumor cells via CD44 receptor-mediated endocytosis. EA binds to GSH to consume it, while SOR is slowly released from the pores to exert antitumor effects while inhibiting GSH production. This results in sustained oxidative stress in the cells, thus enhancing the antitumor efficacy. Both in vitro and in vivo antitumor experiments as well as hemolysis tests have demonstrated that SMEH nanoparticles can accurately target liver cancer cells, effectively downregulate GSH concentration, exhibit good antitumor effects, and possess excellent safety, showing great potential in tumor treatment.

CTNI-45. PHASE 2 STUDY OF SORAFENIB, VALPROIC ACID, AND SILDENAFIL IN THE TREATMENT OF RECURRENT HIGH-GRADE GLIOMA

Abstract PURPOSE Here we report the results of a single-center phase 2 clinical trial combining sorafenib tosylate, valproic acid, and sildenafil for the treatment of patients with recurrent high-grade glioma. PATIENTS AND METHODS Eligible patients were 18 years of age and older with an Eastern Cooperative Oncology Group performance status of 0-2 and pathologically confirmed high-grade glioma (WHO grade 3 or 4), with documented CT or MRI progression or recurrence and measurable or evaluable disease. The treatment schedule was a combination of sorafenib, valproic acid, and sildenafil, each agent administered orally, twice daily continuously. A cycle consisted of 4 weeks. RESULTS Clinical toxicities were grade 1 and grade 2, with one grade 3 toxicity for maculopapular rash (6.4%). For all evaluable patients, the median progression-free survival was 3.65 months and overall survival (OS) 10.0 months. There was promising evidence showing clinical activity and benefit. In the 33 evaluable patients, low protein levels of the chaperone GRP78 (HSPA5) was significantly associated with a better OS (p < 0.0026). A correlation between the expression of PDGFRa and OS approached significance (p < 0.0728). Five patients presently have a mean OS of 73.6 months and remain alive. CONCLUSIONS This is the first therapeutic intervention glioblastoma trial to significantly associate GRP78 expression to OS. Our data suggest that the combination of sorafenib tosylate, valproic acid, and sildenafil requires additional clinical development in the recurrent glioma population.

A Novel ⋅OH-Monitor ER-Targeted Probe to Expose the Function of Sorafenib.

The hydroxyl radical (⋅OH), widely recognized as the most potent free radical, plays a crucial role in numerous physiological and pathological pathways due to its strong oxidizability.Ferroptosis, as a novel mode of cell death, is initiated by the accumulation of iron-dependent lipid peroxidation. Among them, ⋅OH as the original reactive oxygen species (ROSs)is mass-produced due to Fenton reaction in vivo and closely related to cancer treatment.Besides, endoplasmic reticulum (ER) as a membrane-rich structure organelle, is a crucial organelle in all eukaryotes where excessive expression of ROSs, including ⋅OH can triggerER stress which was reported thatwasclosely related toferroptosis. So developing a new probe for their interrelationship research is important. In this paper, we constructed a1,8-naphthalimide-based ER-targeted fluorescence probe named M-1 to monitor ⋅OH variation in vitro and vivo. What's more, we achieved the monitor of ⋅OH during ER stress andferroptosis processesin cancer cells, andfurther explored the important role of ER stress and ferroptosis processes in SF (sorafenib) involved cancer cells.

Engineering Strain-Defects to Enhance Enzymatic Therapy and Induce Ferroptosis.

The effect of mimetic enzyme catalysis is often limited by insufficient activity and a single therapy is not sufficient to meet the application requirements. In this study, a multifunctional nanozyme, MMSR-pS-PEG, is designed and fabricated by modifying poly (ethylene glycol) grafted phosphorylated serine (pS-PEG) on mesoporous hollow MnMoOx spheres, followed by loading sorafenib (SRF) into the pores. Strain engineering-induced oxygen defects endow the nanozyme with enhanced dual-enzymatic activity to mimic catalase and oxidase-like activities, which catalyze the conversion of endogenous H2O2 into oxygen and subsequently into superoxide ions in the acidic tumor microenvironment. Moreover, as an n-type semiconductor, MnMoOx generates reactive oxygen species by separating electrons and holes upon ultrasonic irradiation and simultaneously deplete glutathione by holes, thereby further augmenting its catalytic effect. As a ferroptosis inducer, SRF restrains the system xc - and indirectly inhibits glutathione synthesis, synergistically interacting with the nanozyme to stimulate ferroptosis by promoting lipid peroxidation and accumulation and the downregulation of glutathione peroxidase 4. These results provide valuable insights into the design of enzymatic therapy with high performance and highlight a promising approach for the synergism of ferroptosis and enzymatic tumor therapy.

Design, synthesis, and cytotoxicity screening of novel pyrazolopyrimidines over renal cell carcinoma (UO-31 cells) as p38α inhibitors, and apoptotic cells inducing activities

A series of novel molecules with pyrazolopyrimidine-4-amine core were designed and synthesized as potential cytotoxic agents over Renal Cell Carcinoma cells (UO-31). Results of cytotoxic activity against UO-31 cells showed that pyrazolopyrimidines 19 and 31 were found to be more cytotoxic than sorafenib (SOR). The cytotoxic activity of these compounds appeared to correlate with their ability to inhibit p38α MAPK which are 2.53- and 2.27- folds more potent than SOR. Moreover, results of the cell cycle analysis as well as the results of annexin-V on the (UO-31) cells showed that pyrazolopyrimidines 19 and 31 had a pro-apoptotic activity higher than SOR by 1.42- and 1.20- folds, respectively. Furthermore, compounds 19 and 31 were found to be effective in arresting the cell cycle throughout the accumulation of the cells at G2/M phase. Finally, the tested compounds decreased the TNF concentration as well as increased the expression of tumor suppressor gene p53, Bax/BCL-2 ratio and caspase 3/7.

Successful Management of Incompletely Resected Transitional Cell Carcinoma with Sorafenib Tosylate in a Dog.

Most urinary bladder (UB) tumors are malignant, and transitional cell carcinoma (TCC) is the most common neoplasm affecting the UB in dogs. Sorafenib may be a potential therapeutic agent for canine TCC. A 12 yr old spayed female Maltese dog weighing 3.6 kg and with a history of hematuria was referred for a suspected UB tumor. Abdominal ultrasonography revealed a UB mass attached to the cranioventral wall. The remaining abdominal examinations, including that of the lymph nodes, were unremarkable. Ultrasound-guided traumatic catheterization of the UB mass was performed, and the cytological evaluation of the UB mass indicated TCC. Excision was performed by partial cystectomy, and histopathology confirmed TCC, although the tumor had infiltrated the surgical margins. A chemosensitivity assay was conducted using tissue from the excised tumor. Sorafenib tosylate, a tyrosine kinase inhibitor, showed the greatest effect in the chemosensitivity assay. Therefore, adjuvant chemotherapy with sorafenib tosylate and piroxicam was administered postoperatively. The dog lived without any clinical signs, including hematuria or tumor relapse, for more than 2 yr after the surgery. This is the first report of successful long-term management of TCC with sorafenib tosylate in a dog.

Synergistic anticancer efficacy of polydatin and sorafenib against the MCF-7 breast cancer cell line via inhibiting of PI3K/AKT/mTOR pathway and reducing resistance to treatment

Polydatin (PD), a glucoside derivative of resveratrol, has been investigated for its potential to mitigate sorafenib (SOF) side effects and combat multidrug resistance in cancer treatment. The study evaluated its mechanism of action for inhibiting the protein kinase B/mTOR pathway in promoting breast cancer proliferation. The combined PD and SOF have synergistic effects with a combination index (CI) < 1 in the liver (HepG2) and breast (MCF-7) cancer cell lines. Molecular docking studies were conducted to analyze interactions of PD& SOF with protein kinases as well as apoptotic and multidrug resistance proteins, including AKT1, PI3K, mTOR, Apaf-1, and ABCB1 in MCF-7 cells. Experimental validation through real-time PCR confirmed. PD has a strong binding affinity, particularly with AKT1 (-56 kcal/mol) and ABCB1 (-27.16 kcal/mol), a gene associated with multidrug resistance. These interactions were linked to anti-proliferative anti-angiogenic effects and reduced resistance to treatment, demonstrating PD has potential therapeutic benefits. Furthermore, PD combined with SOF induced apoptosis, inhibited cell growth, and arrested MCF-7 cells in the sub-G1 phase with increased intracellular ROS. This was accompanied by reduced expression of AKT1 and ABCB1 genes, reinforcing the anticancer efficacy of PD/SOF combination therapy. In conclusion, the findings suggest that PD/SOF could serve as a promising anticancer treatment strategy, warranting further investigation for potential clinical applications and mechanistic studies in vivo.

A tumor Microenvironment-triggered protein-binding Near-infrared-II Theranostic nanoplatform for Mild-Temperature photothermal therapy

Photothermal therapy (PTT) has gained significant attention as a non-invasive treatment in clinical oncology. However, the translation of PTT into clinical practice remains constrained by three fundamental limitations: acquired thermal tolerance in tumor cells, restricted light penetration depth in biological matrices, and insufficient therapeutic outcomes from single-modality treatment. To address these issues, a strategy for forming in situ complexes between near-infrared-II (NIR-II) photothermal agents and proteins is developed, aimed at damaging protein conformation and enhancing PTT effectiveness. We developed a nanoplatform called PCy-SF, consisting of the NIR-II photothermal polymer (PCy) and sorafenib (SF). PCy-SF responds to the tumor microenvironment (TME), specifically releasing Cy-CHO and sorafenib from the assemblies. The released Cy-CHO covalently binds to proteins, forming Cy-Protein complexes that activate NIR-II fluorescence, facilitating NIR-II imaging-guided photothermal therapy. Concurrently, the released SF intensifies microvascular damage, synergizing with PTT for enhanced therapeutic efficacy. Notably, PCy-SF induces a strong anticancer immune response, effectively suppressing tumor recurrence and metastasis. This study introduces a promising protein deactivation strategy for achieving mild-temperature PTT, offering broader applicability of PTT and insights for sensitizing tumors to photothermal therapy. Together, this innovative approach combining NIR-II photothermal agents with protein complexation and a responsive nanoplatform enhances PTT precision and efficacy, demonstrating significant potential in the field of cancer nanomedicine.

The mode of action of sorafenib in MDA-MB-231 breast carcinoma cells involves components of apoptotic, necroptotic and autophagy-dependent cell death pathways

We report the identification of an interesting mode of action by sorafenib (SF) (Nexavar) in triple-negative breast adenocarcinoma MDA-MB-231 cells. The dying cells presented features of apoptosis, such as externalization of phosphatidylserine and cleaved caspase-3, and autophagy-mediated cell death, such as formation of autophagosomes and autolysosomes, the overexpression of LC3-II, and the presence of LAMP1-positive vacuoles, while displaying insufficient autophagic flux. Components of endoplasmic reticulum stress (ER stress; PERK and CHOP) and of necroptosis (p-MLKL) were also elevated considerably. Investigating potential target proteins that could modulate this form of cell death, we next investigated the role of tubulin disruption, which is known to induce necroptosis, apoptosis, and autophagy-dependent cell death. Interactions of SF with purified tubulin were investigated in detail using a combination of cellular and biophysical assays, transmission electron microscopy, and computer simulations. A marked reduction in the intrinsic tryptophan fluorescence of tubulin, a concentration-dependent elevation of anilinonaphthalene sulfonate–tubulin complex fluorescence, electron micrographs of deformed in vitro–assembled microtubules, and disrupted and hyper-stabilized cellular microtubules evinced the ability of SF to target tubulin and disrupt cellular microtubules. Molecular docking and molecular dynamic simulations positioned the drug between the α and β subunits of tubulin with considerable stability (ΔGbind, −31.43 kcal/mol), suggesting that drug-induced perturbation of tubulin could contribute to this mode of cell death.

Carvacrol potentiates immunity and sorafenib anti-cancer efficacy by targeting HIF-1α/STAT3/ FGL1 pathway: in silico and in vivo study.

Hypoxia and tumor cell immunological escape greatly hinder the hepatocellular carcinoma (HCC) treatment efficiency. This study is designed to investigate the capability of carvacrol (CVR) to enhance sorafenib (SOR) anti-cancer efficacy and modulate anti-HCC immunity. CVR target and biological activities were predicted using Swiss Target Prediction website and PASS web server. UALCAN and LinkedOmics databases were used to examine hypoxia-inducible factor 1-alpha (HIF-1α) expression and the relationship between studied genes and tumor clinical features. Kaplan-Meier plotter (KM plotter) and TISIDB databases were used to illustrate correlation of HIF-1α with HCC prognosis and immune infiltration. The binding affinities of CVR to p300, KAT2B, CREBBP, and Hsp90 were demonstrated by molecular docking. In vivo analysis was performed in male Sprague-Dawley rats. The STAT3, JAK2, and fibrinogen-like protein 1 (FGL1) expressions were assessed by qRT-PCR. FGL1 was determined by ELISA. CD8+ T cell number was counted by flow cytometry. HIF-1α was determined by immunohistochemistry. CVR showed an HIF-1α inhibitory potential, which is highly expressed in HCC tissues. Also, elevated HIF-1α expression has been found to be correlated with clinicopathological characteristics, poor survival in HCC patients, and tumor immune cell infiltration. CVR/SOR enhanced liver functions and decreased AFP level. CVR/SOR hindered HCC progression by downregulating STAT3, JAK2, and FGL1. CVR/SOR induced tumor immunity via increasing CD8+ T cells. CVR/SOR is a powerful combination for tumor repression and enhancing SOR efficiency in HCC by modulating FGL1. Moreover, CVR/SOR might exert the aforementioned effects through HIF-1α/STAT3/FGL1 pathway.

Multifunctional nanoplatform with near-infrared triggered nitric-oxide release for enhanced tumor ferroptosis

Ferroptosis has emerged as a promising strategy for cancer treatment. Nevertheless, the efficiency of ferroptosis-mediated therapy remains a challenge due to high glutathione (GSH) levels and insufficient endogenous hydrogen peroxide in the tumor microenvironment. Herein, we presented a nitric-oxide (NO) boost-GSH depletion strategy for enhanced ferroptosis therapy through a multifunctional nanoplatform with near-infrared (NIR) triggered NO release. The nanoplatform, IS@ATF, was designed that self-assembled by loading the NO donor L-arginine (L-Arg), ferroptosis inducer sorafenib (SRF), and indocyanine green (ICG) onto tannic acid (TA)-Fe3+‒metal-phenolic networks (MPNs) modified with hydroxyethyl starch. Inside the tumor, SRF could inhibit GSH biosynthesis, impair the activation of glutathione peroxidase 4, and disrupt the ferroptosis defensive system. In conjunction with TA-Fe3+‒MPNs, which has cascaded Fenton catalytic activity, it could navigate the lethal ferroptosis to cancer cells. Upon NIR laser irradiation, the ICG-generated ROS oxidated L-Arg to a substantial quantity of NO, which further depleted the intracellular GSH and caused LPO accumulation, enhancing cell ferroptosis. Moreover, ICG also serves as a photothermal agent that can produce hyperthermia when exposed to irradiation, further potentiating ferroptosis therapy. In addition, the nanoplatform showed significantly improved tumor therapeutic efficacy and anti-metastasis efficiency. This work thus demonstrated that utilizing NO boost-GSH depletion to enhance ferroptosis induction is a feasible and promising strategy for cancer treatment.Graphical abstract

Human epidermal growth factor receptor 2(Her2)-targeted pH-responsive MR/NIRF bimodal imaging-mediated nano-delivery system for the diagnosis and treatment of undifferentiated thyroid cancer.

Undifferentiated thyroid cancer (ATC) is highly malignant and does not respond well to sorafenib (SRF) treatment owing to the lack of specificity of SRF targeting. Drug delivery nanosystems can improve the efficiencies of drug in treating various cancer types. However, many conventional drug delivery nanosystems lack targeting and exhibit unresponsive drug release. Therefore, we developed a pH-responsive nano-targeted drug delivery systems using human serum albumin (HSA) as a carrier to generate manganese dioxide (MnO2)@HSA nanoparticles (NPs), then encapsulated SRF and the fluorescent dye indocyanine green (ICG) and finally modifyed the targeting antibody pertuzumab in the outer layer of the nano complexes, resulting in SRF/ICG/MnO2@HSA-pertuzumab (HISMP) NPs. This system targets human epidermal growth factor receptor 2 on the cell membrane surface of thyroid cancer cells and is designed to accumulate at tumor sites. Then, pH-responsive release of divalent manganese ions, ICG, and SRF enables magnetic resonance/fluorescence (MR/NIRF) dual-modality imaging and precise drug delivery for diagnostic and therapeutic integration. Various characterization analyses including transmission electron microscopy, Fourier infrared spectroscopy, and particle size analysis confirm that we successfully synthesized HISMP NPs with a diameter of 150.709nm. The results of CCK8 cytotoxicity and apoptosis assays show that HISMP NPs exhibited high cytotoxicity and induce apoptosis in thyroid cancer cells. In vivo MR/NIRF imaging experiments confirmed that the HISMP NPs specifically aggregated at tumor sites and have good in vivo MR/NIRF imaging ability and effective anti-tumor activity. The nano-delivery system is expected to provide a theoretical foundation for the efficient ATC diagnosis and therapy.

Intracellular Magnetic Hyperthermia Sensitizes Sorafenib to Orthotopic Hepatocellular Carcinoma Via Amplified Ferroptosis.

Sorafenib (SRF) is recognized as the primary treatment for hepatocellular carcinoma (HCC), yet the emergence of SRF resistance in many HCC patients results in unfavorable outcomes. Enhancing the efficacy of SRF in HCC remains a significant challenge. SRF works in inducing ferroptosis, a form of cell death, in cancer cells through the inhibition of glutathione peroxidase 4 (GPX4). The effectiveness of this process is limited by the low levels of cellular iron and reactive oxygen species (ROS). A promising approach to circumvent this limitation is the use of intracellular magnetic hyperthermia (MH) mediated by magnetic iron oxide nanomaterials (MIONs). When MIONs are subjected to an alternating magnetic field (AMF), they heat up, enhancing the Fenton reaction, which in turn significantly increases the production of ROS within cells. In this study, we explore the capability of MH facilitated by high-performance ferrimagnetic vortex-domain iron oxide nanoring (FVIO) to enhance the effectiveness of SRF treatment in HCC. The increased iron uptake facilitated by FVIO significantly enhances the sensitivity of HCC cells to SRF-induced ferroptosis. Moreover, the nanoheat generated by FVIO in response to an AMF further elevates ROS levels and stimulates lipid hydroperoxide (LPO) production and GPX4 inactivation, thereby intensifying ferroptosis. Both in vitro and in vivo animal studies demonstrate that combining FVIO-mediated MH with SRF significantly reduces cell viability and inhibits tumor growth, primarily through enhanced ferroptosis, with minimal side effects. The effectiveness of this combination therapy is affected by the ferroptosis inhibitor ferrostatin-1 (Fer-1) and the iron chelator deferoxamine (DFO). The combination treatment of FVIO-mediated MH and SRF offers a strategy for HCC treatment by promoting accelerated ferroptosis, presenting a different perspective for the development of ferroptosis-based anticancer therapies.

Study on Several Novel Crystalline Complexes of Sorafenib with Dicarboxylic Acid: Nature Identification and Solubilization Mechanism

The development of solid-state forms of drugs is an effective approach to increase solubility. This study developed three crystalline complexes of sorafenib (SF) with oxalic acid (OA) and malonic acid (MA) using a solvent method, named SF+·OA-·THF, SF+·OA-, and SF-MA. The formation of these complexes was influenced by the crystalline method, solvent polarity, and the carbon chain length of the dicarboxylic acids. Single-crystal X-ray diffraction revealed proton transfer in SF+·OA-·THF, classifying it as a channel-type salt solvate and conformational polymorph due to hydrogen bond formation. 13C solid-state nuclear magnetic resonance and X-ray photoelectron spectroscopy confirmed proton transfer in SF+·OA-·THF and SF+·OA-, but not in SF-MA, indicating that SF+·OA- is a salt while SF-MA is a co-crystal. Fourier Transform Infrared Spectroscopy further supported these findings. Compared with Form Ⅰ, SF+·OA-, SF+·OA-·THF, and SF-MA increased the apparent solubility of SF by 8.3, 7.9, and 6.4 times in pH 1.2 HCl buffer, and by 4.0, 3.1, and 4.5 times in pH 6.8 PBS buffer, respectively. All crystalline complexes exhibited a “spring and parachute” phenomenon due to the solubility difference between the drug and the dicarboxylic acids. Notably, the intermolecular forces between SF and THF in SF+·OA-·THF prolonged the “spring and parachute” process. Additionally, these crystalline complexes demonstrated good stability. This study provides valuable insights into the development and identification of crystalline complexes and their dissolution mechanisms.

Bismuth-based mesoporous nanoball carrying sorafenib for synergistic photothermal and molecularly-targeted therapy in an orthotopic hepatocellular carcinoma xenograft mouse model

Sorafenib (SOR), a multi-kinase inhibitor for advanced hepatocellular carcinoma (HCC), has limited clinical application due to severe side effects and drug resistance. To overcome these challenges, we developed a bismuth-based nanomaterial (BOS) for thermal injury-assisted continuous targeted therapy in HCC. Initially, the mesoporous nanomaterial was loaded with SOR, forming the BOS@SOR nano-carrier system for drug delivery and controlled release. Notably, compared to targeted or photothermal therapy alone, the combination therapy using this nano-carrier system significantly impaired cell proliferation and increased apoptosis. In vivo efficacy evaluations demonstrated that BOS@SOR exhibited excellent biocompatibility, confirmed through hemolysis and biochemical analyses. Additionally, BOS@SOR enhanced contrast in computed tomography, aiding in the precise identification of HCC size and location. The photothermal therapeutic properties of bismuth further contributed to the synergistic anti-tumor activity of BOS@SOR, significantly reducing tumor growth in an orthotopic xenograft HCC model. Taken together, encapsulating SOR within a bismuth-based mesoporous nanomaterial creates a multifunctional and environmentally stable nanocomposite (BOS@SOR), enhancing the therapeutic effect of SOR and presenting an effective strategy for HCC treatment.

Application of Box-Behnken Design for Formulation Optimization of Sorafenib loaded Nanoparticles Targeting to Liver Carcinoma: Ex-vivo Intestinal Permeation and Cytotoxicity Study.

The anticancer drug sorafenib (SFB) was formulated as a polymeric nanoparticle using Box-Behnken design. The solvent evaporation method was utilized to develop the sorafenib polymeric nanoparticles. Formulations were then evaluated in terms of their morphological structure, entrapment efficiency (EE%), zeta potential, polydispersity index (PDI), and particle size. Ex-vivo intestinal permeation studies for pure drugs, as well as optimized formulation, were performed in rats. Furthermore, the anticancer activity was evaluated using the HepG2 cancer cell lines. Transmission electron microscopy (TEM) revealed that the improved formulation had a particle size of 175 nm, PDI of 0.134, zeta-potential of -23.8 mV, and the sorafenib-loaded PLGA NP were recognized as spherical particles. Over 90% of the drug was released in less than 24 hours, with an EE% of 85.1%. Sorafenib-loaded PLGA NP efficiently inhibited HepG2 cells.

Preparation and Characterization of Solid Dispersion of Sorafenib Tosylate for Enhancement of Bioavailability.

Solid dispersions have garnered significant attention as an effective strategy for enhancing the solubility and, consequently, the bioavailability of poorly water-soluble drugs. By forming solid dispersions of these drugs with water-soluble carriers, issues related to limited solubility have been mitigated, leading to improved dissolution rates. The core focus of solid dispersion technology revolves around the creation of two-component systems involving the drug and a polymer, where the successful dispersion and stabilization of the drug play pivotal roles in the formulation development process. As a result, this technology is widely acknowledged as a highly valuable approach for enhancing the dissolution properties of poorly water-soluble drugs. In recent years, a substantial body of knowledge has been amassed concerning solid dispersions. Nonetheless, their practical implementation in the commercial sphere remains somewhat limited. In the current investigation, we embarked on the preparation of a solid dispersion of sorafenib tosylate, with the primary objective of achieving the maximum release of the drug within the shortest possible timeframe. Our aim was to develop and optimize the solid dispersions of sorafenib tosylate in a manner that ensures the successful design and formulation of this system.

Targeted regulation of autophagy using sorafenib-loaded biomineralization nanoenzyme for enhanced photodynamic therapy of hepatoma

Sorafenib (SF), a multi-targeted tyrosine kinase inhibitor, serves as a primary therapeutic modality for advanced liver cancer. Nonetheless, its clinical efficacy is hindered by various obstacles, such as limited bioavailability and inadequate accumulation. This study introduces a novel biomimetic mineralization enzyme, known as BSA@Pt/Ce6/SF@M (PCFM). The PCFM incorporates platinum (Pt) as a catalytic agent, SF as a molecular-targeted therapeutic agent, and Ce6 as a photosensitizer within liver cancer cell membranes. This strategy enables the combination of various anti-tumor treatments, such as photodynamic therapy (PDT) and autophagy induction, leading to increased bioavailability of SF and achieving a multidimensional synergistic anticancer effect. The PDT effect produced by Ce6 in PCFM greatly enhances SF-induced autophagy, effectively promoting autophagic cell death. Furthermore, Pt dissociates from the biomineralization process, acquiring peroxidase properties through chemokinetic reactions. This facilitates the catalysis of significant oxygen generation, addressing the challenge of hypoxia in the tumor microenvironment and improving the efficacy of PDT. Moreover, the SF further enhances therapeutic efficacy by inducing autophagy in response to energy deprivation, as indicated by the reduced levels of HIF-1α, p62, along with increased levels of ROS and LC3-Ⅱ/Ι. This biomineralization-based nanoenzyme exhibits strong anti-tumor characteristics, offering a novel strategy for overcoming challenges in liver cancer treatment.

Improved Topical Delivery of Sorafenib-Meglumine Antimoniate: Elastic Nano-Liposomal Formulation for the Treatment of Cutaneous Leishmaniasis

Background: Cutaneous leishmaniasis (CL) is a widespread parasitic disease with significant health and social impacts. Current systemic treatments have severe side effects, highlighting the need for effective topical alternatives.Objective: This study aimed to develop and evaluate the effectiveness of sorafenib (SF) and meglumine antimoniate (MM) dual-loaded transferosomes (TRs) for topical treatment of CL.Methods: TRs were prepared using a thin film hydration method and incorporated into a carbopol gel. The formulations were characterized for vesicle size, zeta potential, entrapment efficiency, and deformability index. In vivo and ex vivo skin permeation studies were conducted, along with anti-leishmanial efficacy testing on an intramacrophage amastigote model using BALB/c mice.Results: The TRs exhibited a vesicle size of 186.1 ± 65.89 nm, zeta potential of -27.9 mV, and entrapment efficiency of 71.7 ± 3.9% for MM and 78.6 ± 4.2% for SF. Ex vivo studies showed enhanced skin permeation with cumulative permeation of 327.6 ± 29.4 µg/cm² for MM and 291.6 ± 28.3 µg/cm² for SF. In vivo results indicated a significant reduction in lesion size (0.1 ± 0.12 mm) and parasite load (2.7 ± 0.3 log scale).Conclusion: The MM-SF dual-loaded TRs demonstrated effective topical delivery and therapeutic potential for CL, providing a promising alternative to systemic treatments.

Iron-based magnetic nanocomplexes for combined chemodynamic and photothermal cancer therapy through enhanced ferroptosis

Chemodynamic therapy (CDT) guided by Fenton chemistry and iron-containing materials can induce ferroptosis as a prospective cancer treatment method, but the inefficient Fe3+/Fe2+ conversion restricts the monotherapeutic performances. Here, an iron-based nanoplatform (Fe3O4-SRF@FeTA) including a magnetic core and a reductive film is developed for combined CDT and photothermal therapy (PTT) through ferroptosis augmentation. The inner iron oxide core serves as a photothermal transducer, a magnet-responsive module, and an iron reservoir for CDT. The coated Fe3+-tannic acid film (FeTA) provides extra iron and reductants for Fe3+/Fe2+ conversion acceleration, and functions as a door keeper for the pH- and light-responsive release of the embedded ferroptosis inducer sorafenib (SRF). The in vitro results demonstrate that the iron-based nanocomplexes promote the production of lipid peroxide through the amplified Fenton activity, and downregulate glutathione involved in lipid peroxide repair system through the responsively released SRF. Upon accumulation in tumor by magnetic targeting and sequential laser irradiation locoregionally, Fe3O4-SRF@FeTA nanocomplexes present prominent in vivo anticancer efficacy by leveraging PTT and CDT-enhanced ferroptosis.