Journal articles on the topic 'Nanoparticles, brain delivery, natural conpounds'
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Liang, Jianming, Caifang Gao, Ying Zhu, Chengli Ling, Qi Wang, Yongzhuo Huang, Jing Qin, Jue Wang, Weigen Lu, and Jianxin Wang. "Natural Brain Penetration Enhancer-Modified Albumin Nanoparticles for Glioma Targeting Delivery." ACS Applied Materials & Interfaces 10, no. 36 (August 16, 2018): 30201–13. http://dx.doi.org/10.1021/acsami.8b11782.
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O. Elzoghby, Ahmed, Mahmoud M. Abd-Elwakil, Kholod Abd-Elsalam, Mustafa T. Elsayed, Yosra Hashem, and Ola Mohamed. "Natural Polymeric Nanoparticles for Brain-Targeting: Implications on Drug and Gene Delivery." Current Pharmaceutical Design 22, no. 22 (May 31, 2016): 3305–23. http://dx.doi.org/10.2174/1381612822666160204120829.
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Han, Lei, Anling Zhang, Hanjie Wang, Peiyu Pu, Chunsheng Kang, and Jin Chang. "Construction of novel brain-targeting gene delivery system by natural magnetic nanoparticles." Journal of Applied Polymer Science 121, no. 6 (April 12, 2011): 3446–54. http://dx.doi.org/10.1002/app.33995.
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Perteghella, Sara, Giovanna Rassu, Elisabetta Gavini, Antonella Obinu, Elia Bari, Delia Mandracchia, Maria Cristina Bonferoni, Paolo Giunchedi, and Maria Luisa Torre. "Crocetin as New Cross-Linker for Bioactive Sericin Nanoparticles." Pharmaceutics 13, no. 5 (May 9, 2021): 680. http://dx.doi.org/10.3390/pharmaceutics13050680.
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The nose-to-brain delivery route is used to bypass the blood–brain barrier and deliver drugs directly into the brain. Over the years, significant signs of progress have been made in developing nano-drug delivery systems to address the very low drug transfer levels seen with conventional formulations (e.g., nasal solutions). In this paper, sericin nanoparticles were prepared using crocetin as a new bioactive natural cross-linker (NPc) and compared to sericin nanoparticles prepared with glutaraldehyde (NPg). The mean diameter of NPc and NPg was about 248 and 225 nm, respectively, and suitable for nose-to-brain delivery. The morphological investigation revealed that NPc are spherical-like particles with a smooth surface, whereas NPg seem small and rough. NPc remained stable at 4 °C for 28 days, and when freeze-dried with 0.1% w/v of trehalose, the aggregation was prevented. The use of crocetin as a natural cross-linker significantly improved the in vitro ROS-scavenging ability of NPc with respect to NPg. Both formulations were cytocompatible at all the concentrations tested on human fibroblasts and Caco-2 cells and protected them against oxidative stress damage. In detail, for NPc, the concentration of 400 µg/mL resulted in the most promising to maintain the cell metabolic activity of fibroblasts higher than 90%. Overall, the results reported in this paper support the employment of NPc as a nose-to-brain drug delivery system, as the brain targeting of antioxidants is a potential tool for the therapy of neurological diseases.
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Neha, Bhatt, Bhatt Ganesh, and Kothiyal Preeti. "Drug Delivery to The Brain Using Polymeric Nanoparticles: A Review." International Journal of Pharmaceutical and Life Sciences 2, no. 3 (June 24, 2013): 107–32. http://dx.doi.org/10.3329/ijpls.v2i3.15457.
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Nanoparticle drug carriers consist of solid biodegradable particles in size ranging from 10 to 1000 nm (50300 nm generally). The use of minute particles as drug carriers for targeted treatment has been studied over a long period of time. A selective accumulation of active substances in target tissues has been demonstrated for certain so-called nanocarrier systems that are administered bound to pharmaceutical drugs. Great expectations are placed on nanocarrier systems that can overcome natural barriers such as the blood-brain barrier (BBB) and transport the medication directly to the desired tissue and thus heal neurological diseases that were formerly incurable. Polymeric Nanoparticle have been shown to be promising carriers for CNS drug delivery due to their potential both in encapsulating drugs, hence protecting them from excretion and metabolism, and in delivering active agents across the blood brain barrier without inflicting any damage to the barrier. Different polymers have been used and different strategies like surface modification have been done to increase the retention time of nanoparticles. DOI: http://dx.doi.org/10.3329/ijpls.v2i3.15457 International Journal of Pharmaceutical and Life Sciences Vol.2(3) 2013: 107-132
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Ansari, Mohammad A., Ill-Min Chung, Govindasamy Rajakumar, Mohammad A. Alzohairy, Mohammad N. Alomary, Muthu Thiruvengadam, Faheem H. Pottoo, and Niyaz Ahmad. "Current Nanoparticle Approaches in Nose to Brain Drug Delivery and Anticancer Therapy - A Review." Current Pharmaceutical Design 26, no. 11 (April 24, 2020): 1128–37. http://dx.doi.org/10.2174/1381612826666200116153912.
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: Nanoparticles (NPs) are unique may be organic or inorganic, play a vital role in the development of drug delivery targeting the central nervous system (CNS). Intranasal drug delivery has shown to be an efficient strategy with attractive application for drug delivery to the CNS related diseases, such as Parkinson's disease, Alzheimer 's disease and brain solid tumors. Blood brain barrier (BBB) and blood-cerebrospinal fluid barriers are natural protective hindrances for entry of drug molecules into the CNS. Nanoparticles exhibit excellent intruding capacity for therapeutic agents and overcome protective barriers. By using nanotechnology based NPs targeted, drug delivery can be improved across BBB with discharge drugs in a controlled manner. NPs confer safe from degradation phenomenon. Several kinds of NPs are used for nose to the brain (N2B) enroute, such as lipidemic nanoparticles, polymeric nanoparticles, inorganic NPs, solid lipid NPs, dendrimers. Among them, popular lipidemic and polymeric NPs are discussed, and their participation in anti-cancer activity has also been highlighted in this review.
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Pepe, Giuseppe, Enrica Calce, Valentina Verdoliva, Michele Saviano, Vittorio Maglione, Alba Di Pardo, and Stefania De Luca. "Curcumin-Loaded Nanoparticles Based on Amphiphilic Hyaluronan-Conjugate Explored as Targeting Delivery System for Neurodegenerative Disorders." International Journal of Molecular Sciences 21, no. 22 (November 23, 2020): 8846. http://dx.doi.org/10.3390/ijms21228846.
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Identification of molecules able to promote neuroprotective mechanisms can represent a promising therapeutic approach to neurodegenerative disorders including Huntington’s disease. Curcumin is an antioxidant and neuroprotective agent, even though its efficacy is limited by its poor absorption, rapid metabolism, systemic elimination, and limited blood–brain barrier (BBB) permeability. Herein, we report on novel biodegradable curcumin-containing nanoparticles to favor the compound delivery and potentially enhance its brain bioavailability. The prepared hyaluronan-based materials able to self-assemble in stable spherical nanoparticles, consist of natural fatty acids chemically conjugated to the natural polysaccharide. The aim of this study is to provide a possible effective delivery system for curcumin with the expectation that, after having released the drug at the specific site, the biopolymer can degrade to nontoxic fragments before renal excretion, since all the starting materials are provided by natural resource. Our findings demonstrate that curcumin-encapsulated nanoparticles enter the cells and reduce their susceptibility to apoptosis in an in vitro model of Huntington’s disease.
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Habib, Saffiya, and Moganavelli Singh. "Angiopep-2-Modified Nanoparticles for Brain-Directed Delivery of Therapeutics: A Review." Polymers 14, no. 4 (February 12, 2022): 712. http://dx.doi.org/10.3390/polym14040712.
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Nanotechnology has opened up a world of possibilities for the treatment of brain disorders. Nanosystems can be designed to encapsulate, carry, and deliver a variety of therapeutic agents, including drugs and nucleic acids. Nanoparticles may also be formulated to contain photosensitizers or, on their own, serve as photothermal conversion agents for phototherapy. Furthermore, nano-delivery agents can enhance the efficacy of contrast agents for improved brain imaging and diagnostics. However, effective nano-delivery to the brain is seriously hampered by the formidable blood–brain barrier (BBB). Advances in understanding natural transport routes across the BBB have led to receptor-mediated transcytosis being exploited as a possible means of nanoparticle uptake. In this regard, the oligopeptide Angiopep-2, which has high BBB transcytosis capacity, has been utilized as a targeting ligand. Various organic and inorganic nanostructures have been functionalized with Angiopep-2 to direct therapeutic and diagnostic agents to the brain. Not only have these shown great promise in the treatment and diagnosis of brain cancer but they have also been investigated for the treatment of brain injury, stroke, epilepsy, Parkinson’s disease, and Alzheimer’s disease. This review focuses on studies conducted from 2010 to 2021 with Angiopep-2-modified nanoparticles aimed at the treatment and diagnosis of brain disorders.
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Aderibigbe, Blessing Atim, and Tobeka Naki. "Chitosan-Based Nanocarriers for Nose to Brain Delivery." Applied Sciences 9, no. 11 (May 30, 2019): 2219. http://dx.doi.org/10.3390/app9112219.
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In the treatment of brain diseases, most potent drugs that have been developed exhibit poor therapeutic outcomes resulting from the inability of a therapeutic amount of the drug to reach the brain. These drugs do not exhibit targeted drug delivery mechanisms, resulting in a high concentration of the drugs in vital organs leading to drug toxicity. Chitosan (CS) is a natural-based polymer. It has unique properties such as good biodegradability, biocompatibility, mucoadhesive properties, and it has been approved for biomedical applications. It has been used to develop nanocarriers for brain targeting via intranasal administration. Nanocarriers such as nanoparticles, in situ gels, nanoemulsions, and liposomes have been developed. In vitro and in vivo studies revealed that these nanocarriers exhibited enhanced drug uptake to the brain with reduced side effects resulting from the prolonged contact time of the nanocarriers with the nasal mucosa, the surface charge of the nanocarriers, the nano size of the nanocarriers, and their capability to stretch the tight junctions within the nasal mucosa. The aforementioned unique properties make chitosan a potential material for the development of nanocarriers for targeted drug delivery to the brain. This review will focus on chitosan-based carriers for brain targeting.
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Bakrim, Saad, Sara Aboulaghras, Naoual El Menyiy, Nasreddine El Omari, Hamza Assaggaf, Learn-Han Lee, Domenico Montesano, et al. "Phytochemical Compounds and Nanoparticles as Phytochemical Delivery Systems for Alzheimer’s Disease Management." Molecules 27, no. 24 (December 19, 2022): 9043. http://dx.doi.org/10.3390/molecules27249043.
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Alzheimer’s disease remains one of the most widespread neurodegenerative reasons for dementia worldwide and is associated with considerable mortality and morbidity. Therefore, it has been considered a priority for research. Indeed, several risk factors are involved in the complexity of the therapeutic ways of this pathology, including age, traumatic brain injury, genetics, exposure to aluminum, infections, diabetes, vascular diseases, hypertension, dyslipidemia, and obesity. The pathophysiology of Alzheimer’s disease is mostly associated with hyperphosphorylated protein in the neuronal cytoplasm and extracellular plaques of the insoluble β-amyloid peptide. Therefore, the management of this pathology needs the screening of drugs targeting different pathological levels, such as acetylcholinesterase (AchE), amyloid β formation, and lipoxygenase inhibitors. Among the pharmacological strategies used for the management of Alzheimer’s disease, natural drugs are considered a promising therapeutic strategy. Indeed, bioactive compounds isolated from different natural sources exhibit important anti-Alzheimer effects by their effectiveness in promoting neuroplasticity and protecting against neurodegeneration as well as neuroinflammation and oxidative stress in the brain. These effects involve different sub-cellular, cellular, and/or molecular mechanisms, such as the inhibition of acetylcholinesterase (AchE), the modulation of signaling pathways, and the inhibition of oxidative stress. Moreover, some nanoparticles were recently used as phytochemical delivery systems to improve the effects of phytochemical compounds against Alzheimer’s disease. Therefore, the present work aims to provide a comprehensive overview of the key advances concerning nano-drug delivery applications of phytochemicals for Alzheimer’s disease management.
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Roshani, Milad, Nasim Kiaie, and Rouhollah Mehdinavaz Aghdam. "Biomaterials and stem cells as drug/gene-delivery vehicles for Parkinson's treatment: an update." Regenerative Medicine 16, no. 12 (December 2021): 1057–72. http://dx.doi.org/10.2217/rme-2021-0050.
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By introducing biomaterials and stem cells into Parkinson’s disease (PD), therapeutic approaches have led to promising results due to facilitating brain targeting and blood–brain barrier permeation of the drugs and genes. Here, after reviewing the most recent drug- and gene-delivery vehicles including liposomes, exosomes, natural/synthetic polymeric particles/fibers, metallic/ceramic nanoparticles and microbubbles, used for Parkinson’s disease treatment, the effect of stem cells as a reservoir of neurotrophic factors and exosomes is provided.
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Torres, Joana, Inês Costa, Andreia F. Peixoto, Renata Silva, José Manuel Sousa Lobo, and Ana Catarina Silva. "Intranasal Lipid Nanoparticles Containing Bioactive Compounds Obtained from Marine Sources to Manage Neurodegenerative Diseases." Pharmaceuticals 16, no. 2 (February 16, 2023): 311. http://dx.doi.org/10.3390/ph16020311.
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Marine sources contain several bioactive compounds with high therapeutic potential, such as remarkable antioxidant activity that can reduce oxidative stress related to the pathogenesis of neurodegenerative diseases. Indeed, there has been a growing interest in these natural sources, especially those resulting from the processing of marine organisms (i.e., marine bio-waste), to obtain natural antioxidants as an alternative to synthetic antioxidants in a sustainable approach to promote circularity by recovering and creating value from these bio-wastes. However, despite their expected potential to prevent, delay, or treat neurodegenerative diseases, antioxidant compounds may have difficulty reaching the brain due to the need to cross the blood–brain barrier (BBB). In this regard, alternative delivery systems administered by different routes have been proposed, including intranasal administration of lipid nanoparticles, such as solid lipid nanoparticles (SLN) and nanostructured lipid carriers (NLC), which have shown promising results. Intranasal administration shows several advantages, including the fact that molecules do not need to cross the BBB to reach the central nervous system (CNS), as they can be transported directly from the nasal cavity to the brain (i.e., nose-to-brain transport). The benefits of using SLN and NLC for intranasal delivery of natural bioactive compounds for the treatment of neurodegenerative diseases have shown relevant outcomes through in vitro and in vivo studies. Noteworthy, for bioactive compounds obtained from marine bio-waste, few studies have been reported, showing the open potential of this research area. This review updates the state of the art of using SLN and NLC to transport bioactive compounds from different sources, in particular, those obtained from marine bio-waste, and their potential application in the treatment of neurodegenerative diseases.
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Choi, Hojun, Kyungsun Choi, Dae-Hwan Kim, Byung-Koo Oh, Hwayoung Yim, Soojin Jo, and Chulhee Choi. "Strategies for Targeted Delivery of Exosomes to the Brain: Advantages and Challenges." Pharmaceutics 14, no. 3 (March 18, 2022): 672. http://dx.doi.org/10.3390/pharmaceutics14030672.
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Delivering therapeutics to the central nervous system (CNS) is difficult because of the blood–brain barrier (BBB). Therapeutic delivery across the tight junctions of the BBB can be achieved through various endogenous transportation mechanisms. Receptor-mediated transcytosis (RMT) is one of the most widely investigated and used methods. Drugs can hijack RMT by expressing specific ligands that bind to receptors mediating transcytosis, such as the transferrin receptor (TfR), low-density lipoprotein receptor (LDLR), and insulin receptor (INSR). Cell-penetrating peptides and viral components originating from neurotropic viruses can also be utilized for the efficient BBB crossing of therapeutics. Exosomes, or small extracellular vesicles, have gained attention as natural nanoparticles for treating CNS diseases, owing to their potential for natural BBB crossing and broad surface engineering capability. RMT-mediated transport of exosomes expressing ligands such as LDLR-targeting apolipoprotein B has shown promising results. Although surface-modified exosomes possessing brain targetability have shown enhanced CNS delivery in preclinical studies, the successful development of clinically approved exosome therapeutics for CNS diseases requires the establishment of quantitative and qualitative methods for monitoring exosomal delivery to the brain parenchyma in vivo as well as elucidation of the mechanisms underlying the BBB crossing of surface-modified exosomes.
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Martano, Simona, Valeria De Matteis, Mariafrancesca Cascione, and Rosaria Rinaldi. "Inorganic Nanomaterials Versus Polymer-Based Nanoparticles for Overcoming Neurodegeneration." Nanomaterials 12, no. 14 (July 7, 2022): 2337. http://dx.doi.org/10.3390/nano12142337.
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Neurodegenerative disorders (NDs) affect a great number of people worldwide and also have a significant socio-economic impact on the aging population. In this context, nanomedicine applied to neurological disorders provides several biotechnological strategies and nanoformulations that improve life expectancy and the quality of life of patients affected by brain disorders. However, available treatments are limited by the presence of the blood–brain barrier (BBB) and the blood–cerebrospinal fluid barrier (B–CSFB). In this regard, nanotechnological approaches could overcome these obstacles by updating various aspects (e.g., enhanced drug-delivery efficiency and bioavailability, BBB permeation and targeting the brain parenchyma, minimizing side effects). The aim of this review is to carefully explore the key elements of different neurological disorders and summarize the available nanomaterials applied for neurodegeneration therapy looking at several types of nanocarriers. Moreover, nutraceutical-loaded nanoparticles (NPs) and synthesized NPs using green approaches are also discussed underling the need to adopt eco-friendly procedures with a low environmental impact. The proven antioxidant properties related to several natural products provide an interesting starting point for developing efficient and green nanotools useful for neuroprotection.
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Bhattacharya, Tanima, Giselle Amanda Borges e. Soares, Hitesh Chopra, Md Mominur Rahman, Ziaul Hasan, Shasank S. Swain, and Simona Cavalu. "Applications of Phyto-Nanotechnology for the Treatment of Neurodegenerative Disorders." Materials 15, no. 3 (January 21, 2022): 804. http://dx.doi.org/10.3390/ma15030804.
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The strategies involved in the development of therapeutics for neurodegenerative disorders are very complex and challenging due to the existence of the blood-brain barrier (BBB), a closely spaced network of blood vessels and endothelial cells that functions to prevent the entry of unwanted substances in the brain. The emergence and advancement of nanotechnology shows favourable prospects to overcome this phenomenon. Engineered nanoparticles conjugated with drug moieties and imaging agents that have dimensions between 1 and 100 nm could potentially be used to ensure enhanced efficacy, cellular uptake, specific transport, and delivery of specific molecules to the brain, owing to their modified physico-chemical features. The conjugates of nanoparticles and medicinal plants, or their components known as nano phytomedicine, have been gaining significance lately in the development of novel neuro-therapeutics owing to their natural abundance, promising targeted delivery to the brain, and lesser potential to show adverse effects. In the present review, the promising application, and recent trends of combined nanotechnology and phytomedicine for the treatment of neurological disorders (ND) as compared to conventional therapies, have been addressed. Nanotechnology-based efforts performed in bioinformatics for early diagnosis as well as futuristic precision medicine in ND have also been discussed in the context of computational approach.
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Gondim, Brenna Louise Cavalcanti, Jonatas da Silva Catarino, Marlos Aureliano Dias de Sousa, Mariana de Oliveira Silva, Marcela Rezende Lemes, Tamires Marielem de Carvalho-Costa, Tatiana Rita de Lima Nascimento, et al. "Nanoparticle-Mediated Drug Delivery: Blood-Brain Barrier as the Main Obstacle to Treating Infectious Diseases in CNS." Current Pharmaceutical Design 25, no. 37 (December 17, 2019): 3983–96. http://dx.doi.org/10.2174/1381612825666191014171354.
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Background: Parasitic infections affecting the central nervous system (CNS) present high morbidity and mortality rates and affect millions of people worldwide. The most important parasites affecting the CNS are protozoans (Plasmodium sp., Toxoplasma gondii, Trypanosoma brucei), cestodes (Taenia solium) and free-living amoebae (Acantamoeba spp., Balamuthia mandrillaris and Naegleria fowleri). Current therapeutic regimens include the use of traditional chemicals or natural compounds that have very limited access to the CNS, despite their elevated toxicity to the host. Improvements are needed in drug administration and formulations to treat these infections and to allow the drug to cross the blood-brain barrier (BBB). Methods: This work aims to elucidate the recent advancements in the use of nanoparticles as nanoscaled drug delivery systems (NDDS) for treating and controlling the parasitic infections that affect the CNS, addressing not only the nature and composition of the polymer chosen, but also the mechanisms by which these nanoparticles may cross the BBB and reach the infected tissue. Results: There is a strong evidence in the literature demonstrating the potential usefulness of polymeric nanoparticles as functional carriers of drugs to the CNS. Some of them demonstrated the mechanisms by which drugloaded nanoparticles access the CNS and control the infection by using in vivo models, while others only describe the pharmacological ability of these particles to be utilized in in vitro environments. Conclusion: The scarcity of the studies trying to elucidate the compatibility as well as the exact mechanisms by which NDDS might be entering the CNS infected by parasites reveals new possibilities for further exploratory projects. There is an urgent need for new investments and motivations for applying nanotechnology to control parasitic infectious diseases worldwide.
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Behl, Tapan, Aditi Sharma, Lalit Sharma, Aayush Sehgal, Sukhbir Singh, Neelam Sharma, Gokhan Zengin, et al. "Current Perspective on the Natural Compounds and Drug Delivery Techniques in Glioblastoma Multiforme." Cancers 13, no. 11 (June 2, 2021): 2765. http://dx.doi.org/10.3390/cancers13112765.
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Glioblastoma multiforme (GBM) is one of the debilitating brain tumors, being associated with extremely poor prognosis and short median patient survival. GBM is associated with complex pathogenesis with alterations in various cellular signaling events, that participate in cell proliferation and survival. The impairment in cellular redox pathways leads to tumorigenesis. The current standard pharmacological regimen available for glioblastomas, such as radiotherapy and surgical resection following treatment with chemotherapeutic drug temozolomide, remains fatal, due to drug resistance, metastasis and tumor recurrence. Thus, the demand for an effective therapeutic strategy for GBM remains elusive. Hopefully, novel products from natural compounds are suggested as possible solutions. They protect glial cells by reducing oxidative stress and neuroinflammation, inhibiting proliferation, inducing apoptosis, inhibiting pro-oncogene events and intensifying the potent anti-tumor therapies. Targeting aberrant cellular pathways in the amelioration of GBM could promote the development of new therapeutic options that improve patient quality of life and extend survival. Consequently, our review emphasizes several natural compounds in GBM treatment. We also assessed the potential of drug delivery techniques such as nanoparticles, Gliadel wafers and drug delivery using cellular carriers which could lead to a novel path for the obliteration of GBM.
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Panzarini, Elisa, Stefania Mariano, Stefano Tacconi, Elisabetta Carata, Ada Maria Tata, and Luciana Dini. "Novel Therapeutic Delivery of Nanocurcumin in Central Nervous System Related Disorders." Nanomaterials 11, no. 1 (December 22, 2020): 2. http://dx.doi.org/10.3390/nano11010002.
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Nutraceuticals represent complementary or alternative beneficial products to the expensive and high-tech therapeutic tools in modern medicine. Nowadays, their medical or health benefits in preventing or treating different types of diseases is widely accepted, due to fewer side effects than synthetic drugs, improved bioavailability and long half-life. Among herbal and natural compounds, curcumin is a very attractive herbal supplement considering its multipurpose properties. The potential effects of curcumin on glia cells and its therapeutic and protective properties in central nervous system (CNS)-related disorders is relevant. However, curcumin is unstable and easily degraded or metabolized into other forms posing limits to its clinical development. This is particularly important in brain pathologies determined blood brain barrier (BBB) obstacle. To enhance the stability and bioavailability of curcumin, many studies focused on the design and development of curcumin nanodelivery systems (nanoparticles, micelles, dendrimers, and diverse nanocarriers). These nanoconstructs can increase curcumin stability, solubility, in vivo uptake, bioactivity and safety. Recently, several studies have reported on a curcumin exosome-based delivery system, showing great therapeutical potential. The present work aims to review the current available data in improving bioactivity of curcumin in treatment or prevention of neurological disorders.
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Zhi, Kaining, Babatunde Raji, Anantha R. Nookala, Mohammad Moshahid Khan, Xuyen H. Nguyen, Swarna Sakshi, Tayebeh Pourmotabbed, et al. "PLGA Nanoparticle-Based Formulations to Cross the Blood–Brain Barrier for Drug Delivery: From R&D to cGMP." Pharmaceutics 13, no. 4 (April 6, 2021): 500. http://dx.doi.org/10.3390/pharmaceutics13040500.
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The blood–brain barrier (BBB) is a natural obstacle for drug delivery into the human brain, hindering treatment of central nervous system (CNS) disorders such as acute ischemic stroke, brain tumors, and human immunodeficiency virus (HIV)-1-associated neurocognitive disorders. Poly(lactic-co-glycolic acid) (PLGA) is a biocompatible polymer that is used in Food and Drug Administration (FDA)-approved pharmaceutical products and medical devices. PLGA nanoparticles (NPs) have been reported to improve drug penetration across the BBB both in vitro and in vivo. Poly(ethylene glycol) (PEG), poly(vinyl alcohol) (PVA), and poloxamer (Pluronic) are widely used as excipients to further improve the stability and effectiveness of PLGA formulations. Peptides and other linkers can be attached on the surface of PLGA to provide targeting delivery. With the newly published guidance from the FDA and the progress of current Good Manufacturing Practice (cGMP) technologies, manufacturing PLGA NP-based drug products can be achieved with higher efficiency, larger quantity, and better quality. The translation from bench to bed is feasible with proper research, concurrent development, quality control, and regulatory assurance.
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Prakashkumar, Nallasamy, Bhagavathi Sundaram Sivamaruthi, Chaiyavat Chaiyasut, and Natarajan Suganthy. "Decoding the Neuroprotective Potential of Methyl Gallate-Loaded Starch Nanoparticles against Beta Amyloid-Induced Oxidative Stress-Mediated Apoptosis: An In Vitro Study." Pharmaceutics 13, no. 3 (February 25, 2021): 299. http://dx.doi.org/10.3390/pharmaceutics13030299.
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Alzheimer’s disease (AD) is a multifaceted neuronal disorder and a challenge to medical practitioners, as the blood–brain barrier (BBB) acts as a major obstacle for drug delivery to the brain. Development of a nanomaterial-based drug delivery system (DDS) paved a way to penetrate the BBB. Starch, a ubiquitous natural biopolymer, has received much attention as a DDS due to its biocompatibility, biodegradability and eco-friendly nature. The present study focuses on encapsulating methyl gallate (MG) within starch nanoparticles (starch-encapsulated MG (SEMG)) and assesses its neuroprotective potential against β-amyloid (Aβ)-induced toxicity, the key factor for AD pathogenesis in Neuro2A cells. SEMG showed potent acetylcholinesterase inhibitory, antioxidant activity and anti-amyloidogenic activity by attenuating the fibrillation of Aβ and destabilizing the preformed mature fibrils. Furthermore, SEMG also attenuated the cytotoxic effect induced by Aβ in Neuro2A cells (50% inhibitory concentration 18.25 ± 0.025 μg/mL) by mitigating reactive oxygen species (ROS)-mediated macromolecular damage, restoring mitochondrial membrane potential and attenuating apoptosis. Characterization of SEMG revealed amorphous rock-shaped structure with average particle size of 264.6 nm, exhibiting 83% loading efficiency and sustained release of drug, with 73% release within 24 h at physiological pH. Overall, the outcome of the present study signifies starch as a promising nanocarrier for the delivery of drugs for the treatment of AD.
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Straehla, Joelle, Cynthia Hajal, Hannah Safford, Giovanni Offeddu, Jeffrey Wyckoff, Roger Kamm, and Paula Hammond. "EXTH-26. LAYER-BY-LAYER NANOPARTICLES DESIGNED FOR DUAL BLOOD-BRAIN BARRIER AND GLIOMA TARGETING." Neuro-Oncology 23, Supplement_6 (November 2, 2021): vi168—vi169. http://dx.doi.org/10.1093/neuonc/noab196.665.
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Abstract BACKGROUND While biologically diverse, high grade gliomas (HGGs) have a dismal prognosis in both adults and children. Promising therapeutics have been identified for HGGs based on common genomic alterations and aberrant signaling pathways, but achieving effective drug exposure at the tumor site remains a challenge largely due to the blood-brain barrier (BBB). HYPOTHESIS: A tunable nanocarrier platform can improve nanoparticle delivery across the (BBB) and into glioma cells. METHODS We synthesized layer-by-layer nanoparticles by coating anionic, fluorescent liposomes with nanometers-thick layers of oppositely charged polyelectrolytes, creating a library of organic, nontoxic drug carriers with varied surface chemistries. We characterized the library using dynamic light scattering and quantified interactions with a range of pediatric and adult glioma cell lines using flow cytometry. We used intravital two-photon microscopy to quantify nanoparticle trafficking across the intact BBB through a cranial window in anesthetized mice. RESULTS Nanoparticle surface chemistry strongly influences cellular trafficking in vitro, with two polymers identified as particularly high-performing across brain tumors lines: poly-L-aspartic acid (semi-synthetic) and hyaluronic acid (natural polysaccharide). The addition of the angiopep-2 targeting moiety onto these polymers improved nanoparticle uptake into brain microvascular endothelial cells in vitro without abrogating tumor affinity. We developed a new algorithm to quantify permeability of fluorescent compounds across the BBB in vivo and validated our method by measuring dextran permeability at varied molecular weights. In our initial study in non-tumor-bearing mice (n=12), we successfully quantified nanoparticle permeability across the BBB. In this study, surface functionalization did not increase BBB permeability above the control nanoparticle, though it did improve nanoparticle half-life in circulation and may still impart a therapeutic benefit when loaded with drug. Additional investigations in orthotopic tumor-bearing mice are ongoing. In summary, we report the development of layer-by-layer nanocarriers as a modular drug delivery platform with therapeutic potential for gliomas.
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Boissinot, Marjorie, Sarra Limam, Maria Collado-González, Yadira Gonzalez-Espinosa, Heiko Wurdak, Francisco M. Goycoolea, and Susan C. Short. "Non-viral delivery of therapeutic microRNAs to glioma cells using chitosan nanocomplexes." Neuro-Oncology 21, Supplement_4 (October 2019): iv16. http://dx.doi.org/10.1093/neuonc/noz167.068.
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Abstract One of the biggest challenges when treating brain tumours is achieving efficient delivery of therapeutic agents to the brain and more specifically to the cancer cells. MicroRNA-1300 was identified in our group as a very promising therapeutic microRNA given its cytotoxic effect when introduced in both established as well as cancer-stem-like patient-derived glioblastoma cultures, while not affecting differentiated glioblastoma cells. We are now collaborating to assess the potential efficiency of the natural biopolymer chitosan to form nanocomplexes containing the mature form of microRNA-1300 for delivery. Chitosan has been established as a highly attractive biocompatible polymer to deliver both in vitro and in vivo therapeutic nucleotides intracellularly. In previous studies, we have shown chitosan’s efficacy to form spherical nanocomplexes with microRNA and apply them to the downregulation of JAMA-A mRNA in MCF-7 breast cancer cells. Chitosan can also be chemically conjugated to introduce affinity towards a wide range of cellular targets (e.g. with aptamers). Methods We have optimised of the composition and characterised the biophysical properties of chitosan-microRNA nanocomplexes of varying (+/-) charge ratios using both a control nontargeting microRNA coupled to a fluorochrome (CS-miRdy547, efficiency of cell entry) and mature microRNA-1300 (CS-mi1300, efficient release and biological effect). We have tested the nanocomplexes in 2D monolayers and 3D spheroid cultures on established U251 as well as two patient-derived cultures. Reverse transfection was used as positive control. Results The control nanoparticles of CS-miRdy547 are taken up by the patient-derived cultures in 2D and 3D. Analysis is ongoing using the CS-miR-1300 nanoparticles.
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Chan, Ming-Hsien, Wen-Tse Huang, Aishwarya Satpathy, Ting-Yi Su, Michael Hsiao, and Ru-Shi Liu. "Progress and Viewpoints of Multifunctional Composite Nanomaterials for Glioblastoma Theranostics." Pharmaceutics 14, no. 2 (February 21, 2022): 456. http://dx.doi.org/10.3390/pharmaceutics14020456.
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The most common malignant tumor of the brain is glioblastoma multiforme (GBM) in adults. Many patients die shortly after diagnosis, and only 6% of patients survive more than 5 years. Moreover, the current average survival of malignant brain tumors is only about 15 months, and the recurrence rate within 2 years is almost 100%. Brain diseases are complicated to treat. The reason for this is that drugs are challenging to deliver to the brain because there is a blood–brain barrier (BBB) protection mechanism in the brain, which only allows water, oxygen, and blood sugar to enter the brain through blood vessels. Other chemicals cannot enter the brain due to their large size or are considered harmful substances. As a result, the efficacy of drugs for treating brain diseases is only about 30%, which cannot satisfy treatment expectations. Therefore, researchers have designed many types of nanoparticles and nanocomposites to fight against the most common malignant tumors in the brain, and they have been successful in animal experiments. This review will discuss the application of various nanocomposites in diagnosing and treating GBM. The topics include (1) the efficient and long-term tracking of brain images (magnetic resonance imaging, MRI, and near-infrared light (NIR)); (2) breaking through BBB for drug delivery; and (3) natural and chemical drugs equipped with nanomaterials. These multifunctional nanoparticles can overcome current difficulties and achieve progressive GBM treatment and diagnosis results.
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Grilc, Nina Katarina, Matej Sova, and Julijana Kristl. "Drug Delivery Strategies for Curcumin and Other Natural Nrf2 Modulators of Oxidative Stress-Related Diseases." Pharmaceutics 13, no. 12 (December 12, 2021): 2137. http://dx.doi.org/10.3390/pharmaceutics13122137.
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Oxidative stress is associated with a wide range of diseases characterised by oxidant-mediated disturbances of various signalling pathways and cellular damage. The only effective strategy for the prevention of cellular damage is to limit the production of oxidants and support their efficient removal. The implication of the nuclear factor erythroid 2-related factor 2 (Nrf2) pathway in the cellular redox status has spurred new interest in the use of its natural modulators (e.g., curcumin, resveratrol). Unfortunately, most natural Nrf2 modulators are poorly soluble and show extensive pre-systemic metabolism, low oral bioavailability, and rapid elimination, which necessitates formulation strategies to circumvent these limitations. This paper provides a brief introduction on the cellular and molecular mechanisms involved in Nrf2 modulation and an overview of commonly studied formulations for the improvement of oral bioavailability and in vivo pharmacokinetics of Nrf2 modulators. Some formulations that have also been studied in vivo are discussed, including solid dispersions, self-microemulsifying drug delivery systems, and nanotechnology approaches, such as polymeric and solid lipid nanoparticles, nanocrystals, and micelles. Lastly, brief considerations of nano drug delivery systems for the delivery of Nrf2 modulators to the brain, are provided. The literature reviewed shows that the formulations discussed can provide various improvements to the bioavailability and pharmacokinetics of natural Nrf2 modulators. This has been demonstrated in animal models and clinical studies, thereby increasing the potential for the translation of natural Nrf2 modulators into clinical practice.
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Lico, Chiara, Barbara Tanno, Luca Marchetti, Flavia Novelli, Paola Giardullo, Caterina Arcangeli, Simonetta Pazzaglia, et al. "Tomato Bushy Stunt Virus Nanoparticles as a Platform for Drug Delivery to Shh-Dependent Medulloblastoma." International Journal of Molecular Sciences 22, no. 19 (September 29, 2021): 10523. http://dx.doi.org/10.3390/ijms221910523.
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Medulloblastoma (MB) is a primary central nervous system tumor affecting mainly young children. New strategies of drug delivery are urgent to treat MB and, in particular, the SHH-dependent subtype—the most common in infants—in whom radiotherapy is precluded due to the severe neurological side effects. Plant virus nanoparticles (NPs) represent an innovative solution for this challenge. Tomato bushy stunt virus (TBSV) was functionally characterized as a carrier for drug targeted delivery to a murine model of Shh-MB. The TBSV NPs surface was genetically engineered with peptides for brain cancer cell targeting, and the modified particles were produced on a large scale using Nicotiana benthamiana plants. Tests on primary cultures of Shh-MB cells allowed us to define the most efficient peptides able to induce specific uptake of TBSV. Immunofluorescence and molecular dynamics simulations supported the hypothesis that the specific targeting of the NPs was mediated by the interaction of the peptides with their natural partners and reinforced by the presentation in association with the virus. In vitro experiments demonstrated that the delivery of Doxorubicin through the chimeric TBSV allowed reducing the dose of the chemotherapeutic agent necessary to induce a significant decrease in tumor cells viability. Moreover, the systemic administration of TBSV NPs in MB symptomatic mice, independently of sex, confirmed the ability of the virus to reach the tumor in a specific manner. A significant advantage in the recognition of the target appeared when TBSV NPs were functionalized with the CooP peptide. Overall, these results open new perspectives for the use of TBSV as a vehicle for the targeted delivery of chemotherapeutics to MB in order to reduce early and late toxicity.
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Piazzini, Vieri, Elisa Landucci, Giulia Graverini, Domenico Pellegrini-Giampietro, Anna Bilia, and Maria Bergonzi. "Stealth and Cationic Nanoliposomes as Drug Delivery Systems to Increase Andrographolide BBB Permeability." Pharmaceutics 10, no. 3 (August 13, 2018): 128. http://dx.doi.org/10.3390/pharmaceutics10030128.
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(1) Background: Andrographolide (AG) is a natural compound effective for the treatment of inflammation-mediated neurodegenerative disorders. The aim of this investigation was the preparation of liposomes to enhance the penetration into the brain of AG, by modifying the surface of the liposomes by adding Tween 80 (LPs-AG) alone or in combination with Didecyldimethylammonium bromide (DDAB) (CLPs-AG). (2) Methods: LPs-AG and CLPs-AG were physically and chemically characterized. The ability of liposomes to increase the permeability of AG was evaluated by artificial membranes (PAMPA) and hCMEC/D3 cells. (3) Results: Based on obtained results in terms of size, homogeneity, ζ-potential and EE%. both liposomes are suitable for parenteral administration. The systems showed excellent stability during a month of storage as suspensions or freeze-dried products. Glucose resulted the best cryoprotectant agent. PAMPA and hCMEC/D3 transport studies revealed that LPs-AG and CLPs-AG increased the permeability of AG, about an order of magnitude, compared to free AG without alterations in cell viability. The caveolae-mediated endocytosis resulted the main mechanism of up-take for both formulations. The presence of positive charge increased the cellular internalization of nanoparticles. (4) Conclusions: This study shows that developed liposomes might be ideal candidates for brain delivery of AG.
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Cayero-Otero, Maria Dolores, Ana M. Espinosa-Oliva, Antonio J. Herrera, Irene Garcia-Dominguez, Mercedes Fernandez-Arevalo, Lucia Martin-Banderas, and Rocio M. de Pablos. "Potential Use of Nanomedicine for the Anti-inflammatory Treatment of Neurodegenerative Diseases." Current Pharmaceutical Design 24, no. 14 (July 13, 2018): 1589–616. http://dx.doi.org/10.2174/1381612824666180403113015.
Full textAbstract:
Neurodegenerative diseases, like Alzheimer´s and Parkinson´s disease, are a group of disorders that have in common their increasingly high prevalence along with the shortage of effective treatments. In addition, the scientific community faces the challenge of getting the drugs used in these treatments to cross the blood-brain barrier (BBB) and reach the brain in sufficient concentration to be able to exert its effect. Hence, researchers across multiple disciplines are working together in order to improve the ability of therapeutics to penetrate the BBB. In this sense, the use of nanomedicine, nanoscale structures for drug delivery, exhibits a really high therapeutic potential in the field of neurodegenerative diseases therapy. Since there is new evidence that neuroinflammation produced by reactive microglia contributes to the activation and pathogenesis of neurological disorders, many investigations focus on the identification of new targets whose inhibition can reduce, totally or partially, microglial activation. This review analyzes a wide variety of compounds as possible candidates to achieve this target, from compounds with a natural origin to anti-diabetics, antidepressants, antibiotics and hormones. We also discuss the different strategies to enhance the capacity of these compounds to cross the BBB. Although this review focuses on PLGA nanoparticles as one of the most versatile drug delivery nanosystems, we also describe other strategies, such as direct intranasal administration (nose-tobrain), novel viral vectors and novel implanted catheters.
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Dastmalchi, Farhad, Aida Karachi, Yusuf Mehkri, Ashley O’Malley, Vignesh Subramaniam, Thomas Angelini, Duane Mitchell, and Maryam Rahman. "IMMU-20. HYDROGEL-CXCL9 VACCINE RESULTS IN MRNA DELIVERY TO DENDRITIC CELLS AND POTENT ANTI-TUMOR RESPONSES IN GBM." Neuro-Oncology 23, Supplement_6 (November 2, 2021): vi96. http://dx.doi.org/10.1093/neuonc/noab196.379.
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Abstract INTRODUCTION Our group and others have shown mRNA-vaccines have significant anti-tumor efficacy in the treatment of brain tumors and are currently being tested in first-in-human trials. To further enhance mRNA delivery, a hydrogel platform was developed with the addition of CXCL9 to promote immune cell trafficking. METHODS We generated the vaccine by utilizing a hydrogel platform. CXCL9 and Nano-mRNA were loaded into the hydrogel. In vitro recruitment of DCs and NK was evaluated by fluorescence microscopy. In vivo recruitment of immune cells was analyzed by flowcytometry after collecting the fat pad, spleen, and tumor samples from KR158b-luc and Gl261-gp100 tumor-bearing animals 3, 5 and 10 days after vaccine delivery. The efficacy of the vaccine was evaluated by measuring overall survival, and tumor growth was measured by IVIS live-imaging. RESULTS Dendritic cells(DCs) and natural killer(NK) cells were able to efficiently migrate within the hydrogel-CXCL9 platform and uptake and express mRNA in vivo. In vitro, the hydrogel-CXCL9 was combined with nanoparticles loaded with total tumor RNA, and the vaccine was delivered to KR-158-luc and GL261-gp100 tumor-bearing animals via mammary fat pad SQ injection. Flow cytometry of the fat pad and draining lymph nodes demonstrated showed significant recruitment of endogenous DCs including inflammatory-DC(P= 0.0035), conventional-DC1(P= 0.0076), pDC(P=0.0028), NK(p= 0.0025 compared to the control group. In two different tumor models, a single dose of the vaccine resulted in significant survival benefits compared to control animals (n=10,P< 0.0001). SQ injection was superior to intracranial injection of the vaccine. Vaccinated animals showed an increased number of antigen-specific CD8 T cells in spleen(P= 0.0001) and tumor-microenvironment(P= 0.0070). CONCLUSION The hydrogel-CXCL9 platform results in efficient delivery of mRNA loaded nanoparticles to endogenous DCs and also causes an upregulation of NK cells with resultant improved survival in murine GBM models including the highly resistant KR158 model with a single dose. Further studies are ongoing.
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Varlamova, Elena G., Venera V. Khabatova, Sergey V. Gudkov, Egor Y. Plotnikov, and Egor A. Turovsky. "Cytoprotective Properties of a New Nanocomplex of Selenium with Taxifolin in the Cells of the Cerebral Cortex Exposed to Ischemia/Reoxygenation." Pharmaceutics 14, no. 11 (November 16, 2022): 2477. http://dx.doi.org/10.3390/pharmaceutics14112477.
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The neuroprotective effect of the natural antioxidant taxifolin (TAX) is well known for ischemic pathologies. However, the limitations of taxifolin application are described—poor solubility, low ability to penetrate the blood–brain barrier, and side effects from high doses for stroke therapy. We proposed the problem of targeted delivery of taxifolin and achievement effective concentrations could be solved by developing a nanocomplex of selenium nanoparticles (SeNPs) with taxifolin (Se–TAX). In this study, we developed a selenium–taxifolin nanocomplex based on selenium nanoparticles with a 100 nm size. It was shown that TAX, SeNPs, and Se–TAX were all able to suppress the production of ROS in neurons and astrocytes under exposure to exogenous H2O2 and ischemia-like conditions. However, the Se–TAX nanocomplex appeared to be the most effective, displaying a lower working concentration range and negligible pro-oxidant effect compared with pure SeNPs. The mechanism of Se–TAX beneficial effects involved the activation of some antioxidant enzymes and the suppression of ROS-generating systems during OGD/reoxygenation, while TAX and “naked” SeNPs were less effective in regulating the cellular redox status. Naked SeNPs inhibited a global increase in Ca2+ ions in cytosol, but not OGD-induced hyperexcitation of the neuroglial network, while Se–TAX suppressed both [Ca2+]i rise and hyperexcitation. The effect of TAX at similar doses appeared exclusively in inhibiting OGD-induced hyperexcitation. Analysis of necrosis and apoptosis after OGD/reoxygenation revealed the highest efficiency of the Se–TAX nanocomplex as well. Se–TAX suppressed the expression of proinflammatory and proapoptotic proteins with simultaneous activation of protective genes. We conclude that the Se–TAX nanocomplex combines the antioxidative features taxifolin and the antiapoptotic effect of nanoselenium, involving the regulation of Ca2+ dynamics.
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Maffei, Massimo E. "Magnetic Fields and Cancer: Epidemiology, Cellular Biology, and Theranostics." International Journal of Molecular Sciences 23, no. 3 (January 25, 2022): 1339. http://dx.doi.org/10.3390/ijms23031339.
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Humans are exposed to a complex mix of man-made electric and magnetic fields (MFs) at many different frequencies, at home and at work. Epidemiological studies indicate that there is a positive relationship between residential/domestic and occupational exposure to extremely low frequency electromagnetic fields and some types of cancer, although some other studies indicate no relationship. In this review, after an introduction on the MF definition and a description of natural/anthropogenic sources, the epidemiology of residential/domestic and occupational exposure to MFs and cancer is reviewed, with reference to leukemia, brain, and breast cancer. The in vivo and in vitro effects of MFs on cancer are reviewed considering both human and animal cells, with particular reference to the involvement of reactive oxygen species (ROS). MF application on cancer diagnostic and therapy (theranostic) are also reviewed by describing the use of different magnetic resonance imaging (MRI) applications for the detection of several cancers. Finally, the use of magnetic nanoparticles is described in terms of treatment of cancer by nanomedical applications for the precise delivery of anticancer drugs, nanosurgery by magnetomechanic methods, and selective killing of cancer cells by magnetic hyperthermia. The supplementary tables provide quantitative data and methodologies in epidemiological and cell biology studies. Although scientists do not generally agree that there is a cause-effect relationship between exposure to MF and cancer, MFs might not be the direct cause of cancer but may contribute to produce ROS and generate oxidative stress, which could trigger or enhance the expression of oncogenes.
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Taori, Suchet, Breanna Noffsinger, Charlotte A. Miller, Aizhen Xiao, Laryssa Manigat, Qing Zhong, Tajie Harris, and Benjamin Purow. "Abstract 4205: Staged anti-PD-1 therapy with intratumoral recombinant calreticulin improves anti-tumor immunity and survival in glioblastoma mouse models." Cancer Research 82, no. 12_Supplement (June 15, 2022): 4205. http://dx.doi.org/10.1158/1538-7445.am2022-4205.
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Abstract Background: Glioblastoma (GBM), the most common and lethal primary brain tumor, has a median survival of a mere 15 months and leads to approximately 12,000 deaths in the US annually. Targeted and combinatorial-based clinical trial therapies have shown poor efficacy in GBM treatment, partly due to the restrictive nature of the blood-brain barrier, an immunosuppressive tumor microenvironment, GBM’s heterogeneity and adaptability, and GBM’s ability to metastasize and invade critical regions of the brain. However, promising recent literature has indicated that neoadjuvant anti-PD-1 checkpoint-inhibition immunotherapy - i.e., starting it right before surgery for recurrence - improves survival outcomes in human GBM patients. Results: Here, we demonstrate a proposed mechanism of action wherein localized intratumoral danger-associated molecular pattern (DAMP, a known immunogenic driver) injection of calreticulin - used to mimic natural DAMP release from necrotic cells during surgery - combined with neoadjuvant anti-PD-1 immunotherapy leads to better survival outcomes in both orthotopic mouse CT2A and CT2A-Luc GBM models. This survival benefit is also seen in a more aggressive (larger tumor inoculation size) orthotopic CT2A-Luc GBM model. Flow cytometry indicates increased microglia cell counts and activation marker expression, and increased myeloid activation marker expression in mice brains treated with our combination immunotherapy in a CT2A GBM model. Additionally, in vivo treatment with our combination immunotherapy led to increases in the local T and NK cell numbers, the CD8:CD4 ratio, and the proliferation of CD4 T cells in mice brains of a CT2A GBM model. In vitro results suggest that co-culture with CT2A cells increased PD-1 expression in macrophages and microglia and that our combination treatment of calreticulin and anti-PD-1 immunotherapy reduces the viability of mouse GBM cells when mixed with macrophages. Significance: This project paves the path for a novel immunotherapeutic approach to tackle GBM and other cancers. Future studies could incorporate relevant DAMP’s into nanoparticles for sustained release after intratumoral injection and possibly viral delivery of DAMP’s that are constitutively secreted, thereby prolonging an anticipated immune response. Citation Format: Suchet Taori, Breanna Noffsinger, Charlotte A. Miller, Aizhen Xiao, Laryssa Manigat, Qing Zhong, Tajie Harris, Benjamin Purow. Staged anti-PD-1 therapy with intratumoral recombinant calreticulin improves anti-tumor immunity and survival in glioblastoma mouse models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 4205.
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Freire, Carla, Huy Pho, Jacob Ramsey, Stone Streeter, Ryo Kojima, Slava Berger, Thomaz Fleury-Curado, et al. "003 Treatment of Sleep Disordered Breathing with Leptin Loaded Exosomes." Sleep 44, Supplement_2 (May 1, 2021): A1—A2. http://dx.doi.org/10.1093/sleep/zsab072.002.
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Abstract Introduction Obstructive sleep apnea (OSA) is characterized by recurrent periods of upper airway obstruction. The prevalence of OSA exceeds 50% in obese individuals and in 10–20% of obese patients OSA coexists with obesity hypoventilation syndrome (OHS) defined as daytime hypercapnia and hypoventilation during sleep attributed to the depressed control of breathing. There is no effective pharmacotherapy for OSA and OHS. Leptin is a potent respiratory stimulant and a potential therapeutic candidate. However, diet-induced obesity (DIO) results in reduced permeability of the blood-brain barrier (BBB) for leptin. Previous studies have shown that the BBB can be penetrated by exosomes, natural nanoparticles that can be used as drug delivery vehicles. In this study, we aimed to determine if exosomes overcome the BBB and treat OSA and OHS in DIO mice. Methods o examine the ability of exosomes to cross the BBB, male, lean (n=5) and DIO (n=5) C57BL/6J mice were injected with fluorescent exosomes or saline into the lateral tail vein. After 4h fluorescent exosomes biodistribution was evaluated by an in vitro imaging system (IVIS). Saline injected mice images were used for background adjustment. A separate subgroup of male, DIO (n=10) and lean (n=10) mice were headmounted with EEG and nuchal EMG leads. Sleep studies were performed in a plethysmography chamber and mice received saline, empty exosomes, free leptin, or leptin-loaded exosomes in a crossover manner. Results Exosomes were successfully delivered to the brain and the transport across the BBB was more efficient in DIO mice with 2-times greater relative fluorescence units measured in DIO when compared to lean mice (p<0.005). In DIO mice, exosomal leptin induced dramatic 1.7-2.2-fold increases in minute ventilation and 1.5-2.0-fold increases in maximal inspiratory flow during both flow-limited (upper airway/sleep apnea) and non-flow limited breathing (control of breathing) (p<0.05). In contrast, free leptin had no effect. Lean mice did not present significant sleep disordered breathing and no differences were observed between groups. Conclusion We demonstrated that exosomes overcome the BBB and that leptin-loaded exosomes treat OSA and OHS in DIO mice. Support (if any) R01HL 128970, R01HL 138932, R61 HL156240, U18 DA052301, FAPESP 2018/08758-3
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Gregory, Jason V., Padma Kadiyala, Robert Doherty, Melissa Cadena, Samer Habeel, Erkki Ruoslahti, Pedro R. Lowenstein, Maria G. Castro, and Joerg Lahann. "Systemic brain tumor delivery of synthetic protein nanoparticles for glioblastoma therapy." Nature Communications 11, no. 1 (November 10, 2020). http://dx.doi.org/10.1038/s41467-020-19225-7.
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Abstract Glioblastoma (GBM), the most aggressive form of brain cancer, has witnessed very little clinical progress over the last decades, in part, due to the absence of effective drug delivery strategies. Intravenous injection is the least invasive drug delivery route to the brain, but has been severely limited by the blood-brain barrier (BBB). Inspired by the capacity of natural proteins and viral particulates to cross the BBB, we engineered a synthetic protein nanoparticle (SPNP) based on polymerized human serum albumin (HSA) equipped with the cell-penetrating peptide iRGD. SPNPs containing siRNA against Signal Transducer and Activation of Transcription 3 factor (STAT3i) result in in vitro and in vivo downregulation of STAT3, a central hub associated with GBM progression. When combined with the standard of care, ionized radiation, STAT3i SPNPs result in tumor regression and long-term survival in 87.5% of GBM-bearing mice and prime the immune system to develop anti-GBM immunological memory.
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Xie, Jiaxi, Cailing Zhong, Tingting Wang, Dan He, Luyang Lu, Jie Yang, Ziyi Yuan, and Jingqing Zhang. "Better Bioactivity, Cerebral Metabolism and Pharmacokinetics of Natural Medicine and Its Advanced Version." Frontiers in Pharmacology 13 (June 27, 2022). http://dx.doi.org/10.3389/fphar.2022.937075.
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Currently, many people are afflicted by cerebral diseases that cause dysfunction in the brain and perturb normal daily life of people. Cerebral diseases are greatly affected by cerebral metabolism, including the anabolism and catabolism of neurotransmitters, hormones, neurotrophic molecules and other brain-specific chemicals. Natural medicines (NMs) have the advantages of low cost and low toxicity. NMs are potential treatments for cerebral diseases due to their ability to regulate cerebral metabolism. However, most NMs have low bioavailability due to their low solubility/permeability. The study is to summarize the better bioactivity, cerebral metabolism and pharmacokinetics of NMs and its advanced version. This study sums up research articles on the NMs to treat brain diseases. NMs affect cerebral metabolism and the related mechanisms are revealed. Nanotechnologies are applied to deliver NMs. Appropriate delivery systems (exosomes, nanoparticles, liposomes, lipid polymer hybrid nanoparticles, nanoemulsions, protein conjugation and nanosuspensions, etc.) provide better pharmacological and pharmacokinetic characteristics of NMs. The structure-based metabolic reactions and enzyme-modulated catalytic reactions related to advanced versions of NMs alter the pharmacological activities of NMs.
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Ngu, Alice, Shu Wang, Haichuan Wang, Afsana Khanam, and Janos Zempleni. "Milk exosomes in nutrition and drug delivery." American Journal of Physiology-Cell Physiology, March 23, 2022. http://dx.doi.org/10.1152/ajpcell.00029.2022.
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Exosomes are natural nanoparticles that originate in the endocytic system. Exosomes play an important role in cell-to-cell communication by transferring RNAs, lipids and proteins from donor cells to recipient cells or by binding to receptors on the recipient cell surface. The concentration of exosomes and the diversity of cargos is high in milk, and they resist degradation in the gastrointestinal tract and during processing of milk in dairy plants, are absorbed and accumulate in tissues following oral administrations, cross the blood-brain barrier, and dietary depletion and supplementation elicit phenotypes. These features have sparked the interest of the nutrition and pharmacology communities for exploring milk exosomes as novel bioactive food compounds and for delivering drugs to diseased tissues. This review discusses the current knowledgebase, uncertainties, and controversies in these lines of scholarly endeavor and health research.
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Dar, Ghulam Hassan, Raied Badierah, Erica G. Nathan, Mohmad Abass Bhat, Abid Hamid Dar, and Elrashdy M. Redwan. "Extracellular vesicles: A new paradigm in understanding, diagnosing and treating neurodegenerative disease." Frontiers in Aging Neuroscience 14 (November 3, 2022). http://dx.doi.org/10.3389/fnagi.2022.967231.
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Neurodegenerative disorders (NDs) are becoming one of the leading causes of disability and death across the globe due to lack of timely preventions and treatments. Concurrently, intensive research efforts are being carried out to understand the etiology of these age-dependent disorders. Extracellular vesicles (EVs)—biological nanoparticles released by cells—are gaining tremendous attention in understanding their role in pathogenesis and progression of NDs. EVs have been found to transmit pathogenic proteins of NDs between neurons. Moreover, the ability of EVs to exquisitely surmount natural biological barriers, including blood-brain barrier and in vivo safety has generated interest in exploring them as potential biomarkers and function as natural delivery vehicles of drugs to the central nervous system. However, limited knowledge of EV biogenesis, their heterogeneity and lack of adequate isolation and analysis tools have hampered their therapeutic potential. In this review, we cover the recent advances in understanding the role of EVs in neurodegeneration and address their role as biomarkers and delivery vehicles to the brain.
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Li, Yi-Xuan, Hong-Bo Wang, Jian-Bo Jin, Chun-Lin Yang, Jing-Bo Hu, and Jing Li. "Advances in the research of nano delivery systems in ischemic stroke." Frontiers in Bioengineering and Biotechnology 10 (October 21, 2022). http://dx.doi.org/10.3389/fbioe.2022.984424.
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Ischemic stroke is the most common type of cerebrovascular disease with high disability rate and mortality. The blood-brain barrier (BBB) protects the homeostasis of the brain’s microenvironment and impedes the penetration of 98% of drugs. Therefore, effective treatment requires the better drug transport across membranes and increased drug distribution. Nanoparticles are a good choice for drugs to cross BBB. The main pathways of nano delivery systems through BBB include passive diffusion, adsorption-mediated endocytosis, receptor-mediated transport, carrier-mediated transport, etc. At present, the materials used in brain-targeted delivery can be divided into natural polymer, synthetic polymers, inorganic materials and phospholipid. In this review, we first introduced several ways of nano delivery systems crossing the BBB, and then summarized their applications in ischemic stroke. Based on their potential and challenges in the treatment of ischemic stroke, new ideas and prospects are proposed for designing feasible and effective nano delivery systems.
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Zhu, Feng-Dan, Yu-Jiao Hu, Lu Yu, Xiao-Gang Zhou, Jian-Ming Wu, Yong Tang, Da-Lian Qin, Qing-Ze Fan, and An-Guo Wu. "Nanoparticles: A Hope for the Treatment of Inflammation in CNS." Frontiers in Pharmacology 12 (May 26, 2021). http://dx.doi.org/10.3389/fphar.2021.683935.
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Neuroinflammation, an inflammatory response within the central nervous system (CNS), is a main hallmark of common neurodegenerative diseases, including Alzheimer’s disease (AD), Parkinson’s disease (PD), and amyotrophic lateral sclerosis (ALS), among others. The over-activated microglia release pro-inflammatory cytokines, which induces neuronal death and accelerates neurodegeneration. Therefore, inhibition of microglia over-activation and microglia-mediated neuroinflammation has been a promising strategy for the treatment of neurodegenerative diseases. Many drugs have shown promising therapeutic effects on microglia and inflammation. However, the blood–brain barrier (BBB)—a natural barrier preventing brain tissue from contact with harmful plasma components—seriously hinders drug delivery to the microglial cells in CNS. As an emerging useful therapeutic tool in CNS-related diseases, nanoparticles (NPs) have been widely applied in biomedical fields for use in diagnosis, biosensing and drug delivery. Recently, many NPs have been reported to be useful vehicles for anti-inflammatory drugs across the BBB to inhibit the over-activation of microglia and neuroinflammation. Therefore, NPs with good biodegradability and biocompatibility have the potential to be developed as an effective and minimally invasive carrier to help other drugs cross the BBB or as a therapeutic agent for the treatment of neuroinflammation-mediated neurodegenerative diseases. In this review, we summarized various nanoparticles applied in CNS, and their mechanisms and effects in the modulation of inflammation responses in neurodegenerative diseases, providing insights and suggestions for the use of NPs in the treatment of neuroinflammation-related neurodegenerative diseases.
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Heidarzadeh, Morteza, Yasemin Gürsoy-Özdemir, Mehmet Kaya, Aysan Eslami Abriz, Amir Zarebkohan, Reza Rahbarghazi, and Emel Sokullu. "Exosomal delivery of therapeutic modulators through the blood–brain barrier; promise and pitfalls." Cell & Bioscience 11, no. 1 (July 22, 2021). http://dx.doi.org/10.1186/s13578-021-00650-0.
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AbstractNowadays, a large population around the world, especially the elderly, suffers from neurological inflammatory and degenerative disorders/diseases. Current drug delivery strategies are facing different challenges because of the presence of the BBB, which limits the transport of various substances and cells to brain parenchyma. Additionally, the low rate of successful cell transplantation to the brain injury sites leads to efforts to find alternative therapies. Stem cell byproducts such as exosomes are touted as natural nano-drug carriers with 50–100 nm in diameter. These nano-sized particles could harbor and transfer a plethora of therapeutic agents and biological cargos to the brain. These nanoparticles would offer a solution to maintain paracrine cell-to-cell communications under healthy and inflammatory conditions. The main question is that the existence of the intact BBB could limit exosomal trafficking. Does BBB possess some molecular mechanisms that facilitate the exosomal delivery compared to the circulating cell? Although preliminary studies have shown that exosomes could cross the BBB, the exact molecular mechanism(s) beyond this phenomenon remains unclear. In this review, we tried to compile some facts about exosome delivery through the BBB and propose some mechanisms that regulate exosomal cross in pathological and physiological conditions.
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Woon, Choy Ker, Wong Kah Hui, Razif Abas, Muhammad Huzaimi Haron, Srijit Das, and Teoh Seong Lin. "Natural product-based nanomedicine: Recent advances and issues for the treatment of Alzheimer's disease." Current Neuropharmacology 20 (December 17, 2021). http://dx.doi.org/10.2174/1570159x20666211217163540.
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: Alzheimer's disease (AD) affects the elderly and is characterized by progressive neurodegeneration caused by different pathologies. The most significant challenges in treating AD include the inability of medications to reach the brain because of its poor solubility, low bioavailability, and the presence of the blood-brain barrier (BBB). Additionally, current evidence suggests the disruption of BBB plays an important role in the pathogenesis of AD. One of the critical challenges in treating AD is the ineffective treatments and its severe adverse effects. Nanotechnology offers an alternative approach to facilitate the treatment of AD by overcoming the challenges in drug transport across the BBB. Various nanoparticles (NP) loaded with natural products were reported to aid in drug delivery for the treatment of AD. The nano- sized entities of NP are great platforms for incorporating active materials from natural products into formulations that can be delivered effectively to the intended action site without compromising the material’s bioactivity. The review highlights the applications of medicinal plants, their derived components, and various nanomedicine-based approaches for the treatment of AD. The combination of medicinal plants and nanotechnology may lead to new theragnostic solutions for the treatment of AD in the future.