Enhance Cancer Treatment Research Articles

Formulation and Characterization Studies of Paclitaxel Incorporated Kollidon® SR and Chitosan Nanoparticles: An In vitro Evaluation for Potential Use for Colorectal Cancer Treatment

Background: Chemotherapy is regarded as first-line therapy in various cancer types besides surgical procedures. However, lack of cell selectivity and poor drug targeting to the cancer zone of the active agents results in accumulation in normal tissues with considerably high severe side effects. Therefore, novel drug delivery systems are required to enhance cancer treatment. Objective: In this study, Paclitaxel (PTX) incorporated Kollidon® SR (KSR) and Chitosan (CS) based polymeric nanoparticles were prepared for potential use for colorectal cancer treatment. Methods: Polymeric nanoparticles were prepared by spray dying method. Physicochemical characterization studies were performed with particle size (PS), polydispersity index (PDI), zeta potential (ZP), drug loading (DL %), encapsulation efficiency (EE %) and structural evaluations using differential scanning calorimetry (DSC), X-ray diffractometry (XRD), Fourier transform infrared spectroscopy (FT-IR) and proton nuclear magnetic resonance (1H-NMR) analyses. Cytotoxicity of the nanoparticles was screened on HT-29 (human colorectal adenocarcinoma) and HTC-15 (Dukes' type C, colorectal adenocarcinoma) cell lines with MTT assay. Results: Analysis revealed the successful incorporation of PTX into the polymeric lattices. Particles showed cytotoxic activity on HT-29 and HTC-15 cell lines, depending on the application dose after 48 hours. Nanoparticles also remained stable at 5°C ± 3°C and 25°C ± 2°C (60% ± 5 Relative Humidity (RH)) during the storage period of 6 months. Conclusion: As a result of the study, KSR and CS-based nanoparticles could be regarded as promising nano-carriers for improved therapeutic efficacy of PTX for colorectal cancer treatment.

Engineered CAR-T cells: An immunotherapeutic approach for cancer treatment and beyond.

Chimeric Antigen Receptor (CAR) T cell therapy is a type of adoptive immunotherapy that offers a promising avenue for enhancing cancer treatment since traditional cancer treatments like chemotherapy, surgery, and radiation therapy have proven insufficient in completely eradicating tumors, despite the relatively positive outcomes. It has been observed that CAR-T cell therapy has shown promising results in treating the majority of hematological malignancies but also have a wide scope for other cancer types. CAR is an extra receptor on the T-cell that helps to increase and accelerate tumor destruction by efficiently activating the immune system. It is made up of three domains, the ectodomain, transmembrane, and the endodomain. The ectodomain is essential for antigen recognition and binding, whereas the co-stimulatory signal is transduced by the endodomain. To date, the Food and Drug Administration (FDA) has granted approval for six CAR-T cell therapies. However, despite its remarkable success, CAR-T therapy is associated with numerous adverse events and has certain limitations. This chapter focuses on the structure and function of the CAR domain, various generations of CAR, and the process of CAR-T cell development, adverse effects, and challenges in CAR-T therapy. CAR-T cell therapy also has scopes in other disease conditions which include systemic lupus erythematosus, multiple sclerosis, and myocardial fibrosis, etc.

Nanotherapeutic approaches for delivery of long non-coding RNAs: an updated review with emphasis on cancer.

The long noncoding RNAs (lncRNAs) comprise a wide range of RNA species whose length exceeds 200 nucleotides, which regulate the expression of genes and cellular functions in a wide range of organisms. Several diseases, including malignancy, have been associated with lncRNA dysregulation. Due to their functions in cancer development and progression, lncRNAs have emerged as promising biomarkers and therapeutic targets in cancer diagnosis and treatment. Several studies have investigated the anti-cancer properties of lncRNAs; however, only a few lncRNAs have been found to exhibit tumor suppressor properties. Furthermore, their length and poor stability make them difficult to synthesize. Thus, to overcome the instability of lncRNAs, poor specificity, and their off-target effects, researchers have constructed nanocarriers that encapsulate lncRNAs. Recently, translational medicine research has focused on delivering lncRNAs into tumor cells, including cancer cells, through nano-drug delivery systems in vivo. The developed nanocarriers can protect, target, and release lncRNAs under controlled conditions without appreciable adverse effects. To deliver lncRNAs to cancer cells, various nanocarriers, such as exosomes, microbubbles, polymer nanoparticles, 1,2-dioleyl-3-trimethylammoniumpropane chloride nanocarriers, and virus-like particles, have been successfully developed. Despite this, every nanocarrier has its own advantages and disadvantages when it comes to delivering nucleic acids effectively and safely. This article examines the current status of nanocarriers for lncRNA delivery in cancer therapy, focusing on their potential to enhance cancer treatment.

Synthesis of three cisplatin-conjugated asymmetric porphyrin photosensitizers for photodynamic therapy.

Photodynamic therapy provides a promising solution for treating various cancer types. In this study, three distinct asymmetric porphyrin-cisplatin complex photosensitizers (ZnPt-P1, ZnPt-P2, and ZnPt-P3) were synthesized, each having unique side chains. Through a set of experiments involving singlet oxygen detection and density functional theory, ZnPt-P1 was demonstrated to have excellent efficacy, exceeding that of ZnPt-P2 and ZnPt-P3. Notably, ZnPt-1 showed significant phototoxicity while maintaining low dark toxicity when tested on HepG2 cells. Additionally, further examination revealed that ZnPt-P1 had the capability to generate reactive oxygen species within cancer cells when exposed to light irradiation. Taken together, these results highlight the potential of ZnPt-P1 as a photosensitizer for use in photodynamic therapy. This study contributes to enhancing cancer treatment methodologies and provides insights for the future development of innovative drugs for photosensitization.

Bioinspired ginsenoside Rg3 PLGA nanoparticles coated with tumor-derived microvesicles to improve chemotherapy efficacy and alleviate toxicity.

Breast cancer, a pervasive malignancy affecting women, demands a diverse treatment approach including chemotherapy, radiotherapy, and surgical interventions. However, the effectiveness of doxorubicin (DOX), a cornerstone in breast cancer therapy, is limited when used as a monotherapy, and concerns about cardiotoxicity persist. Ginsenoside Rg3, a classic compound of traditional Chinese medicine found in Panax ginseng C. A. Mey., possesses diverse pharmacological properties, including cardiovascular protection, immune modulation, and anticancer effects. Ginsenoside Rg3 is considered a promising candidate for enhancing cancer treatment when combined with chemotherapy agents. Nevertheless, the intrinsic challenges of Rg3, such as its poor water solubility and low oral bioavailability, necessitate innovative solutions. Herein, we developed Rg3-PLGA@TMVs by encapsulating Rg3 within PLGA nanoparticles (Rg3-PLGA) and coating them with membranes derived from tumor cell-derived microvesicles (TMVs). Rg3-PLGA@TMVs displayed an array of favorable advantages, including controlled release, prolonged storage stability, high drug loading efficiency and a remarkable ability to activate dendritic cells in vitro. This activation is evident through the augmentation of CD86+CD80+ dendritic cells, along with a reduction in phagocytic activity and acid phosphatase levels. When combined with DOX, the synergistic effect of Rg3-PLGA@TMVs significantly inhibits 4T1 tumor growth and fosters the development of antitumor immunity in tumor-bearing mice. Most notably, this delivery system effectively mitigates the toxic side effects of DOX, particularly those affecting the heart. Overall, Rg3-PLGA@TMVs provide a novel strategy to enhance the efficacy of DOX while simultaneously mitigating its associated toxicities and demonstrate promising potential for the combined chemo-immunotherapy of breast cancer.

Enhancing Cancer Therapy: Boron-Rich Polyboronate Ester Micelles for Synergistic Boron Neutron Capture Therapy and PD-1/PD-L1 Checkpoint Blockade.

Malignant cancers, known for their pronounced heterogeneity, pose substantial challenges to monotherapeutic strategies and contribute to the risk of metastasis. Addressing this, our study explores the synergistic potential of combining boron neutron capture therapy (BNCT) with immune checkpoint blockade to enhance cancer treatment efficacy. We synthesized boron-rich block copolymer micelles as a novel boron drug for BNCT. Characterization was conducted using nuclear magnetic resonance, gel-permeation chromatography, transmission electron microscopy, and dynamic light scattering. These micelles, with an optimal size of 91.3 nm and a polydispersity index of 0.18, are suitable for drug delivery applications. Invitro assessments on B16-F10 melanoma cells showed a 13-fold increase in boron uptake with the micelles compared to borophenyl alanine (BPA), the conventional boron drug for BNCT. This resulted in a substantial increase in BNCT efficacy, reducing cell viability to 77% post-irradiation in micelle-treated cells, in contrast to 90% in BPA-treated cells. Invivo, melanoma-bearing mice treated with these micelles exhibited an 8-fold increase in boron accumulation in tumor tissues versus those treated with BPA, leading to prolonged tumor growth delay (5.4 days with micelles versus 3.3 days with BPA). Moreover, combining BNCT with anti-PD-L1 immunotherapy further extended the tumor growth delay to 6.6 days, and enhanced T-cell infiltration and activation at tumor sites, thereby indicating a boosted immune response. This combination demonstrates a promising approach by enhancing cytotoxic T-cell priming and mitigating the immunosuppressive effects of melanoma tumors.

Unveiling the Anticancer Potential of Pasak Bumi (Eurycoma Longifolia Jack) Root Extract in Prostate Cancer Treatment.

Prostate cancer remains a significant global health concern, necessitating the exploration of novel therapeutic avenues to enhance treatment efficacy and mitigate adverse effects. Objective This study delves into the potential anticancer properties of Pasak Bumi (Eurycoma longifolia Jack) root extract, a traditional Southeast Asian medicinal plant, against prostate cancer. The research employs a multifaceted approach, encompassing molecular and cellular analyses to unravel the intricate mechanisms underlying Pasak Bumi's effects on prostate cancer cells. Primary focus is given to the PTEN/P13k/Akt pathway, a critical regulator of cell survival and apoptosis. Various concentrations of Pasak Bumi root extract are applied to prostate cancer cell lines, and the impact on apoptosis, cell proliferation, and key molecular targets is assessed. Preliminary findings reveal that Pasak Bumi root extract induces apoptosis in prostate cancer cells, evidenced by downstream molecular events associated with programmed cell death. The extract demonstrates concentration-dependent effects, with higher concentrations exhibiting more pronounced anticancer activity. Moreover, Pasak Bumi root extract appears to modulate the PTEN/P13k/Akt pathway, providing a potential mechanistic link to its anticancer effects. Discussion: The study's significance lies in its contribution to the evolving landscape of natural compounds as anticancer agents, particularly in the context of prostate cancer. Pasak Bumi's traditional use as a medicinal plant, coupled with emerging scientific evidence, underscores its potential translational value. The observed modulation of the PTEN/P13k/Akt pathway aligns with the current understanding of prostate cancer pathogenesis, offering a plausible explanation for Pasak Bumi's anticancer effects. This research sheds light on the promising anticancer potential of Pasak Bumi root extract against prostate cancer. Further exploration of its molecular interactions, synergy with conventional therapies, and efficacy at different stages of cancer progression is warranted. The findings present Pasak Bumi as a nature-inspired candidate for prostate cancer treatment, warranting continued investigation into its therapeutic applications. As the scientific community endeavors to enhance cancer treatment modalities, Pasak Bumi emerges as a captivating subject in the pursuit of effective and minimally invasive prostate cancer therapies.

Network-based prediction of anti-cancer drug combinations.

Drug combinations have emerged as a promising therapeutic approach in cancer treatment, aimed at overcoming drug resistance and improving the efficacy of monotherapy regimens. However, identifying effective drug combinations has traditionally been time-consuming and often dependent on chance discoveries. Therefore, there is an urgent need to explore alternative strategies to support experimental research. In this study, we propose network-based prediction models to identify potential drug combinations for 11 types of cancer. Our approach involves extracting 55,299 associations from literature and constructing human protein interactomes for each cancer type. To predict drug combinations, we measure the proximity of drug-drug relationships within the network and employ a correlation clustering framework to detect functional communities. Finally, we identify 61,754 drug combinations. Furthermore, we analyze the network configurations specific to different cancer types and identify 30 key genes and 21 pathways. The performance of these models is subsequently assessed through in vitro assays, which exhibit a significant level of agreement. These findings represent a valuable contribution to the development of network-based drug combination design strategies, presenting potential solutions to overcome drug resistance and enhance cancer treatment outcomes.

Comprehensive Evaluation of Traditional Herbal Medicine Combined With Adjuvant Chemotherapy on Post-Surgical Gastric Cancer: A Systematic Review and Meta-Analysis.

Gastric cancer is a common cause of global mortality, with significant challenges during treatment due to side effects and complications. Traditional herbal medicine (THM) has emerged as a potential adjuvant therapy to enhance cancer treatment by reducing side effects and bolstering the immune response. This study conducted a meta-analysis to assess the efficacy and safety of THM as an adjuvant therapy in post-surgical gastric cancer patients. PubMed, Cochrane Library, EMBASE, CNKI, CiNii, KMBASE, KISS, OASIS, RISS, and ScienceON databases were searched from inception through December, 2021. The outcomes considered in this analysis encompassed tumor response, quality of life (QoL), side effects, and tumor markers. Additionally, a frequency analysis of the most commonly used herbs in the included studies was conducted. A total of 36 randomized controlled trials (RCTs) were included, and data were extracted according to study design. The analysis compared groups receiving chemotherapy alone with those receiving both chemotherapy and THM treatment. The group receiving both chemotherapy and THM showed substantial improvement in tumor response compared to the chemotherapy-only control group (RR 1.25, 95% CI [1.09, 1.45]). QoL also significantly increased in the THM-treated group. Most drug adverse reactions displayed statistical significance, except for platelet reduction. Tumor markers CEA, CA19-9, and CA72-4 exhibited significant improvements, but CA125 did not. The 1, 2, and 3-year survival rates improved, with RR values of 1.08 (95% CI [1.02, 1.14]), 1.32 (95% CI [1.19, 1.47]), and 1.42 (95% CI [1.12, 1.79]) respectively. However, some publication bias was indicated. THM may offer potential benefits as a complementary approach to post-surgical anticancer therapy in gastric cancer patients. Improved tumor response, quality of life, and survival rates were reported. However, it is important to exercise caution due to the possibility of publication bias, and further research is needed to confirm these findings.Registration:PROSPERO CRD 42022354133.

Deep Learning for the Accurate Prediction of Triggered Drug Delivery.

The need to mitigate the adverse effects of chemotherapy has driven the exploration of innovative drug delivery approaches. One emerging trend in cancer treatment is the utilization of Drug Delivery Systems (DDSs), facilitated by nanotechnology. Nanoparticles, ranging from 1 nm to 1000 nm, act as carriers for chemotherapeutic agents, enabling precise drug delivery. The triggered release of these agents is vital for advancing this novel drug delivery system. Our research investigated this multifaceted delivery capability using liposomes and metal organic frameworks as nanocarriers and utilizing all three targeting techniques: passive, active, and triggered. Liposomes are modified using targeting ligands to render them more targeted toward certain cancers. Moieties are conjugated to the surfaces of these nanocarriers to allow for their binding to receptors overexpressed on cancer cells, thus increasing the accumulation of the agent at the tumor site. A novel class of nanocarriers, namely metal organic frameworks, has emerged, showing promise in cancer treatment. Triggering techniques (both intrinsic and extrinsic) can be used to release therapeutic agents from nanoparticles, thus enhancing the efficacy of drug delivery. In this study, we develop a predictive model combining experimental measurements with deep learning techniques. The model accurately predicts drug release from liposomes and MOFs under various conditions, including low- and high-frequency ultrasound (extrinsic triggering), microwave exposure (extrinsic triggering), ultraviolet light exposure (extrinsic triggering), and different pH levels (intrinsic triggering). The deep learning-based predictions significantly outperform linear predictions, proving the utility of advanced computational methods in drug delivery. Our findings demonstrate the potential of these nanocarriers and highlight the efficacy of deep learning models in predicting drug release behavior, paving the way for enhanced cancer treatment strategies.

A novel computational tool for tracking cancer energy hijacking from immune cells.

Recent studies revealed a new biological process that malignant cancer cells hijack mitochondria from nearby T cells, providing another potential mechanism for immune evasion. We further confirmed this process at the single-cell genomic level through MERCI, a novel algorithm for tracking mitochondrial (MT) transfer. Applied to human cancer samples, MERCI identified a new cancer phenotype linked to MT hijacking, correlating with rapid tumour proliferation and poor patient survival. This discovery offers insights into the limitations of current cancer immunotherapies and suggests new therapeutic avenues targeting MT transfer to enhance cancer treatment efficacy.

Association of Clostridium butyricum Therapy Using the Live Bacterial Product CBM588 with the Survival of Patients with Lung Cancer Receiving Chemoimmunotherapy Combinations.

The gut microbiota has emerged as a key regulator of immune checkpoint inhibitor (ICI) efficacy. Therapeutic approaches aimed at manipulating the microbiota through targeted reconstitution to enhance cancer treatment outcomes have garnered considerable attention. A single live microbial biotherapeutic bacterium, Clostridium butyricum MIYAIRI 588 strain (CBM588), has been shown to enhance the effects of ICI monotherapy in patients with advanced lung cancer. However, whether CBM588 affects the outcomes of chemoimmunotherapy combinations in lung cancer remains unknown. We hypothesized that CBM588 augments the effect of chemoimmunotherapy combinations and restores diminished effectiveness in patients with non-small cell lung cancer (NSCLC) receiving dysbiosis-inducing drugs. To validate this hypothesis, we retrospectively analyzed 106 patients with stage IV or recurrent metastatic NSCLC consecutively treated with chemoimmunotherapy combinations. A survival analysis was performed employing univariate and multivariate Cox proportional hazard models with inverse probability of treatment weighting (IPTW) using propensity scores. Forty-five percent of patients received Clostridium butyricum therapy. CBM588 significantly extended overall survival in patients with NSCLC receiving chemoimmunotherapy. The favorable impact of CBM588 on the efficacy of chemoimmunotherapy combinations varied based on tumor-programmed cell death ligand 1 (PD-L1) expression. The survival benefit of CBM588 in the PD-L1 <1% cohort was higher than that in the PD-L1 1-49% and PD-L1 ≥ 50% cohorts. Furthermore, CBM588 was associated with improved overall survival in patients receiving proton pump inhibitors and/or antibiotics. CBM588-induced manipulation of the commensal microbiota holds the potential to enhance the efficacy of chemoimmunotherapy combinations, warranting further exploration of the synergy between CBM588 and immunotherapy.

Exploring the cooperation between rehabilitation medicine and CAR-T cell therapy for enhanced cancer treatment

The most common cause of death worldwide is cancer, and the sophisticated and aggressive medications used to treat it can have serious side effects and limitations. Immunotherapy known as chimeric antigen receptor T-cell (CAR-T) therapy has become a viable treatment option for some cancers, notably hematologic malignancies. However, it is linked to a number of adverse effects that may have a detrimental influence on patients' quality of life and access to care. Because it focuses on recovering patients' functional abilities and enhancing their quality of life rehabilitation medicine is essential to the treatment of cancer. This literature review aims to explore the cooperation between them to achieve better cancer treatment outcomes. This literature review will analyze and evaluate the literature on side effects of CAR-T Cell Therapy, the role of rehabilitation medicine in cancer treatment, and the rationale behind combining these two approaches for improved cancer treatment.

Novel Sulforaphane Analog Disrupts Phosphatidylinositol-3-Kinase-Protein Kinase B Pathway and Inhibits Cancer Cell Progression via Reactive Oxygen Species-Mediated Caspase-Independent Apoptosis.

Sulforaphane, a naturally occurring isothiocyanate, has gained attention due to its tremendous anticancer potential. Thus, an array of sulforaphane analogs were synthesized and evaluated for their cytotoxic potentials on a wide range of malignant cell lines. Among these derivatives, compound 4a displayed exceptional potency in inhibiting the proliferation of cancer cell lines and a negligible effect on normal cell lines through G2/M phase arrest. The lead compound induced reactive oxygen species (ROS)-mediated mitochondrial dysfunction, leading to apoptosis. Further mechanistic studies established the interaction of the compound 4a with the insulin-like growth factor-1 receptor (IGF-R1) and blocking of the phosphatidylinositol-3-kinase (PI3K)-protein kinase B (PKB/Akt) pathway. This led to suppression of nuclear factor erythroid 2-related factor 2 (NRF-2) protein expression, thus increasing the free radicals in the tumor cells. Moreover, compound 4a induced ROS-mediated caspase-independent apoptosis. Finally, compound 4a reduced tumor progression in a 4T1 injected BALB/c syngeneic mice tumor model. In conclusion, this study summarizes the mechanism of compound 4a-mediated ROS-mediated caspase-independent apoptosis. According to the study's findings, compound 4a can be used as a powerful new anticancer agent to enhance cancer treatment.

Cancer stem cells: Signaling pathways and therapeutic targeting

AbstractCancer stem cells (CSCs) constitute a minority cell population characterized by unbounded proliferative potential in both solid and hematological cancers. Despite sharing key stem cell attributes, CSCs possess unique traits, including the initiation and propagation of tumors and resistance to conventional therapies. The purpose of this review is to delve into the origins and fundamental characteristics of CSCs, emphasizing their role in tumor growth and metastasis. The focus extends to unraveling cellular signaling pathways driving oncogenic processes and understanding aberrant cellular crosstalk crucial for targeted cancer therapies. Beginning with an exploration of CSC properties and behavior, we progress to dissecting the cellular signaling network that fuels oncogenic pathways. The discussion spans the inception of CSCs, their survival strategies, and adaptation to new environments. We then transit to recent therapeutic advancements targeting CSCs, culminating in an exploration for precise therapeutic targeting. This review henceforth, underscores the vital significance of comprehending CSCs in cancer progression and treatment resistance. By unraveling the complex signaling pathways and survival mechanisms unique to CSCs, it paves the way for targeted therapeutic strategies that hold immense promise in enhancing cancer treatment efficacy while minimizing collateral damage.

A Synergetic Approach Utilizing Nanotechnology, Chemotherapy, and Radiotherapy for Pancreatic Cancer Treatment

&lt;img src=” https://s3.amazonaws.com/production.scholastica/article/90447/large/prnano_1112023ga.jpg?1700670543”&gt; The objective of this study was to assess the anticancer effectiveness of gold nanoparticles (GNPs) and lipid-encapsulated docetaxel prodrug (LNPDTX-P) with radiotherapy (RT). The study utilized a co-culture spheroid model comprising MIA PaCa-2 cancer cells and patient-derived cancer-associated fibroblasts (CAF-98) to mimic pancreatic cancer conditions. The spheroids underwent treatment with GNPs (7.5 μg/mL), LNPDTX-P (99 nM of DTX pro-drug), and 2 Gy of RT. Cell viability of the spheroids was evaluated using the CellTiter-Glo 3D assay. At the same time, DNA double-strand breaks (DSBs) were assessed by examining the expression of the DNA damage marker 53BP1 through an immunofluorescence assay. Alt-hough GNPs/RT and RT/LNPDTX-P showed a reduction in spheroid size and an apparent in-crease in DNA DSB damage, the combination of the two nanoparticles, GNPs, and LNPDTX-P, with RT, significantly enhanced the anticancer efficacy, resulting in a 28% decrease in spheroid size and an estimated 39% increase in DNA DSB. The combination of GNPs and LNPDTX-P with RT showed a synergetic effect due to their radiosensitizing properties, improving the ther-apeutic efficacy of each treatment modality alone. This triple modality offers a hopeful strategy to enhance cancer treatment efficacy while reducing adverse effects.

Application of Engineered Dendritic Cell Vaccines in Cancer Immunotherapy: Challenges and Opportunities.

The primary objective of this study is to evaluate the effectiveness of cancer vaccines containing genetically modified dendritic cells (DCs) in inducing transformational immune responses. This paper sheds considerable light on DCs' function in advancing treatment techniques. This objective is achieved by thoroughly analyzing the many facets of DCs and their strategic integration into cancer treatment. Due to their role as immune response regulators, DCs can potentially enhance cancer treatment strategies. DCs have the potential to revolutionize immunotherapy, as shown by a comprehensive analysis of their numerous characteristics. The review deftly transitions from examining the fundamentals of preclinical research to delving into the complexities of clinical implementation while acknowledging the inherent challenges in translating DC vaccine concepts into tangible progress. The analysis also emphasizes the potential synergistic outcomes that can be achieved by combining DC vaccines with established pharmaceuticals, thereby emphasizing the importance of employing a holistic approach to enhance treatment efficacy. Despite the existence of transformative opportunities, advancement is hindered by several obstacles. The exhaustive analysis of technical complexities, regulatory dynamics, and upcoming challenges provides valuable insights for overcoming obstacles requiring strategic navigation to incorporate DC vaccines successfully. This document provides a comprehensive analysis of the developments in DC-based immunotherapy, concentrating on its potential to transform cancer therapy radically.

Hedgehog signaling and the glioma-associated oncogene in cancer radioresistance.

Tumor radioresistance remains a key clinical challenge. The Hedgehog (HH) signaling pathway and glioma-associated oncogene (GLI) are aberrantly activated in several cancers and are thought to contribute to cancer radioresistance by influencing DNA repair, reactive oxygen species production, apoptosis, autophagy, cancer stem cells, the cell cycle, and the tumor microenvironment. GLI is reported to activate the main DNA repair pathways, to interact with cell cycle regulators like Cyclin D and Cyclin E, to inhibit apoptosis via the activation of B-cell lymphoma-2, Forkhead Box M1, and the MYC proto-oncogene, to upregulate cell stemness related genes (Nanog, POU class 5 homeobox 1, SRY-box transcription factor 2, and the BMI1 proto-oncogene), and to promote cancer stem cell transformation. The inactivation of Patched, the receptor of HH, prevents caspase-mediated apoptosis. This causes some cancer cells to survive while others become cancer stem cells, resulting in cancer recurrence. Combination treatment using HH inhibitors (including GLI inhibitors) and conventional therapies may enhance treatment efficacy. However, the clinical use of HH signaling inhibitors is associated with toxic side effects and drug resistance. Nevertheless, selective HH agonists, which may relieve the adverse effects of inhibitors, have been developed in mouse models. Combination therapy with other pathway inhibitors or immunotherapy may effectively overcome resistance to HH inhibitors. A comprehensive cancer radiotherapy with HH or GLI inhibitor is more likely to enhance cancer treatment efficacy while further studies are still needed to overcome its adverse effects and drug resistance.

EXTH-18. DEVELOPMENT OF A TRANSGENIC MOUSE MODEL ENABLING COMPARATIVE ANALYSIS OF CHIMERIC ANTIGEN RECEPTOR (CAR)-EXPRESSING IMMUNE CELL POPULATIONS FOR CANCER IMMUNOTHERAPY

Abstract We reported the creation of C57BL/6J-background transgenic (Tg) mice carrying the anti-epidermal growth factor receptor (EGFR)vIII-CAR with CD3z-CD28-4-1BB downstream of a Lox-Stop-Lox cassette in the Rosa26 locus. Breeding these mice with CD4-Cre Tg allows rigorous and reproducible evaluation of CAR-T cell therapy in syngeneic models (Chuntova et al. Neuro-Onc 2022). As the extension of the approach, we crossed the EGFRvIII-CAR Tg mice with mice carrying Vav-Cre, which allowed the expression of anti-EGFRvIII CAR in all hematopoietic cells. In particular, we evaluated CAR-T, CAR-NKT, CAR-NK cells, and CAR-macrophages. CAR-NK cells displayed a robust antigen-specific cytolytic activity against EGFRvIII-expressing SB28 cells, comparable to CAR-T cells in vitro and mice bearing intracerebral EGFRvIII-expressing SB28 gliomas. Remarkably, CAR-NKT cells produced higher levels of inflammatory cytokines when co-cultured with EGFRvIII-expressing SB28 cells, such as IFN-g, Perforin, IL4, and IL17. On the other hand, despite their in vitro cytotoxic effects against SB28 cells, CAR-NK cells failed to mediate a therapeutic response in mice bearing intracerebral glioma. Future studies will be directed at improving the in vivo persistence of CAR-NK cells using engineered cytokines, such as IL-2 superkine. In addition, we extensively investigated CAR-macrophages in vitro and in vivo. Unfortunately, we did not observe significant CAR-specific anti-tumor effects. Consequently, we modified the intracellular domain of CAR from CD3z-CD28-4-1BB to CD3z alone. This alteration led to increased TNF-α production through CAR signaling. This transgenic mouse model offers rigorous and reproducible evaluations of CAR-expressing hematopoietic cells. Furthermore, the model provides a platform for developing combination therapies, such as CAR-T plus CAR-NKT or CAR-T plus CAR-NK cells, with potential implications for enhanced cancer treatment strategies.

Biomimetic theranostic nanoparticles for effective anticancer therapy and MRI imaging

Cancer remains a leading cause of mortality worldwide, necessitating the development of innovative therapeutic approaches. Nanoparticle-based drug delivery systems have garnered significant interest due to their multifunctionality, offering the potential to enhance cancer treatment efficacy and improve patient tolerability. Membrane-coated drug delivery systems hold great potential for enhancing the therapeutic outcome of nanoparticle-based anticancer therapies. In this study, we report the synthesis of multifunctional iron-functionalized mesoporous polydopamine nanoparticles (MPDAFe NPs). These nanoformulations demonstrate substantial potential for combining efficient drug delivery and magnetic resonance imaging (MRI) and showcase the advantages of biomimetic coating with tumor cell-derived membranes. This coating confers prolonged circulation and improved the targeting capabilities of the nanoparticles. Furthermore, comprehensive biosafety evaluations reveal negligible toxicity to normal cells, while the combined chemo- and phototherapy exhibited significant cytotoxicity towards cancer cells. Additionally, the photothermal effect evaluation highlights the enhanced cytotoxicity achieved through laser irradiation, showcasing the synergistic effects of the nanomaterials and photothermal therapy. Importantly, our chemotherapeutic effect evaluation demonstrates the superior efficacy of doxorubicin-loaded MPDAFe@Mem NPs (cancer cell membrane-coated MPDAFe NPs) in inhibiting cancer cell viability and proliferation, surpassing the potency of free doxorubicin. This study comprehensively investigates theranostic, membrane-coated drug delivery systems, underlining their potential to increase the efficacy of cancer treatment strategies. The multifunctional nature of the iron-functionalized polydopamine nanoparticles allows for efficient drug delivery and imaging capabilities, while the biomimetic coating enhances their biocompatibility and targeting ability. These findings contribute valuable insights towards the development of advanced nanomedicine for improved cancer therapeutics.