Search Results (242)

Glioblastoma (GBM) remains one of the most aggressive and treatment-resistant brain tumors, largely due to its profound intratumoral heterogeneity and immunosuppressive microenvironment. Various classifications of GBM subtypes were created based on transcriptional and methylation profiles. This effort, followed by the development of new technology such as single-nuclei sequencing (snRNAseq) and spatial transcriptomics, led to a better understanding of the glioma cells’ plasticity and their ability to transition between diverse cellular states. GBM cells can mimic neurodevelopmental programs to resemble oligodendrocyte or neural progenitor behavior and hitchhike the local neuronal network to support their growth. The tumor microenvironment, especially under hypoxic conditions, drives the tumor cell clonal selection, which then reshapes the immune cells’ functions. These adaptations contribute to immune evasion by progressively disabling T cell and myeloid cell functions, ultimately establishing a highly immunosuppressive tumor milieu. This complex and metabolically constrained environment poses a major barrier to effective antitumor immunity and limits the success of conventional therapies. Understanding the dynamic interactions between glioma cells and their microenvironment is essential for the development of more effective immunotherapies and rational combination strategies aimed at overcoming resistance and improving patient outcomes. Full article

In the preceding and early stages of cancer progression, local drug delivery to pre-cancerous and cancerous skin lesions may be applied as an alternative or supplementary therapy. At present, 5-Fluorouracil, imiquimod, and tirbanibulin creams and ointments have established their place in practice, while several other active pharmaceutical ingredients (APIs) (e.g., calcipotriol, tretinoin, diclofenac) have been repurposed, used off-label, or are currently being investigated in mono- or combined chemotherapies of skin cancers. Apart from them, dozens to hundreds of therapeutics of natural and synthetic origin are proven to possess anti-tumor activity against melanoma, squamous cell carcinoma (SCC), and other skin cancer types in in vitro studies. Their clinical introduction is most often limited by low skin permeability, challenged targeted drug delivery, insufficient chemical stability, non-selective cytotoxicity, or insufficient safety data. A variety of prodrug and nanotechnological approaches, including vesicular systems, micro- and nanoemulsions, solid lipid nanoparticles, nanostructured lipid carriers, polymeric nanoparticles, and others, offer versatile solutions for overcoming the biophysical barrier function of the skin and the undesirable physicochemical nature of some drug molecules. This review aims to present the most significant aspects and latest achievements on the subject. Full article

Background/Objectives: The heterogeneity of cancer disease and the frequent ineffectiveness and resistance observed with currently available treatments highlight the importance of developing new antitumor therapies. The properties of gold nanoparticles, such as their photon-energy heating, are attractive for oncology therapy; this can be effective and localized. The combination of chemotherapy and hyperthermia is promising. Our aim was to evaluate the combination therapy of photon hyperthermia with 5-fluorouracil (5-FU) both in vitro and in vivo. Methods: This study evaluated the antitumor efficacy of a combined chemo-photothermal therapy using 5-fluorouracil (5-FU) and branched gold nanoshells (BGNSs) in a colorectal cancer model. BGNSs were synthesized via a seed-mediated method and characterized by electron microscopy and UV–vis spectroscopy, revealing an average diameter of 126.3 nm and a plasmon resonance peak at 800 nm, suitable for near-infrared (NIR) photothermal applications. In vitro assays using SW620-GFP colon cancer cells demonstrated a ≥90% reduction in cell viability after 24 h of combined treatment with 5-FU and BGNS under NIR irradiation. In vivo, xenograft-bearing nude mice received weekly intratumoral administrations of the combined therapy for four weeks. The group treated with 5-FU + BGNS + NIR exhibited a final tumor volume of 0.4 mm³ on day 28, compared to 1010 mm³ in the control group, corresponding to a tumor growth inhibition (TGI) of 100.74% (p < 0.001), which indicates not only complete inhibition of tumor growth but also regression below the initial tumor volume. Thermographic imaging confirmed that localized hyperthermia reached 45 ± 0.5 °C at the tumor site. Results: These findings suggest that the combination of 5-FU and BGNS-mediated hyperthermia may offer a promising strategy for enhancing therapeutic outcomes in patients with colorectal cancer while potentially minimizing systemic toxicity. Conclusions: This study highlights the potential of integrating nanotechnology with conventional chemotherapy for more effective and targeted cancer treatment. Full article

Colorectal liver metastasis (CRLM) poses a significant challenge in oncology due to its high incidence and poor prognosis in unresectable cases. Current treatments, including surgical resection, systemic chemotherapy, and liver-directed therapies, often fail to effectively target hypoxic tumor regions, which are inherently more resistant to these interventions. This review examines the potential of a novel therapeutic strategy combining irreversible electroporation (IRE) ablation and Clostridium novyi-nontoxic (C. novyi-NT) bacterial therapy. IRE is a non-thermal tumor ablation technique that uses high-voltage electric pulses to create permanent nanopores in cell membranes, leading to cell death while preserving surrounding structures, and is often associated with temporary tumor hypoxia due to disrupted perfusion. C. novyi-NT is an attenuated, anaerobic bacterium engineered to selectively germinate and proliferate in hypoxic tumor regions, resulting in localized tumor cell lysis while sparing healthy, oxygenated tissue. The synergy between IRE-induced hypoxia and hypoxia-sensitive C. novyi-NT may enhance tumor destruction and stimulate systemic antitumor immunity. Furthermore, the integration of advanced imaging and artificial intelligence can support precise treatment planning and real-time monitoring. This integrated approach holds promise for improving outcomes in patients with CRLM, though further preclinical and clinical validation is needed. Full article

Background/Objectives: Glioblastoma (GBM) remains the most aggressive primary brain tumor, characterized by high malignancy, recurrence rate, and dismal prognosis, thereby demanding innovative therapeutic strategies. In this study, we report a novel in situ targeting inclusion complex hydrogel hybrid system (DOX/RGD-CD@Gel) that integrates doxorubicin (DOX) with RGD-conjugated cyclodextrin (RGD-CD) and a thermosensitive hydrogel for enhanced GBM therapy. Methods: The DOX/RGD-CD@Gel system was prepared by conjugating doxorubicin (DOX) with RGD-modified cyclodextrin (RGD-CD) and embedding it into a thermosensitive hydrogel. The drug delivery and antitumor efficacy of this system were evaluated in vitro and in vivo. Results: In vitro and in vivo evaluations demonstrated that DOX/RGD-CD@Gel significantly enhanced cytotoxicity compared to free DOX or DOX/CD formulations. The targeted delivery system effectively promoted apoptosis and inhibited cell proliferation and metastasis in GBM cells. Moreover, the hydrogel-based system exhibited prolonged drug retention in the brain, as evidenced by its temperature- and pH-responsive release characteristics. In a GBM mouse model, DOX/RGD-CD@Gel significantly suppressed tumor growth and improved survival rates. Conclusions: This study presents a paradigm of integrating a targeted inclusion complex with a thermosensitive hydrogel, offering a safe and efficacious strategy for localized GBM therapy with potential translational value. Full article

Salmonella therapies are a promising tool for the treatment of solid tumors. Salmonella can be engineered to increase their tumor infiltration, cell killing abilities, and immunostimulatory properties. However, bacterial therapies have often failed in clinical trials due to poor characterization. Mathematical models are useful for predicting the immune response to cancer treatments and characterizing the properties of bacterial invasion. Herein we develop an ordinary differential equation-based model that combines bacterial therapies with classical anti-tumor immunotherapies. Our modeling results suggest that increasing bacterial localization to the tumor is key for therapeutic efficacy; however, increased intracellular invasion and direct bacterial mediated cytotoxicity does not reduce tumor growth. Further, the model suggests that enhancing T cell-mediated cell death by both bacterial stimulation of pro-inflammatory cytokines and activation of T cells via antigen cascade is critical for therapeutic efficacy. A balance of intracellular and extracellular Salmonella leads to more effective therapeutic response, which suggests a strategy for strain design to be tested in vivo. Overall, this model provides a system to predict which engineered features of Salmonella therapies lead to effective treatment outcomes. Full article

Background: Glioblastoma (GBM) resists current therapies due to its rapid proliferation, diffuse invasion, and heterogeneous cell populations. We previously showed that a single cold atmospheric plasma discharge tube (DT) reduces GBM viability via broad-spectrum electromagnetic (EM) emissions. Here, we tested whether two DTs arranged in a helmet configuration could generate overlapping EM fields to amplify the anti-tumor effects without thermal injury. Methods: The physical outputs of the single- and dual-DT setups were characterized by infrared thermography, broadband EM field probes, and oscilloscope analysis. Human U87-MG cells were exposed under the single or dual configurations. The viability was quantified with WST-8 assays mapped across 96-well plates; the intracellular reactive oxygen species (ROS), membrane integrity, apoptosis, and mitochondrial potential were assessed by multiparametric flow cytometry. Our additivity models compared the predicted versus observed dual-DT cytotoxicity. Results: The dual-DT operation produced constructive EM interference, elevating electric and magnetic field amplitudes over a broader area than either tube alone, while temperatures remained <39 °C. The single-DT exposure lowered the cell viability by ~40%; the dual-DT treatment reduced the viability by ~60%, exceeding the additive predictions. The regions of greatest cytotoxicity co-localized with the zones of highest EM field overlap. The dual-DT exposure doubled the intracellular ROS compared with single-DT and Annexin V positivity, confirming oxidative stress-driven cell death. The out-of-phase operation of the discharge tubes enabled the localized control of the treatment regions, which can guide future treatment planning. Conclusions: Two synchronously operated plasma discharge tubes synergistically enhanced GBM cell killing through non-thermal mechanisms that coupled intensified overlapping EM fields with elevated oxidative stress. This positions modular multi-DT arrays as a potential non-invasive adjunct or alternative to existing electric-field-based therapies for glioblastoma. Full article

Background/Objectives: Anti-vascular therapy presents a potential strategy for activating anti-tumor immunity. Disrupted vascular debris provides effective antigens that activate dendritic cells, leading to subsequent immune responses. However, the resulting tumor hypoxia following vascular disruption may contribute to immune suppression, thereby hindering effective immune activation. Ultrasound-stimulated microbubble cavitation can locally disrupt tumor vessels through mechanical effects to achieve physical anti-vascular therapy. Therefore, this study designed oxygen-loaded nanobubbles (ONBs) to combine anti-vascular effects with local oxygen release under ultrasound stimulation. The feasibility of enhancing anti-tumor immune activation by alleviating tumor hypoxia was evaluated. Methods: A murine pancreatic subcutaneous solid tumor model was used to evaluate the efficacy of anti-vascular therapy-associated immunotherapy. Results: After ONB treatment, tumor perfusion was reduced to 52 ± 5%, which resulted in a subsequent 57 ± 11% necrosis and a 29 ± 4% reduction in hypoxia, demonstrating the anti-vascular effect and reoxygenation, respectively. However, subsequent immune responses exhibited no significant activation in intratumoral cytokine expression or splenic immune cell composition. Primary tumors exhibited a 15.7 ± 5.0% increase in necrosis following ONB treatment, but distant tumor growth was not significantly inhibited. Conclusions: These results highlighted a crucial issue regarding the complex correlations between vessel disruption, antigen production, oxygen delivery, hypoxia, and immunity when combining anti-vascular therapy with immunotherapy. Full article

Titanium (Ti)-based metallic biomaterials (MBs) are traditionally employed as mechanical supports and constraints in clinical practice, owing to their superb comprehensive mechanical properties, great corrosion resistance, and good biocompatibility. Recently, Ti-based MBs have emerged as promising candidates for antitumor applications. These developments focus on the functionalization of Ti-based MBs to inhibit tumor propagation and recurrence. This work systematically examines the antitumor approaches of Ti-based MBs and categorizes them into physical and chemical approaches. Physical strategies, such as the photothermal and photocatalytic techniques, are usually related to material-specific properties. Chemical approaches often employ controlled local drug delivery (LDD) systems. Ti-based LDD systems enable the targeted release of chemotherapeutics, metal ions, or immunomodulatory agents at tumor sites. This review highlights the efficacy of these surface-functionalized Ti-based MBs against diverse tumors. Additionally, the challenges and prospects of antitumor Ti-based MBs are also discussed. Full article

Breast cancer remains the most frequently diagnosed cancer and the second highest cause of cancer death in females. Metastatic recurrence that is resistant to traditional therapies presents a major challenge, necessitating the development of an innovative treatment strategy. Immunotherapy has gained popularity in the treatment of cancer, particularly melanoma, lung cancer, and more recently breast cancer. Major developments in immunotherapy have been made with a better understanding of the tumor microenvironment and how the microenvironment can be manipulated to induce an anti-tumor immune response. Intratumorally delivered immunotherapy can be used to create a local immune response. This review provides a comprehensive overview of intratumoral immunotherapy for breast cancer and its resultant changes in the tumor microenvironment. The discussed immunotherapeutics include oncolytic viruses, nucleic acids, innate immune agonists, bacteria, chimeric antigen receptor T cells, and dendritic cells. The review also evaluates completed clinical trials using these therapies. Lastly, the review offers future perspectives in the development of breast cancer immunotherapy. Full article

Proton beam therapy (PBT) is a rapidly advancing modality of hadron therapy. The primary advantage of proton therapy lies in a unique depth-dose distribution characterized by the Bragg peak, which enables a highly targeted irradiation of the area limited to the tumor, while minimizing the impact on healthy tissues. However, a broader clinical adoption of the ion beam therapy is limited by both economic and radiobiological constraints. One of the possible ways to increase the relative biological effectiveness (RBE) of proton therapy involves the use of radiosensitizers. Background/Objectives: In this work, we investigated the efficacy of using colloidal solutions of lanthanum hexaboride (LaB₆) nanoparticles (NPs) coated with polyacrylic acid (PAA) as sensitizers to increase the antitumor biological effectiveness of proton irradiation. This material has not yet been studied extensively so far, despite its promising physical and chemical properties and several reports on its biocompatibility. Methods: LaB₆ NPs were synthesized by femtosecond pulsed laser ablation, functionalized with PAA and characterized. The safety of NPs was evaluated in vitro using a Live/Dead assay on cell cultures: EMT6/P, BT-474, and in vivo in Balb/c mice after intravenous (i.v.) administration. The efficacy of binary proton therapy was evaluated in vitro on cell cultures: EMT6/P, BT-474, and in vivo in the model of human ductal carcinoma of the mammary gland BT-474 in female Nu/j mice after intratumoral (i.t.) administration at a dose of 2.0 mg/mouse and local proton irradiation (fractional exposure of 31 Gy + 15 Gy). The biodistribution of LaB₆-PAA NPs in the animal body was also evaluated. Results: Significant enhancement in cancer cell death following proton beam irradiation was demonstrated in vitro on EMT6/P, BT-474 cell lines. Although the antitumor efficacy observed in vivo was comparatively lower—likely due to the high sensitivity of the BT-474 xenografts—both proton monotherapy and binary treatment were well tolerated. Conclusions: LaB₆-PAA NPs show promise as efficient sensitizers capable of enhancing the biological efficacy of proton therapy, offering a potential path forward for improving therapeutic outcomes. Full article

Malignant skin conditions are classified as the most common forms of cancer, with an evolution of one million new cases reported every year. Research efforts in the medical field are focused on developing innovative strategies for the dissemination of measures for preventing cancer and providing new antitumor compounds. The present research examines the development and evaluation of 1% Carbopol-based hydrogels incorporating two porphyrin derivatives—5,10,15,20-tetrakis-(4-acetoxy-3-methoxyphenyl) porphyrin (P2.1) and 5-(4-hydroxy-3-methoxyphenyl)-10,15,20-tris-(4-acetoxy-3-methoxyphenyl) porphyrin (P2.2)—to create formulations suitable for topical photodynamic therapy (PDT) applications. The physicochemical properties of the obtained hydrogels were carefully evaluated, revealing the successful integration of the porphyrins into the 1% Carbopol hydrogel matrix. Rheological analysis demonstrated pseudoplastic behavior, with an increase in viscosity properties for P2.1 and P2.2, suggesting interactions with the Carbopol polymer structure. UV-visible and fluorescence spectroscopy confirmed the maintenance of the porphyrins’ photodynamic properties, essential for therapeutic efficacy. Pharmacotechnical studies highlighted the hydrogels’ suitability for topical applications. The formulations maintained an optimal pH range, ensuring skin compatibility and minimizing the potential for skin irritation. Their mechanical properties, including elasticity and rigidity, provided stability during handling and application. The high swelling capacity indicated effective moisture retention, enhancing skin hydration and drug release potential. Furthermore, the hydrogels demonstrated excellent spreadability, enabling uniform application and coverage, crucial for efficient light activation of the photosensitizers. The combination of robust physicochemical and pharmacotechnical properties highlights the potential of these porphyrin-loaded 1% Carbopol hydrogels as promising carriers for topical PDT. These results permit further biological and therapeutic investigations to optimize the formulation for clinical use, advancing the development of effective localized photodynamic therapies. Full article

Background/Objectives: Prostate cancer (PCa) cells may acquire radioresistance during radiation therapy (RT), resulting in PCa recurrence. This study was aimed at investigating the radiosensitizing effect of 5-aminolevulinic acid (5-ALA) on radioresistant PCa cells. Methods: Radioresistant PCa cells were developed through successive irradiation of two human PCa cell lines (PC-3 and DU 145) and a murine PCa cell line (Myc-CaP). The radiosensitivity of these PCa cells and the radiosensitizing effect of 5-ALA were evaluated using clonogenic assays. Mitochondrial accumulation of protoporphyrin IX (PpIX) and mitochondrial reactive oxygen species (ROS) were evaluated. A syngeneic mouse model with radioresistant PCa was established, and the immunohistochemistry of cell specimens from PCa patients with local recurrence after primary RT was examined. Results: Radioresistant PCa cells showed lower radiosensitivity compared to parental PCa cells. In radioresistant PCa cells with 5-ALA administration, compared to the group administered irradiation alone, the survival rate after irradiation was significantly reduced by promoting mitochondria-mediated apoptosis caused by increased PpIX accumulation and mitochondrial ROS generation. Similar results were observed in vivo. However, compared with parental PCa cells, radioresistant PCa cells were less affected by the radiosensitizing effect of 5-ALA, owing to decreased PpIX accumulation and mitochondrial ROS production caused by upregulated expression of the drug transporter ABCG2. ABCG2 expression was upregulated in human PCa specimens with post-RT recurrence. Conclusions: 5-ALA enhanced the antitumor effects of RT in radioresistant PCa cells; however, ABCG2 upregulation decreased PpIX accumulation, resulting in a reduced radiosensitizing effect of 5-ALA on radioresistant PCa cells compared with that on parental PCa cells. ABCG2 could be a potential therapeutic target for overcoming radioresistance. Full article

The survival of patients with locally advanced and metastatic bladder cancer (BCa) is persistently low. Hence, new treatment options are urgently needed. Artesunate (ART) a derivative of artemisinin, used in Traditional Chinese Medicine, shows anti-tumor activity extending over a broad spectrum of human cancers. As we have previously shown, ART inhibits growth in cisplatin-sensitive (parental) and cisplatin-resistant BCa cells. However, how ART acts on the metastatic potential of BCa remained unclear. To clarify, we applied ART to parental and cisplatin-resistant RT4, RT112, T24, and TCCSup BCa cell lines. We examined tumor cell adhesion to vascular endothelium and immobilized collagen and evaluated chemotactic activity, migration, and invasive activity of the BCa cells. Adhesion receptors, integrin α and β subtypes, integrin-linked kinase (ILK), and focal adhesion kinase (FAK) were investigated. The functional relevance of integrin expression altered by ART was determined by blocking studies. ART significantly reduced tumor cell adhesion to vascular endothelium and immobilized collagen in parental as well as in cisplatin-resistant BCa cells. Depending on cell type, ART suppressed tumor cell motility and diminished integrin expression (surface and total). Functional blocking of integrins altered by ART reduced cell adhesion and invasion of the BCa cells. Thus, the metastatic potential of parental and cisplatin-resistant BCa cells was significantly inhibited by ART, making it a promising treatment option for patients with advanced or therapy-resistant BCa. Full article

Background: Cisplatin, a widely used chemotherapeutic agent, is associated with significant ototoxicity, leading to progressive and irreversible sensorineural hearing loss in up to 93% of patients. Cisplatin generates reactive oxygen species (ROS) in the cochlea, activating apoptotic and necroptotic pathways that result in hair cell death. Inflammatory processes and nitrative stress also contribute to cochlear damage. Methods: This literature review was conducted to explore the mechanisms underlying cisplatin-induced ototoxicity and evaluate protective strategies, including both current and emerging approaches. A structured search was performed in multiple scientific databases, including PubMed and ScienceDirect, for articles published up to November 2024. Results: Current otoprotective strategies include systemic interventions such as antioxidants, anti-inflammatory agents, and apoptosis inhibitors, as well as localized delivery methods like intratympanic injection and nanoparticle-based systems. However, these approaches have limitations, including potential interference with cisplatin’s antitumor efficacy and systemic side effects. Emerging strategies focus on genetic and biomarker-based risk stratification, novel otoprotective agents targeting alternative pathways, and combination therapies. Repurposed drugs like pravastatin also show promise in reducing cisplatin-induced ototoxicity. Conclusions: Despite these advancements, significant research gaps remain in translating preclinical findings to clinical applications and developing selective otoprotective agents that do not compromise cisplatin’s efficacy. This review examines the mechanisms of cisplatin-induced ototoxicity, current otoprotective strategies, and emerging approaches to mitigate this adverse effect. Full article