A carrier free delivery system of a MAGL inhibitor is effective on ovarian cancer.

Monoacylglycerol lipase (MAGL) is a promising target for cancer therapy due to its involvement in lipid metabolism and its impact on cancer hallmarks like cell proliferation, migration, and tumor progression. A potent reversible MAGL inhibitor, MAGL23, has been recently developed by our group, demonstrating promising anticancer activities. To enhance its pharmacological properties, a nanoformulation using nanocrystals coated with albumin was prepared (MAGL23AF). In a previous work, the formulated inhibitor showed to maintain its potency in ovarian and colon cancer cell lines in terms of IC50, and the formulation was tested on mice in order to assess its biocompatibility, organs biodistribution and toxicity. In the present work, we expanded the investigation to assess the potential in vivo application of MAGL23AF. Stability assays in serum and in human derived microsomes showed a good structural stability in physiological conditions of MAGL23AF. Antitumor efficacy tested on mice bearing ovarian cancer tumor highlighted that MAGL23AF has a more potent antitumor efficacy compared to non-formulated drug and leads to a necrosis-driven cancer cell death. In vivo studies revealed that albumin-complexed nanocrystals improved the therapeutic window of MAGL23, exhibiting a favorable biodistribution with slightly increased accumulation in the tumor. In conclusion, the MAGL23AF showed increased in vitro stability in conditions mirroring the bloodstream environment and hepatic metabolism coupled with an optimal antitumor efficacy in vivo. These results not only validates the efficacy of our formulation but also positions it as a promising strategy for addressing challenges related to the solubility of drugs in body fluids.

An Engineered M13 Filamentous Nanoparticle as an Antigen Carrier for a Malignant Melanoma Immunotherapeutic Strategy.

Bacteriophages, prokaryotic viruses, hold great potential in genetic engineering to open up new avenues for vaccine development. Our study aimed to establish engineered M13 bacteriophages expressing MAGE-A1 tumor peptides as a vaccine for melanoma treatment. Through in vivo experiments, we sought to assess their ability to induce robust immune responses. Using phage display technology, we engineered two M13 bacteriophages expressing MAGE-A1 peptides as fusion proteins with either pVIII or pIIII coat proteins. Mice were intraperitoneally vaccinated three times, two weeks apart, using two different engineered bacteriophages; control groups received a wild-type bacteriophage. Serum samples taken seven days after each vaccination were analyzed by ELISA assay, while splenocytes harvested seven days following the second boost were evaluated by ex vivo cytotoxicity assay. Fusion proteins were confirmed by Western blot and nano-LC-MS/MS. The application of bacteriophages was safe, with no adverse effects on mice. Engineered bacteriophages effectively triggered immune responses, leading to increased levels of anti-MAGE-A1 antibodies in proportion to the administered bacteriophage dosage. Anti-MAGE-A1 antibodies also exhibited a binding capability to B16F10 tumor cells in vitro, as opposed to control samples. Splenocytes demonstrated enhanced CTL cytotoxicity against B16F10 cells. We have demonstrated the immunogenic capabilities of engineered M13 bacteriophages, emphasizing their potential for melanoma immunotherapy.

Copper nitroprusside: An innovative approach for targeted cancer therapy via ROS modulation.

The clinical application of nanomaterials for chemodynamic therapy (CDT), which generate multiple reactive oxygen species (ROS), presents significant challenges. These challenges arise due to insufficient levels of endogenous hydrogen peroxide and catalytic ions necessary to initiate Fenton reactions. As a result, sophisticated additional delivery systems are required. In this study, a novel bimetallic copper (II) pentacyanonitrosylferrate (Cu(II)NP, Cu[Fe(CN) 5 NO]) material was developed to address these limitations. This material functions as a multiple ROS generator at tumoral sites by self-inducing hydrogen peroxide and producing peroxynitrite (ONOO-) species. The research findings demonstrate that this material exhibits low toxicity towards normal liver organoids, yet shows potent antitumoral effects on High Grade Serous Ovarian Cancer (HGSOC) organoid patients, regardless of platinum resistance. Significantly, this research introduces a promising therapeutic opportunity by proposing a single system capable of replacing the need for H2O2, additional catalysts, and NO-based delivery systems. This innovative system exhibits remarkable multiple therapeutic mechanisms, paving the way for potential advancements in clinical treatments.

Targeting Non-Coding RNAs for the Development of Novel Hepatocellular Carcinoma Therapeutic Approaches.

Hepatocellular carcinoma (HCC) remains a global health challenge, representing the third leading cause of cancer deaths worldwide. Although therapeutic advances have been made in the few last years, the prognosis remains poor. Thus, there is a dire need to develop novel therapeutic strategies. In this regard, two approaches can be considered: (1) the identification of tumor-targeted delivery systems and (2) the targeting of molecule(s) whose aberrant expression is confined to tumor cells. In this work, we focused on the second approach. Among the different kinds of possible target molecules, we discuss the potential therapeutic value of targeting non-coding RNAs (ncRNAs), which include micro interfering RNAs (miRNAs), long non-coding RNAs (lncRNAs) and circular RNAs (circRNAs). These molecules represent the most significant RNA transcripts in cells and can regulate many HCC features, including proliferation, apoptosis, invasion and metastasis. In the first part of the review, the main characteristics of HCC and ncRNAs are described. The involvement of ncRNAs in HCC is then presented over five sections: (a) miRNAs, (b) lncRNAs, (c) circRNAs, (d) ncRNAs and drug resistance and (e) ncRNAs and liver fibrosis. Overall, this work provides the reader with the most recent state-of-the-art approaches in this field, highlighting key trends and opportunities for more advanced and efficacious HCC treatments.

Estimating quantitative physiological and morphological tissue parameters of murine tumor models using hyperspectral imaging and optical profilometry.

Understanding tumors and their microenvironment are essential for successful and accurate disease diagnosis. Tissue physiology and morphology are altered in tumors compared to healthy tissues, and there is a need to monitor tumors and their surrounding tissues, including blood vessels, non-invasively. This preliminary study utilizes a multimodal optical imaging system combining hyperspectral imaging (HSI) and three-dimensional (3D) optical profilometry (OP) to capture hyperspectral images and surface shapes of subcutaneously grown murine tumor models. Hyperspectral images are corrected with 3D OP data and analyzed using the inverse-adding doubling (IAD) method to extract tissue properties such as melanin volume fraction and oxygenation. Blood vessels are segmented using the B-COSFIRE algorithm from oxygenation maps. From 3D OP data, tumor volumes are calculated and compared to manual measurements using a vernier caliper. Results show that tumors can be distinguished from healthy tissue based on most extracted tissue parameters ( p < 0.05 ). Furthermore, blood oxygenation is 50% higher within the blood vessels than in the surrounding tissue, and tumor volumes calculated using 3D OP agree within 26% with manual measurements using a vernier caliper. Results suggest that combining HSI and OP could provide relevant quantitative information about tumors and improve the disease diagnosis.

Comparison of general anesthesia and continuous intravenous sedation for electrochemotherapy of head and neck skin lesions.

Background: Electrochemotherapy of cutaneous tumor nodules requires local or general anesthesia. For multiple and larger nodules, general anesthesia is recommended by standard operating procedures. The choice of general anesthesia is at the discretion of the treating center. Continuous intravenous sedation is also an option. Our study aimed to elucidate the tolerability, safety and possible advantages of continuous intravenous sedation in comparison to general anesthesia in patients undergoing electrochemotherapy. Patients and methods: In the prospective study, 27 patients undergoing electrochemotherapy were either under general anesthesia or under continuous intravenous sedation. Evaluated were different endpoints, such as feasibility and safety, duration of anesthesia and compliance with the patients. Results: Ten patients were treated under general anesthesia, and 17 patients were under continuous intravenous sedation. The comparison of the approaches indicated that continuous intravenous sedation required a lower overall dosage of propofol, a shorter duration of anesthesia, a shorter time to reach an Aldrete score >8, and greater satisfaction of the patients with the procedure compared to general anesthesia. Conclusion: The results indicate the feasibility and safety of continuous intravenous sedation for patients undergoing electrochemotherapy of cutaneous tumor nodules. This proved the preferred choice of anesthesia due to its shorter duration and better compliance with the patients compared to general anesthesia.

Tumor perfusion evaluation using dynamic contrast-enhanced ultrasound after electrochemotherapy and IL-12 plasmid electrotransfer in murine melanoma.

Electrochemotherapy with bleomycin (ECT BLM) is an effective antitumor treatment already used in clinical oncology. However, ECT alone is still considered a local antitumor therapy because it cannot induce systemic immunity. When combined with adjuvant gene electrotransfer of plasmid DNA encoding IL-12 (GET pIL-12), the combined therapy leads to a systemic effect on untreated tumors and distant metastases. Although the antitumor efficacy of both therapies alone or in combination has been demonstrated at both preclinical and clinical levels, data on the predictors of efficacy of the treatments are still lacking. Herein, we evaluated the results of dynamic contrast-enhanced ultrasound (DCE-US) as a predictive factor for ECT BLM and GET pIL-12 in murine melanoma. Melanoma B16F10 tumors grown in female C57Bl/6NCrl mice were treated with GET pIL-12 and ECT BLM. Immediately after therapy, 6 h and 1, 3, 7 and 10 days later, tumors were examined by DCE-US. Statistical analysis was performed to inspect the correlation between tumor doubling time (DT) and DCE-US measurements using semilinear regression models and Bland-Altman plots. Therapeutic groups in which DCE-US showed reduced tumor perfusion had longer tumor DTs. It was confirmed that the DCE-US parameter peak enhancement (PE), reflecting relative blood volume, had predictive value for the outcome of therapy: larger PE correlated with shorter DT. In addition, perfusion heterogeneity was also associated with outcome: tumors that had more heterogeneous perfusion had faster growth, i.e., shorter DTs. This study demonstrates that DCE-US can be used as a method to predict the efficacy of electroporation-based treatment.

Literature Review and Our Experience With Bleomycin-Based Electrochemotherapy for Cutaneous Vulvar Metastases From Endometrial Cancer.

Endometrial carcinoma is the most common gynecological malignancy and the fifth most common malignancy in women. The worldwide incidence is 15.9 new cases per 100,000 women per year, and the incidence in Europe is 22.7 new cases. Minority of cases are diagnosed at an advanced stage of the disease. Cutaneous metastases are very rare with a prevalence of 0.8%. If cutaneous metastases are present, the prognosis is poor with an overall survival of up to 12 months. In this review, we presented clinical data on treatment of gynecological cancers with electrochemotherapy, with focus on treatment of cutaneous vulvar metastases from endometrial cancer. Further, we present our data on the case of a 64-year-old woman with recurrent endometrial adenocarcinoma with vulvar skin metastases. Treatment of endometrial carcinoma metastases is multimodal with surgery, chemotherapy, radiotherapy and hormone treatment. There is still no consensus about the specific treatment of cutaneous metastases from endometrial cancer, in particular in order to release symptoms. Electrochemotherapy may be a treatment option to reduce pain and bleeding and a safe option to treat multiple skin metastases.

Molecular heterogeneity in breast carcinoma cells with increased invasive capacities.

Background Metastatic progression of breast cancer is still a challenge in clinical oncology. Therefore, an elucidation how carcinoma cells belonging to different breast cancer subtypes realize their metastatic capacities is needed. The aim of this study was to elucidate a similarity of activated molecular pathways underlying an enhancement of invasiveness of carcinoma cells belonging to different breast carcinoma subtypes. Materials and methods In order to reach this aim, parental and invasive (INV) MDA-MB-231 (triple-negative), T47D (hormone receptor-positive), and Au565 (Her2-positive) breast carcinoma cells were used and their molecular phenotypes were compared using a proteomic approach. Results Independently from breast cancer subtypes, INV cells have demonstrated fibroblast-like morphology accompanied by enhancement of invasive and migratory capacities, increased expression of cancer stem cell markers, and delayed tumor growth in in vivo animal models. However, the global proteomic analysis has highlighted that INV cells were different in protein expressions from the parental cells, and Her2-positive Au565-INV cells showed the most pronounced molecular differences compared to the triple-negative MDA-MB-231-INV and hormone receptor-positive T47D-INV cells. Although Au565-INV breast carcinoma cells possessed the highest number of deregulated proteins, they had the lowest overlapping in proteins commonly expressed in MDA-MB-231-INV and T47D-INV cells. Conclusions We can conclude that hormone receptor-positive cells with increased invasiveness acquire the molecular characteristics of triple-negative breast cancer cells, whereas Her2-positive INV cells specifically changed their own molecular phenotype with very limited partaking in the involved pathways found in the MDA-MB-231-INV and T47D-INV cells. Since hormone receptor-positive invasive cells share their molecular properties with triple-negative breast cancer cells, we assume that these types of metastatic disease can be treated rather equally with an option to add anti-hormonal agents. In contrast, Her2-positive metastasis should be carefully evaluated for more effective therapeutic approaches which are distinct from the triple-negative and hormone-positive metastatic breast cancers.