Treatment Of Brain Cancer Research Articles

Next Generation of Brain Cancer Nanomedicines to Overcome the Blood–Brain Barrier (BBB): Insights on Transcytosis, Perivascular Tumor Growth, and BBB Models

AbstractBrain cancers, particularly malignant gliomas such as glioblastoma, are highly invasive and characterized by elevated complexity, heterogeneity, and high infiltration ability. Therefore, they pose a significant challenge to conventional treatments due to the limited drug permeability of the blood–brain barrier (BBB), the involvement of numerous acquired and intrinsic drug resistance mechanisms in metastatic brain tumors, and the high sensitivity of surrounding healthy tissues. Despite recent advances in diagnosis and treatment, their prognosis remains poor, with their median overall survival rarely exceeding 12 months. To overcome these limitations, different nanomedicine‐based therapeutic approaches have recently been proposed, aiming to provide more effective and safer drug delivery for targeting brain cancers. However, most reported nanomedicines to date have failed to meet the high expectations in the clinic. This fact can be attributed to limited understanding of brain tumor biology and lack of knowledge about bio‐nanoparticle interactions, among other factors. This review discusses recent progress in brain cancer nanomedicines, with a particular focus in understanding intracellular sorting mechanisms, perivascular tumor growth, and the design of advanced BBB models. It also highlights how an improved understanding of brain tumor biology can pave the way for designing safer and more effective nanomedicines for brain cancer treatment.

BBB opening by low pulsed electric fields, depicted by delayed-contrast MRI, enables efficient delivery of therapeutic doxorubicin doses into mice brains

BackgroundPharmacological treatment of CNS diseases is limited due to the presence of the blood-brain barrier (BBB). Recent years showed significant advancement in the field of CNS drug delivery enablers, with technologies such as MR-guided focused ultrasound reaching clinical trials. This have inspired researchers in the field to invent novel brain barriers opening (BBo) technologies that are required to be simple, fast, safe and efficient. One such technology, recently developed by us, is BDF (Barrier Disrupting Fields), based on low pulsed electric fields (L-PEFs) for opening the BBB in a controlled, safe, reversible and non-invasive manner. Here, we conducted an in vivo study to show that BDF is a feasible technology for delivering Doxorubicin (Doxo) into mice brain. Means for depicting BBBo levels were developed and applied for monitoring the treatment and predicting response. Overall, the goals of the presented study were to demonstrate the feasibility for delivering therapeutic Doxo doses into naïve and tumor-bearing mice brains and applying delayed–contrast MRI (DCM) for monitoring the levels of BBBo.MethodsL-PEFs were applied using plate electrodes placed on the intact skull of naïve mice. L-PEFs/Sham mice were scanned immediately after the procedure by DCM (“MRI experiment”), or injected with Doxo and Trypan blue followed by delayed (4 h) perfusion and brain extraction (“Doxo experiment”). Doxo concentrations were measured in brain samples using confocal microscopy and compared to IC50 of Doxo in glioma cell lines in vitro. In order to map BBBo extent throughout the brain, pixel by pixel MR image analysis was performed using the DCM data. Finally, the efficacy of L-PEFs in combination with Doxo was tested in nude mice bearing intracranial human glioma tumors.ResultsSignificant amount of Doxo was found in cortical regions of all L-PEFs-treated mice brains (0.50 ± 0.06 µg Doxo/gr brain) while in Sham brains, Doxo concentrations were below or on the verge of detection limit (0.03 ± 0.02 µg Doxo/gr brain). This concentration was x97 higher than IC50 of Doxo calculated in gl261 mouse glioma cells and x8 higher than IC50 of Doxo calculated in U87 human glioma cells. DCM analysis revealed significant BBBo levels in the cortical regions of L-PEFs-treated mice; the average volume of BBBo in the L-PEFs-treated mice was x29 higher than in the Sham group. The calculated BBBo levels dropped exponentially as a function of BBBo threshold, similarly to the electric fields distribution in the brain. Finally, combining non-invasive L-PEFs with Doxo significantly decreased brain tumors growth rates in nude mice.ConclusionsOur results demonstrate significant BBBo levels induced by extra-cranial L-PEFs, enabling efficient delivery of therapeutic Doxo doses into the brain and reducing tumor growth. As BBBo was undetectable by standard contrast-enhanced MRI, DCM was applied to generate maps depicting the BBBo levels throughout the brain. These findings suggest that BDF is a promising technology for efficient drug delivery into the brain with important implications for future treatment of brain cancer and additional CNS diseases.

Complete patient exposure during paediatric brain cancer treatment for photon and proton therapy techniques including imaging procedures.

In radiotherapy, especially when treating children, minimising exposure of healthy tissue can prevent the development of adverse outcomes, including second cancers. In this study we propose a validated Monte Carlo framework to evaluate the complete patient exposure during paediatric brain cancer treatment. Organ doses were calculated for treatment of a diffuse midline glioma (50.4 Gy with 1.8 Gy per fraction) on a 5-year-old anthropomorphic phantom with 3D-conformal radiotherapy, intensity modulated radiotherapy (IMRT), volumetric modulated arc therapy (VMAT) and intensity modulated pencil beam scanning (PBS) proton therapy. Doses from computed tomography (CT) for planning and on-board imaging for positioning (kV-cone beam CT and X-ray imaging) accounted for the estimate of the exposure of the patient including imaging therapeutic dose. For dose calculations we used validated Monte Carlo-based tools (PRIMO, TOPAS, PENELOPE), while lifetime attributable risk (LAR) was estimated from dose-response relationships for cancer induction, proposed by Schneider etal. Out-of-field organ dose equivalent data of proton therapy are lower, with doses between 0.6 mSv (testes) and 120 mSv (thyroid), when compared to photon therapy revealing the highest out-of-field doses for IMRT ranging between 43 mSv (testes) and 575 mSv (thyroid). Dose delivered by CT ranged between 0.01 mSv (testes) and 72 mSv (scapula) while a single imaging positioning ranged between 2 μSv (testes) and 1.3 mSv (thyroid) for CBCT and 0.03 μSv (testes) and 48 μSv (scapula) for X-ray. Adding imaging dose from CT and daily CBCT to the therapeutic demonstrated an important contribution of imaging to the overall radiation burden in the course of treatment, which is subsequently used to predict the LAR, for selected organs. The complete patient exposure during paediatric brain cancer treatment was estimated by combining the results from different Monte Carlo-based dosimetry tools, showing that proton therapy allows significant reduction of the out-of-field doses and secondary cancer risk in selected organs.

NHS BRAIN CANCER HEALTHCARE AND RESEARCH: DOES IT MATTER WHERE YOU ARE TREATED?

Abstract AIMS The Tessa Jowell Centre of Excellence designation initiative recognizes and awards neuro-oncology centres for excellence in patient treatment, care and research. METHOD Twenty-eight NHS centres were assessed through an extensive application form, virtual site visits and patient feedback. Applications were reviewed against a set of standards established through an iterative process in- volving expert specialists in brain cancer treatment and care. RESULTS Many pockets of excellence and innovations were found across the entire patient pathway. Centres demonstrated consistencies in service provision, common challenges threatening service development and sustainability, as well as areas of significant variations. Patients are most likely to experience variations in genetic testing of their tumour samples, access to clinical studies and the extensiveness of nurse and allied health professional- led care and support they receive. To date, 17 centres have been awarded Excellence status and all applicant centres have obtained support through the Tessa Jowell Academy to develop services and innovate. CONCLUSIONS Based on the findings, patients being treated for brain cancer in any UK centre will be able to obtain an effective standard of care, delivered by a motivated team. There are however areas of striking variation, with disparities in the design, quality and extent of the treatment and care pathway. Service development and addressing gaps in treatment and care will require a tailored approach at both a hospital and national level. In 2023/24, a new application round will open for all UK centres to re-apply to be assessed.

TRANSFORMING BRAIN CANCER TREATMENT, CARE AND RESEARCH: A CASE STUDY OF A SPECIALISED NATIONAL DIGITAL LEARNING AND NETWORKING PLATFORM FOR NHS HEALTH PROFESSIONALS

Abstract AIMS The aim of this case study is to highlight the outcomes of a specialized digital learning platform, the Tessa Jowell Academy, to share excellence and jointly tackle challenges in brain cancer treatment, research and care. The free platform is co-designed with the professional community to address unmet needs and offers members features such as virtual courses, a clinical trial finder and a peer-to-peer learning service. METHOD Performance data has been collected over the last 12 months from: online member surveys and platform data (workshop registrations, member registrations, member logins, resource downloads, video views, certificate downloads, feature requests, clinical trial updates and national network sign-ups). RESULTS The platform has over 800 member registrations from 29 NHS hospitals from a range of disciplines. There have been: 42 peers matched through the platform, 19 clinical trials added, 4 national networks set-up and 35 workshops delivered to 1200 attendees live and on-demand. Common themes from member feedback include increased learning and networking opportunities, increased specialist support, improved confidence in MDT participation and increased knowledge of other sub-specialties. CONCLUSIONS It is well evidenced that specialized knowledge sharing between centres can contribute to better outcomes, improved patient satisfaction and access to research for rare diseases. This case study highlights the national demand and potential benefits of a specialized, national digital learning platform for NHS professionals working in brain cancer. As the platform grows, the impact will continue to be measured on a national level.

Unravelling the Glioblastoma Tumour Microenvironment: Can Aptamer Targeted Delivery Become Successful in Treating Brain Cancers?

The key challenges to treating glioblastoma multiforme (GBM) are the heterogeneous and complex nature of the GBM tumour microenvironment (TME) and difficulty of drug delivery across the blood-brain barrier (BBB). The TME is composed of various neuronal and immune cells, as well as non-cellular components, including metabolic products, cellular interactions, and chemical compositions, all of which play a critical role in GBM development and therapeutic resistance. In this review, we aim to unravel the complexity of the GBM TME, evaluate current therapeutics targeting this microenvironment, and lastly identify potential targets and therapeutic delivery vehicles for the treatment of GBM. Specifically, we explore the potential of aptamer-targeted delivery as a successful approach to treating brain cancers. Aptamers have emerged as promising therapeutic drug delivery vehicles with the potential to cross the BBB and deliver payloads to GBM and brain metastases. By targeting specific ligands within the TME, aptamers could potentially improve treatment outcomes and overcome the challenges associated with larger therapies such as antibodies.

Progress and Challenges in the Diagnosis and Treatment of Brain Cancer Using Nanotechnology.

Primary brain cancer or brain cancer is the overgrowth of abnormal or malignant cells in the brain or its nearby tissues that form unwanted masses called brain tumors. People with malignant brain tumors suffer a lot, and the expected life span of the patients after diagnosis is often only around 14 months, even with the most vigorous therapies. The blood-brain barrier (BBB) is the main barrier in the body that restricts the entry of potential chemotherapeutic agents into the brain. The chances of treatment failure or low therapeutic effects are some significant drawbacks of conventional treatment methods. However, recent advancements in nanotechnology have generated hope in cancer treatment. Nanotechnology has shown a vital role starting from the early detection, diagnosis, and treatment of cancer. These tiny nanomaterials have great potential to deliver drugs across the BBB. Beyond just drug delivery, nanomaterials can be simulated to generate fluorescence to detect tumors. The current Review discusses in detail the challenges of brain cancer treatment and the application of nanotechnology to overcome those challenges. The success of chemotherapeutic treatment or the surgical removal of tumors requires proper imaging. Nanomaterials can provide imaging and therapeutic benefits for cancer. The application of nanomaterials in the diagnosis and treatment of brain cancer is discussed in detail by reviewing past studies.

Melatonin Prevents Depression but Not Anxiety-like Behavior Produced by the Chemotherapeutic Agent Temozolomide: Implication of Doublecortin Cells and Hilar Oligodendrocytes.

Melatonin is a hormone synthesized by the pineal gland with neuroprotective and neurodevelopmental effects. Also, melatonin acts as an antidepressant by modulating the generation of new neurons in the dentate gyrus of the hippocampus. The positive effects of melatonin on behavior and neural development may suggest it is used for reverting stress but also for the alterations produced by chemotherapeutic drugs influencing behavior and brain plasticity. In this sense, temozolomide, an alkylating/anti-proliferating agent used in treating brain cancer, is associated with decreased cognitive functions and depression. We hypothesized that melatonin might prevent the effects of temozolomide on depression- and anxiety-like behavior by modulating some aspects of the neurogenic process in adult Balb/C mice. Mice were treated with temozolomide (25 mg/kg) for three days of two weeks, followed by melatonin (8 mg/kg) for fourteen days. Temozolomide produced short- and long-term decrements in cell proliferation (Ki67-positive cells: 54.89% and 53.38%, respectively) and intermediate stages of the neurogenic process (doublecortin-positive cells: 68.23% and 50.08%, respectively). However, melatonin prevented the long-term effects of temozolomide with the increased number of doublecortin-positive cells (47.21%) and the immunoreactivity of 2' 3'-Cyclic-nucleotide-3 phosphodiesterase (CNPase: 82.66%), an enzyme expressed by mature oligodendrocytes, in the hilar portion of the dentate gyrus. The effects of melatonin in the temozolomide group occurred with decreased immobility in the forced swim test (45.55%) but not anxiety-like behavior. Thus, our results suggest that melatonin prevents the harmful effects of temozolomide by modulating doublecortin cells, hilar oligodendrocytes, and depression-like behavior tested in the forced swim test. Our study could point out melatonin's beneficial effects for counteracting temozolomide's side effects.

Wanita 74 Tahun Dengan Metastasis Pada Lobus Parieto-Oksipital Pada Melanoma Maligna

Melanoma is a tumor that is produced by the malignant transformation of melanocyte cells. Melanoma is the leading cause of premature death from cancer. Known risk factors include personal or family history of melanoma, large numbers of naevi and/or dysplastic naevi, congenital melanocytic naevi, sun-damaged skin, history of non-melanoma skin cancer, and immunodeficiency. Based on the Basic Health Research Results (Riskesdas) report, skin cancer as a whole ranks 3rd in Indonesia. Epidemiological studies of skin cancer have reported in Jakarta in 2014–2017, where out of 263 cases of skin cancer, malignant melanoma ranks third with the highest incidence of skin cancer (5.7%). Diagnosis of melanoma can be made by assessing the skin lesions with the naked eye and also by the patient's clinical symptoms. A person's risk of metastases is directly related to the depth of invasion and ulceration of their primary lesion. Among solid tumors, melanoma has one of the highest propensities to cause brain metastases with a proportion of more than 25% of patients. Although the current cancer treatment paradigm may reflect a combination of surgery, chemotherapy, radiotherapy, and immunotherapy with medical management, options for the treatment of metastatic brain cancer remain limited.

Liposomes for the Treatment of Brain Cancer-A Review.

Due to their biocompatibility, non-toxicity, and surface-conjugation capabilities, liposomes are effective nanocarriers that can encapsulate chemotherapeutic drugs and facilitate targeted delivery across the blood-brain barrier (BBB). Additionally, strategies have been explored to synthesize liposomes that respond to internal and/or external stimuli to release their payload controllably. Although research into liposomes for brain cancer treatment is still in its infancy, these systems have great potential to fundamentally change the drug delivery landscape. This review paper attempts to consolidate relevant literature regarding the delivery to the brain using nanocarriers, particularly liposomes. The paper first briefly explains conventional treatment modalities for cancer, followed by describing the blood-brain barrier and ways, challenges, and techniques involved in transporting drugs across the BBB. Various nanocarrier systems are introduced, with attention to liposomes, due to their ability to circumvent the challenges imposed by the BBB. Relevant studies involving liposomal systems researched to treat brain tumors are reviewed in vitro, in vivo, and clinical studies. Finally, the challenges associated with the use of liposomes to treat brain tumors and how they can be addressed are presented.

Magnetic self-assembly of 3D multicellular microscaffolds: A biomimetic brain tumor-on-a-chip for drug delivery and selectivity testing.

In recent years, the need for highly predictive brain cancer models to test new anticancer compounds and experimental therapeutic approaches has significantly increased. Realistic in vitro brain tumor-on-a-chip platforms would allow a more accurate selection of valid candidate drugs and nanomedicines, therefore alleviating the economic and ethical issues of unsuccessful studies in vivo. Here, we present a multi-functional self-assembled brain tumor-on-a-chip model characterized by 3D glioma cultures interfaced both to nonmalignant brain cells of the peritumoral niche and to a 3D-real-scale blood-brain barrier (BBB) microfluidic system. This platform allowed us to screen multiple features, such as BBB crossing capabilities, apoptotic efficacy against GBM cells, and side effects on nonmalignant brain cells of a promising anticancer drug, nutlin-3a, which is fundamental for the treatment of brain cancer.

Irradiation and lithium treatment alter the global DNA methylation pattern and gene expression underlying a shift from gliogenesis towards neurogenesis in human neural progenitors

Central nervous system (CNS) tumors account for almost a third of pediatric cancers and are the largest contributor to cancer-related death in children. Cranial radiation therapy (CRT) is, often in combination with chemotherapy and surgery, effective in the treatment of high-grade childhood brain cancers, but it has been associated with late complications in 50–90% of survivors, such as decline in cognition and mood, decreased social competence, and fatigue. A leading hypothesis to explain the decline in cognition, at least partially, is injury to the neural stem and progenitor cells (NSPCs), which leads to apoptosis and altered fate choice, favoring gliogenesis over neurogenesis. Hence, treatments harnessing neurogenesis are of great relevance in this context. Lithium, a well-known mood stabilizer, has neuroprotective and antitumor effects and has been found to reverse irradiation-induced damage in rodents, at least in part by regulating the expression of the glutamate decarboxylase 2 gene (Gad2) via promoter demethylation in rat NSPCs. Additionally, lithium was shown to rescue irradiation-induced cognitive defects in mice. Here, we show that irradiation (IR) alone or in combination with lithium chloride (LiCl) caused major changes in gene expression and global DNA methylation in iPSC-derived human NSPCs (hNSPCs) compared to untreated cells, as well as LiCl-only-treated cells. The pattern of DNA methylation changes after IR-treatment alone was stochastic and observed across many different gene groups, whereas differences in DNA methylation after LiCl-treatment of irradiated cells were more directed to specific promoters of genes, including genes associated with neurogenesis, for example GAD2. Interestingly, IR and IR + LiCl treatment affected the promoter methylation and expression of several genes encoding factors involved in BMP signaling, including the BMP antagonist gremlin1. We propose that lithium in addition to promoting neuronal differentiation, also represses glial differentiation in hNSPCs with DNA methylation regulation being a key mechanism of action.

Cyclic Ruthenium-Peptide Conjugates as Integrin-Targeting Phototherapeutic Prodrugs for the Treatment of Brain Tumors.

To investigate the potential of tumor-targeting photoactivated chemotherapy, a chiral ruthenium-based anticancer warhead, Λ/Δ-[Ru(Ph2phen)2(OH2)2]2+, was conjugated to the RGD-containing Ac-MRGDH-NH2 peptide by direct coordination of the M and H residues to the metal. This design afforded two diastereoisomers of a cyclic metallopeptide, Λ-[1]Cl2 and Δ-[1]Cl2. In the dark, the ruthenium-chelating peptide had a triple action. First, it prevented other biomolecules from coordinating with the metal center. Second, its hydrophilicity made [1]Cl2 amphiphilic so that it self-assembled in culture medium into nanoparticles. Third, it acted as a tumor-targeting motif by strongly binding to the integrin (Kd = 0.061 μM for the binding of Λ-[1]Cl2 to αIIbβ3), which resulted in the receptor-mediated uptake of the conjugate in vitro. Phototoxicity studies in two-dimensional (2D) monolayers of A549, U87MG, and PC-3 human cancer cell lines and U87MG three-dimensional (3D) tumor spheroids showed that the two isomers of [1]Cl2 were strongly phototoxic, with photoindexes up to 17. Mechanistic studies indicated that such phototoxicity was due to a combination of photodynamic therapy (PDT) and photoactivated chemotherapy (PACT) effects, resulting from both reactive oxygen species generation and peptide photosubstitution. Finally, in vivo studies in a subcutaneous U87MG glioblastoma mice model showed that [1]Cl2 efficiently accumulated in the tumor 12 h after injection, where green light irradiation generated a stronger tumoricidal effect than a nontargeted analogue ruthenium complex [2]Cl2. Considering the absence of systemic toxicity for the treated mice, these results demonstrate the high potential of light-sensitive integrin-targeted ruthenium-based anticancer compounds for the treatment of brain cancer in vivo.

Epidemiology and etiology of brain cancer in Africa: A systematic review.

Cancer is a significant threat to public health and a leading cause of morbidity across the globe. Of all cancers, brain cancer can be particularly catastrophic as treatment often fails to achieve the desired degree of effectiveness and diagnosis remains associated with a high mortality rate. Africa, as a continent with resource-limited countries, needs to allocate the necessary proper healthcare infrastructure to significantly reduce cancer rates and improve patient survival. In addition, the relative paucity of data within this field in Africa makes effective management a challenge. This review is aimed at elucidating the currently available evidence base with regard to the epidemiology and etiology of brain cancer within resource-limited African countries. This review hopes to bring to the attention of the wider clinical community the growing burden of brain cancer within Africa and to encourage future research into this field of research. The available literature for this Systematic Review was searched on two bibliographic databases, PubMed and Scopus, using an individually verified, prespecified approach. In addition, the Global Cancer Observatory and Global Burden of Disease databases were also utilized. Studies reporting on the epidemiology, etiology, and impact of brain cancer in Africa were suitable for inclusion. The level of evidence of the included studies was considered as per the Centre for Evidence-Based Medicine recommendations. Out of the four databases searched, 3848 articles were initially screened rigorously, filtered into 54 articles, and finally assessed qualitatively and quantitatively. We have demonstrated a poor survival rate and lack of proper funds/resources necessary to report, identify, and treat cases, as well as the dearth of comprehensive research on the subject of brain cancer that has become a challenging healthcareconcern in many African developing nations. Also, because of the gradual improvement in healthcare facilities and the increasing population within many countries in Africa, the number of patients with central nervous system and intracranial tumors is rising specifically in the elder population. In addition, the population in West Africa is at a higher risk of HIV-related malignancies due to the high prevalence of HIV in West Africa. The burden of brain cancer in Africa is increasing in comparison with the developed parts of the world in which it is decreasing. Moreover, the mismanagement of cancers in Africa leads to higher morbidity and mortality and decreased quality of life. This study addresses the burden of brain cancer as a major public health crisis in Africa. Improved treatment modalities and access to screening are required to better address the burden of this disease. Therefore, there is a clear need for more substantial and comprehensive research on etiology, epidemiology, and treatment of brain cancer within Africa to understand its epidemiological distribution and provide a means for managing and reducing the associated morbidity and mortality.

The effect of laser beam profile on brain cancer treatment through photothermal therapy

The effect of laser beam profile on brain cancer treatment through photothermal therapy

Combination beta-adrenergic blockade and immunotherapy for the treatment of primary and metastatic brain cancer.

e14017 Background: Brain tumors present a unique challenge to immunotherapeutic success, as immune responses in patients with brain tumors are suppressed both within the tumor microenvironment and peripherally. The systemic immunosuppression observed in brain tumor patients limits the capacity of the immune system to respond to immunotherapy. Brain tumor patients, particularly those with primary brain tumors like glioblastoma, represent a population in dire need of more thoughtful, targeted treatment approaches. Through this work we present an immunosuppressive axis specifically activated in the context of intracranial malignancies that inhibits immunotherapeutic success in these patients. We demonstrate that overactive adrenergic signaling is a major barrier to immunotherapeutic success. More specifically, beta-adrenergic signaling is known to suppress immune responses in various contexts. Our data indicate that combining beta-adrenergic blockade with immunotherapy provides a survival benefit in the setting of brain tumors, where immunotherapy alone has proven ineffective. Methods: Using the SEER Medicaid database, we retrospectively examined outcomes in patients with melanoma and lung adenocarcinoma brain metastasis who received checkpoint blockade therapy alone vs those concurrently on beta-blocker therapy. Results: We found that patients receiving combination therapy showed increased overall survival compared to those receiving checkpoint blockade alone. We then validated these findings in preclinical models of both glioma and melanoma brain metastases, demonstrating that combining immunotherapy and propranolol, a highly-prescribed FDA-approved beta-blocker, extended survival. Conclusions: Moving forward, we suggest that combination therapy with propranolol and immunotherapy, particularly checkpoint blockade, represents a promising translational treatment platform for patients with primary or metastatic intracranial malignancies.

Nanocomposite of chitosan/gelatin/carbon quantum dots as a biocompatible and efficient nanocarrier for improving the Curcumin delivery restrictions to treat brain cancer

Curcumin (CUR) is among the most appropriate and natural-based anticancer drugs that can be applied effectively treat different classes of cancers. However, CUR suffers from a low half-life and stability in the body, which has restricted the efficacy of its delivery applications. This study is dedicated to introducing the pH-sensitive nanocomposite of chitosan (CS)/gelatin (GE)/carbon quantum dots (CQDs) as an applicable nanocarrier for enhancing CUR half-life and its delivery restrictions. The CS/GE hydrogel was synthesized by the physical crosslinking method, which improves the biocompatibility of this hydrogel. Moreover, the water-in-oil-in-water (W/O/W) double emulsion approach is involved in fabricating the drug-loaded CS/GE/CQDs@CUR nanocomposite. Afterward, drug encapsulation (EE) and loading efficiencies (LE) have been determined. Furthermore, FTIR and XRD assessments were performed to confirm the CUR incorporation into the prepared nanocarrier and crystalline features of the nanoparticles. Then, by employing Zeta potential and dynamic light scattering (DLS) analysis, the size distribution and stability of the drug-loaded nanocomposites have been assessed, which indicated monodisperse and stable nanoparticles. Furthermore, field emission scanning electron microscopy (FE-SEM) was utilized that confirmed the homogeneous distribution of the nanoparticles with smooth and quite spherical structures. In vitro drug release pattern was studied and the kinetic analysis was performed using a curve fitting technique to determine the governing release mechanism at both acidic pH and physiological conditions. The obtained outcomes from release data revealed a controlled release behavior with a 22-hour half-life, while the EE% and EL% were acquired at 46.75 % and 87.5 %, respectively. In addition, the MTT assay has been carried out on U-87 MG cell lines to evaluate the cytotoxicity of the nanocomposite. The findings showed that the fabricated nanocomposite of CS/GE/CQDs can be assumed as a biocompatible CUR nanocarrier, while the drug-loaded nanocomposite of CS/GE/CQDs@CUR showed enhanced cytotoxicity compared to the pure CUR. Based on the obtained results, this study suggests the CS/GE/CQDs nanocomposite as a biocompatible and potential nanocarrier for ameliorating CUR delivery restrictions to treat brain cancers.

Hybrid lipid-biopolymer nanocarrier as a strategy for GBM photodynamic therapy (PDT)

Glioblastoma (GBM) is the most common brain cancer characterized by aggressive and infiltrated tumors. For this, hybrid biopolymer-lipid nanoparticles coated with biopolymers such as chitosan and lipidic nanocarriers (LN) loaded with a photosensitizer (AlClPc) can be used for GBM photodynamic therapy. The chitosan-coated LN exhibited stable physicochemical characteristics and presented as an excellent lipid nanocarrier with highly efficiently encapsulated photosensitizer chloro-aluminum phthalocyanine (AlClPc). LN(AlClPc)Ct0.1% in the presence of light produced more reactive oxygen species and reduced brain tumor cell viability and proliferation. Confirm the effects of in vivo LN applications with photodynamic therapy confirmed that the total brain tumor area decreased without systemic toxicity in mice. These results suggest a promising strategy for future clinical applications to improve brain cancer treatment.

Amino Acid Derivatives of Chlorin-e6-A Review.

Details of the structural elucidation of the clinically useful photodynamic therapy sensitizer NPe6 (15) are presented. NPe6, also designated as Laserphyrin, Talaporfin, and LS-11, is a second-generation photosensitizer derived from chlorophyll-a, currently used in Japan for the treatment of human lung, esophageal, and brain cancers. After the initial misidentification of the structure of this chlorin-e6 aspartic acid conjugate as (13), NMR and other synthetic procedures described herein arrived at the correct structure (15), confirmed using single crystal X-ray crystallography. Interesting new features of chlorin-e6 chemistry (including the intramolecular formation of an anhydride (24)) are reported, allowing chemists to regioselectively conjugate amino acids to each available carboxylic acid on positions 131 (formic), 152 (acetic), and 173 (propionic) of chlorin e6 (14). Cellular investigations of several amino acid conjugates of chlorin-e6 revealed that the 131-aspartylchlorin-e6 derivative is more phototoxic than its 152- and 173-regioisomers, in part due to its nearly linear molecular conformation.

Radiation combined with oncolytic vaccinia virus provides pronounced antitumor efficacy and induces immune protection in an aggressive glioblastoma model

Glioblastoma (GB) is a malignant and immune-suppressed brain cancer that remains incurable despite the current standard of care. Radiotherapy is a mainstay of GB treatment, however invasive cancer cells outside the irradiated field and radioresistance preclude complete eradication of GB cells. Oncolytic virus therapy harnesses tumor-selective viruses to spread through and destroy tumors while stimulating antitumor immune responses, and thus has potential for use following radiotherapy. We demonstrate that oncolytic ΔF4LΔJ2R vaccinia virus (VACV) replicates in and induces cytotoxicity of irradiated brain tumor initiating cells in vitro. Importantly, a single 10 Gy dose of radiation combined with ΔF4LΔJ2R VACV produced considerably superior anticancer effects relative to either monotherapy when treating immune-competent orthotopic CT2A-luc mouse models—significantly extending survival and curing the majority of mice. Mice cured by the combination displayed significantly increased survival relative to naïve age-matched controls following intracranial tumor challenge, with some complete rejections. Further, the combination therapy was associated with an increased ratio of CD8+ effector T cells to regulatory T cells compared to either monotherapy. This study validates the use of radiation with an oncolytic ΔF4LΔJ2R VACV to improve treatment of this malignant brain cancer.