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    Near-infrared light-responsive, pramipexole-loaded biodegradable PLGA microspheres for therapeutic use in Parkinson's disease. Li Shuang,Liu Jiaxin,Li Ge,Zhang Xueyan,Xu Fei,Fu Zhijiang,Teng Lesheng,Li Youxin,Sun Fengying European journal of pharmaceutics and biopharmaceutics : official journal of Arbeitsgemeinschaft fur Pharmazeutische Verfahrenstechnik e.V Parkinson's disease (PD) is associated with symptoms such as tremor and bradykinesia which, together with a rigorous dosing regimen, can place an untenable burden on patients. These issues underscore the need for triggerable, modulated drug delivery systems. Currently, pramipexole (PRX) is the most widely used non-ergot dopamine agonist for the treatment of PD. In this study, near-infrared light-responsive PRX and hollow gold nanospheres (HGNS)-loaded biodegradable poly (D, L-lactide-co-glycolide) (PLGA) microspheres (PRX/HGNS MS) were fabricated using solid-in-oil-in-water (S/O/W) and water-in-oil-in-water (W/O/W) emulsion-solvent evaporation techniques to achieve modulated drug release. The PRX/HGNS MS were uniform, with an average diameter of approximately 24 µm, favorable PRX and HGNS encapsulation efficiencies (51.71 ± 0.54% and 65.15 ± 2.30%, respectively) and rapid, controllable drug release both in vitro and in vivo. Cytotoxicity tests revealed no significant differences between HGNS and PRX/HGNS MS when compared with a negative control. Pharmacodynamics and immunohistochemistry studies revealed a more rapid recovery of striatum in the group treated with PRX/HGNS MS produced using the S/O/W method. The results clearly demonstrate that light-responsive PRX/HGNS MS produced using the S/O/W method have the potential to address PD patients' mobility problems in a smart, controllable and remotely triggerable manner. 10.1016/j.ejpb.2019.05.013
    Gold nanoclusters for Parkinson's disease treatment. Gao Guanbin,Chen Rui,He Meng,Li Jing,Li Jing,Wang Liyun,Sun Taolei Biomaterials Drug discovery for Parkinson's disease (PD) is challenging. Here we report that gold nanoclusters (AuNCs) can serve as a novel candidate for the design of anti-PD drugs. With N-isobutyryl-l-cysteine (L-NIBC) protected AuNCs as an example, we show that AuNCs effectively prevent α-Synuclein (α-Syn) fibrillation in in vitro experiments. Cell experiments demonstrate good neuroprotective effects in PD cell models. More significantly, experiments of mouse PD model further show that AuNCs largely ameliorate the behavioral disorders of sick mice. In addition, immunohistochemical and western blot (WB) analyses indicate that AuNCs can significantly reverse dopaminergic (DA) neuron loss in substantia nigra and striatum of sick mice. This study opens up a novel avenue to develop anti-PD drugs and points a new direction for AuNCs in medicinal applications. 10.1016/j.biomaterials.2018.12.013
    Neuronal mitochondria-targeted therapy for Alzheimer's disease by systemic delivery of resveratrol using dual-modified novel biomimetic nanosystems. Han Yang,Chu Xiaoyang,Cui Lin,Fu Shiyao,Gao Chunsheng,Li Yi,Sun Baoshan Drug delivery Reactive oxygen species (ROS)-induced neuronal mitochondrial dysfunction is a key pathologic factor in sporadic Alzheimer's disease (AD). Neuronal mitochondria have been proposed to be a promising therapeutic target for AD, especially for the failures of phase III clinical trials on conventional amyloid-β (Aβ) targeted therapy. However, the efficient intravenous delivery of therapeutic agents to neuronal mitochondria in the brain remains a major challenge due to the complicated physiological environment. Recently, biomaterials-based nanomedicine has been widely investigated for the treatment of AD. Herein, we devised a strategy for functional antioxidant delivery to neuronal mitochondria by loading antioxidants into red blood cell (RBC) membrane-coated nanostructured lipid carriers (NLC) bearing rabies virus glycoprotein (RVG29) and triphenylphosphine cation (TPP) molecules attached to the RBC membrane surface (RVG/TPP NPs@RBCm). With the advantage of suitable physicochemical properties of NLC and unique biological functions of the RBC membrane, RVG/TPP NPs@RBCm are stabilized and enabled sustained drug release, providing improved biocompatibility and long-term circulation. Under the synergistic effects of RVG29 and TPP, RVG/TPP NPs@RBCm can not only penetrate the blood-brain barrier (BBB) but also target neuron cells and further localize in the mitochondria. After encapsulating Resveratrol (RSV) as the model antioxidant, the data demonstrated that RVG/TPP-RSV NPs@RBCm can relieve AD symptoms by mitigating Aβ-related mitochondrial oxidative stress both and . The memory impairment in APP/PS1 mice is significantly improved following the systemic administration of RVG/TPP-RSV NPs@RBCm. In conclusion, intravenous neuronal mitochondria-targeted dual-modified novel biomimetic nanosystems are a promising therapeutic candidate for ROS-induced mitochondrial dysfunction in AD. 10.1080/10717544.2020.1745328
    The Role of the SLC Transporters Protein in the Neurodegenerative Disorders. Ayka Asli,Şehirli Ahmet Özer Clinical psychopharmacology and neuroscience : the official scientific journal of the Korean College of Neuropsychopharmacology The solute carrier (SLC) superfamily is one of the major sub-groups of membrane proteins in mammalian cells. The solute carrier proteins include more than 400 different membrane-spanning solute carriers organized with 65 families in the human. In solute carrier family neurons, neurotransmitter is considered to be a pharmacological target of neuropsychiatric drugs because of their important role in the recovery of neurotransmitters such as GABA, glutamate, serotonin, dopamine and noradrenaline and regulation of their concentration in synaptic regions. Therefore, solute carrier transporters play vital and different roles in neurodegenerative disorders. In this article, the role of solute carrier transporters in neurodegenerative disorders such as Alzheimer disease, amyotrophic lateral sclerosis, Huntington disease, Parkinson's diseases, depression, post-traumatic stress disorder, dementia, schizophrenia, and Epilepsy reviewed and discussed to see how defects or absences in SLC transporter cause neurodegenerative disorders. In this review, we try to summarize what is known about solute carriers with respect to brain distribution and expression. The review summarizes current knowledge on the roles of solute carrier transporters in neurodegenerative disorders. 10.9758/cpn.2020.18.2.174
    α-Synuclein Oligomer Detection with Aptamer Switch on Reduced Graphene Oxide Electrode. Jang Seung Joo,Lee Chang-Seuk,Kim Tae Hyun Nanomaterials (Basel, Switzerland) Protein aggregation of alpha-synuclein (α-Syn) is implicated in Parkinson's disease (PD), and, thus, α-Syn aggregates are a potentially promising candidate biomarker for PD diagnosis. Here, we describe a simple and sensitive electrochemical sensor to monitor the aggregation of α-Syn for early PD diagnosis. The sensor utilizes methylene blue (MB)-tagged aptamer (Apt) adsorbed on electrochemically reduced graphene oxide (ERGO) by π-π stacking. The binding of α-Syn oligomer to the Apt induces desorption of the Apt from the ERGO surface, which leads to the electrochemical signal change. The resulting sensor allowed the highly sensitive and selective detection of α-Syn oligomer according to the voltammetric change. Under optimized conditions, the linear range of detection was observed to be from 1 fM to 1 nM of the α-Syn oligomer and the limit of detection (LOD) was estimated to be 0.64 fM based on S/N = 3. The sensor also showed good reproducibility and stability, enabling real sample analysis of the α-Syn oligomer in human blood serum. With its ultrasensitivity and good performance for α-Syn oligomer detection, the sensor provides one promising tool for the early diagnosis of PD. 10.3390/nano10050832
    Methylene blue protects dopaminergic neurons against MPTP-induced neurotoxicity by upregulating brain-derived neurotrophic factor. Bhurtel Sunil,Katila Nikita,Neupane Sabita,Srivastav Sunil,Park Pil-Hoon,Choi Dong-Young Annals of the New York Academy of Sciences The relatively old, yet clinically used, drug methylene blue (MB) is known to possess neuroprotective properties by reducing aggregated proteins, augmenting the antioxidant response, and enhancing mitochondrial function and survival in various models of neurodegenerative diseases. In this study, we aimed to examine the effects of MB in Parkinson's disease (PD) in vivo and in vitro models by using 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)/1-methyl-4-phenylpyridinium (MPP ) with a focus on possible effects on induction of neurotrophic factors. Our results indicate that pretreatment with MB significantly attenuated MPTP-induced loss of dopaminergic neurons, glial cell activation, and depletion of dopamine. We also found that MB upregulated brain-derived neurotrophic factor (BDNF) and activated its downstream signaling pathways, suggesting that BDNF might be a contributor to MB-associated neuroprotection. Specific inhibition of the BDNF receptor or extracellular signal-regulated kinase (Erk) reversed the MB-mediated protection against MPP toxicity, thus implying a role for BDNF and the Erk pathway in the neuroprotective effects. Taken together, our data suggest that MB protects neurons from MPTP neurotoxicity via induction of BDNF. Further study to determine whether MB preserves dopaminergic neurons in the brains of PD patients is warranted. 10.1111/nyas.13870
    Targeting the Brain with a Neuroprotective Omega-3 Fatty Acid to Enhance Neurogenesis in Hypoxic Condition in Culture. Lo Van Amanda,Sakayori Nobuyuki,Hachem Mayssa,Belkouch Mounir,Picq Madeleine,Fourmaux Baptiste,Lagarde Michel,Osumi Noriko,Bernoud-Hubac Nathalie Molecular neurobiology Docosahexaenoic acid (DHA, 22:6n-3) is an essential omega-3 polyunsaturated fatty acid (PUFA) that is required for proper brain development and cerebral functions. While DHA deficiency in the brain was shown to be linked to the emergence of cerebral diseases, a dietary intake of omega-3 PUFA could prevent or attenuate neurologic disturbances linked with aging or neurodegenerative diseases. In this context, targeting the brain with DHA might offer great promise in developing new therapeutics for neurodegenerative diseases. We previously synthesized a stabilized form of DHA-containing lysophosphatidylcholine a major vector of DHA transportation to the brain, which is 1-acetyl,2-docoshexaenoyl-glycerophosphocholine, named AceDoPC®. Injection of AceDoPC® or DHA after experimental ischemic stroke showed that both molecules had neuroprotective effects but AceDoPC® was the most potent. This study aims to investigate the beneficial effects of DHA either unesterified or esterified within AceDoPC® on a model of neurogenesis in vitro, under physiological or pathological conditions. The effect of protectin DX (PDX, a double lipoxygenase product of DHA) was also tested. We cultured neural stem progenitor cells (NSPCs) derived from the adult mouse brain under normal or hypoxigenic (ischemic) conditions in vitro. Neurogenesis study of cell cultures with AceDoPC® showed enhanced neurogenesis compared to addition of unesterified DHA, PDX, or vehicle control, especially under pathological conditions. Our studies of the potential mechanisms involved in neuroprotection hinted that AceDoPC® neuroprotective and regenerative effects might be due in part to its anti-oxidative effects. These results indicate the potential for novel therapeutics against stroke that target the brain. 10.1007/s12035-018-1139-0
    Brain targeting with docosahexaenoic acid as a prospective therapy for neurodegenerative diseases and its passage across blood brain barrier. Hachem Mayssa,Belkouch Mounir,Lo Van Amanda,Picq Madeleine,Bernoud-Hubac Nathalie,Lagarde Michel Biochimie Docosahexaenoic acid (DHA, 22:6n-3) is the main omega-3 polyunsaturated fatty acid in brain tissues necessary for common brain growth and function. DHA can be provided to the body through two origins: an exogenous origin, from direct dietary intakes and an endogenous one, from the bioconversion of the essential α-linolenic acid (ALA, 18:3n-3) in the liver. In humans, the biosynthesis of DHA from its precursor ALA is very low. A reduction in the cerebral amount of DHA is detected in patients suffering from neurodegenerative diseases such as Alzheimer's and Parkinson's diseases. Considering the vital functions of DHA for the brain, new methodologies to target the brain with DHA offers encouraging perceptions in the improvement of precautionary and therapeutic approaches for neurodegenerative diseases. The aim of the present review was to provide better understanding of the cerebral uptake of DHA in different form including free fatty acids, Lysophosphatidylcholines LysoPC-DHA as well as structured phospholipids. First, we explored the special structure of the blood-brain barrier BBB, BBB being a physical and metabolic barrier with restrictive properties. Then, we discussed the incorporation of DHA into the membrane phospholipids of the brain, the neuroprotective and therapeutic effect of DHA for neurological diseases. 10.1016/j.biochi.2020.01.013
    Design and Development of Lomustine Loaded Chitosan Nanoparticles for Efficient Brain Targeting. Anand Anupriya,Iyer Bharadhwaj Ramesh,Ponnusamy Chandrasekar,Pandiyan Rajesh,Sugumaran Abimanyu Cardiovascular & hematological agents in medicinal chemistry AIMS:The present research work discussed the preparation of lomustine loaded with chitosan nanoparticles (LNCp) by ionic gelation method with homogenization using the design on experiments by Box-Behnken design. METHODS:The nanoparticles are evaluated by particle size, zeta potential, surface morphology, drug content, entrapment efficiency and in-vitro drug release. RESULTS:The FT-IR results support that drug have no interaction with excipients, which are used in the preparation of nanoparticle. The particle size, drug content and encapsulation efficiency of the developed nanoparticles ranged from 190 to 255 nm, 80.88% to 94.02%, and 77.12 to 88.74%, respectively. The drug release rate is diffusion-controlled over 8 hours. The F-value for all of the responses shows that the models are significant. The p-value, less than 0.05 for all the responses reveals the significance of the models. Graphical optimisation is done by desirability plot and overlay plot, which contains optimal values of independent variables with the desirability of 1. CONCLUSION:In conclusion, the results suggested that the optimised lomustine loaded chitosan nanoparticles are useful for brain targeting hence hold the potential for further research and clinical application. 10.2174/1871525718666200203112502
    Dual functionalized brain-targeting nanoinhibitors restrain temozolomide-resistant glioma via attenuating EGFR and MET signaling pathways. Meng Xiangqi,Zhao Yu,Han Bo,Zha Caijun,Zhang Yangong,Li Ziwei,Wu Pengfei,Qi Tengfei,Jiang Chuanlu,Liu Yang,Cai Jinquan Nature communications Activation of receptor tyrosine kinase (RTK) protein is frequently observed in malignant progression of gliomas. In this study, the crosstalk activation of epidermal growth factor receptor (EGFR) and mesenchymal-epithelial transition factor (MET) signaling pathways is demonstrated to contribute to temozolomide (TMZ) resistance, resulting in an unfavorable prognosis for patients with glioblastoma. To simultaneously mitigate EGFR and MET activation, a dual functionalized brain-targeting nanoinhibitor, BIP-MPC-NP, is developed by conjugating Inherbin3 and cMBP on the surface of NHS-PEG-Mal modified MPC-nanoparticles. In the presence of BIP-MPC-NP, DNA damage repair is attenuated and TMZ sensitivity is enhanced via the down-regulation of E2F1 mediated by TTP in TMZ resistant glioma. In vivo magnetic resonance imaging (MRI) shows a significant repression in tumor growth and a prolonged survival of mice after injection of the BIP-MPC-NP and TMZ. These results demonstrate the promise of this nanoinhibitor as a feasible strategy overcoming TMZ resistance in glioma. 10.1038/s41467-019-14036-x
    An overview of nanomedicines for neuron targeting. Garcia-Chica Jesus,D Paraiso West Kristian,Tanabe Shihori,Serra Dolors,Herrero Laura,Casals Núria,Garcia Jordi,Ariza Xavier,Quader Sabina,Rodriguez-Rodriguez Rosalia Nanomedicine (London, England) Medical treatments of neuron-related disorders are limited due to the difficulty of targeting brain cells. Major drawbacks are the presence of the blood-brain barrier and the lack of specificity of the drugs for the diseased cells. Nanomedicine-based approaches provide promising opportunities for overcoming these limitations. Although many previous reviews are focused on brain targeting with nanomedicines in general, none of those are concerned explicitly on the neurons, while targeting neuronal cells in central nervous diseases is now one of the biggest challenges in nanomedicine and neuroscience. We review the most relevant advances in nanomedicine design and strategies for neuronal drug delivery that might successfully bridge the gap between laboratory and bedside treatment in neurology. 10.2217/nnm-2020-0088
    Formulation Strategies of Nano Lipid Carrier for Effective Brain Targeting of Anti-AD Drugs. Alexander Amit,Agrawal Mukta,Saraf Swarnlata,Saraf Shailendra,Ajazuddin ,Chougule Mahavir B Current pharmaceutical design NLC is a next-generation lipid nanocarrier, which holds many advantages over other colloidal lipid carrier systems like higher drug loading, better and controlled release and enhanced stability. Owing to the unique structural composition, i.e. crystallized solid and liquid lipid blend, it offers excellent biocompatibility and higher permeation across physiological membranes like BBB. Moreover, the surface of NLC can easily be modified with target-specific ligands, proteins, peptides, etc. which makes it a potential candidate for brain targeting of CNS acting drugs. NLC has found various applications for the treatment of various CNS disorders including Alzheimer's disease, Parkinson's disease, schizophrenia, epilepsy, migraine, cerebral ischemia, etc. Among these, the application of NLC towards the treatment of AD has been well-explored in the past two decades. In this piece of work, we have discussed the types of NLC, its composition, fabrication techniques, characterization, stability profile and application in the treatment of AD. 10.2174/1381612826666200212120947
    Intranasal delivery of paeoniflorin nanocrystals for brain targeting. Wu Chaoyin,Li Benyue,Zhang Yi,Chen Tingting,Chen Chuangrong,Jiang Wei,Wang Qi,Chen Tongkai Asian journal of pharmaceutical sciences Paeoniflorin (PA) is an anti-Parkinson Chinese medicine with inferior bioavailability and difficulty in delivery to the brain. This research is to develop an efficacious PA nanocrystal formulation (PA-NCs) that is suitable for intranasal administration to treat Parkinson's disease (PD). PA-NCs were fabricated through an antisolvent precipitation method using TPGS as the stabilizer. The rod-shaped PA-NCs had particle size of 139.6 ± 1.3 nm and zeta potential of -23.2 ± 0.529 mV. A molecular dynamics simulation indicated that van der Waals forces are the primary drivers of interactions between PA and TPGS. In the nasal mucosa permeation assay, the cumulative drug release at 24 h was 87.14% ± 5.34%, which was significantly higher than that of free PA. PA-NCs exhibited substantially improved cellular uptake as well as permeability on Calu-3 cells as compared to PA alone. FRET imaging analysis demonstrated that intact NCs could be internalized into Calu-3 cells. Moreover, PA-NCs conferred desirable protective effect against MPP-induced SH-SY5Y cellular damage. Pharmacokinetic studies revealed a higher PA concentration in the brain following intranasal delivery of PA-NCs. In summary, the intranasal administration of PA-NCs is a promising treatment strategy for PD. 10.1016/j.ajps.2019.11.002
    Recent expansions of novel strategies towards the drug targeting into the brain. Alexander Amit,Agrawal Mukta,Uddin Ajaz,Siddique Sabahuddin,Shehata Ahmed M,Shaker Mahmoud A,Ata Ur Rahman Syed,Abdul Mohi Iqbal M,Shaker Mohamed A International journal of nanomedicine The treatment of central nervous system (CNS) disorders always remains a challenge for the researchers. The presence of various physiological barriers, primarily the blood-brain barrier (BBB) limits the accessibility of the brain and hinders the efficacy of various drug therapies. Hence, drug targeting to the brain, particularly to the diseased cells by circumventing the physiological barriers is essential to develop a promising therapy for the treatment of brain disorders. Presently, the investigations emphasize the role of different nanocarrier systems or surface modified target specific novel carrier system to improve the efficiency and reduce the side effects of the brain therapeutics. Such approaches supposed to circumvent the BBB or have the ability to cross the barrier function and thus increases the drug concentration in the brain. Although the efficacy of novel carrier system depends upon various physiological factors like active efflux transport, protein corona of the brain, stability, and toxicity of the nanocarrier, physicochemical properties, patient-related factors and many more. Hence, to develop a promising carrier system, it is essential to understand the physiology of the brain and BBB and also the other associated factors. Along with this, some alternative route like direct nose-to-brain drug delivery can also offer a better means to access the brain without exposure of the BBB. In this review, we have discussed the role of various physiological barriers including the BBB and blood-cerebrospinal fluid barrier (BCSFB) on the drug therapy and the mechanism of drug transport across the BBB. Further, we discussed different novel strategies for brain targeting of drug including, polymeric nanoparticles, lipidic nanoparticles, inorganic nanoparticles, liposomes, nanogels, nanoemulsions, dendrimers, quantum dots, etc. along with the intranasal drug delivery to the brain. We have also illustrated various factors affecting the drug targeting efficiency of the developed novel carrier system. 10.2147/IJN.S210876
    Liposome-based targeting of dopamine to the brain: a novel approach for the treatment of Parkinson's disease. Kahana Meygal,Weizman Abraham,Gabay Martin,Loboda Yelena,Segal-Gavish Hadar,Gavish Avishai,Barhum Yael,Offen Dani,Finberg John,Allon Nahum,Gavish Moshe Molecular psychiatry Delivery of drugs into the brain is poor due to the blood brain barrier (BBB). This study describes the development of a novel liposome-based brain-targeting drug delivery system. The liposomes incorporate a diacylglycerol moiety coupled through a linker to a peptide of 5 amino acids selected from amyloid precursor protein (APP), which is recognized by specific transporter(s)/receptor(s) in the BBB. This liposomal system enables the delivery of drugs across the BBB into the brain. The brain-directed liposomal system was used in a mouse model of Parkinson's disease (PD). Intra-peritoneal (IP) administration of liposomes loaded with dopamine (DA) demonstrated a good correlation between liposomal DA dose and the behavioral effects in hemiparkinsonian amphetamine-treated mice, with an optimal DA dose of 60 µg/kg. This is significantly lower dose than commonly used doses of the DA precursor levodopa (in the mg/kg range). IP injection of the APP-targeted liposomes loaded with a DA dose of 800 µg/kg, resulted in a significant increase in striatal DA within 5 min (6.9-fold, p < 0.05), in amphetamine-treated mice. The increase in striatal DA content persisted for at least 3 h after administration, which indicates a slow DA release from the delivery system. No elevation in DA content was detected in the heart or the liver. Similar increases in striatal DA were observed also in rats and mini-pigs. The liposomal delivery system enables penetration of compounds through the BBB and may be a candidate for the treatment of PD and other brain diseases. 10.1038/s41380-020-0742-4
    Preparation, characterization, and optimization of asenapine maleate mucoadhesive nanoemulsion using Box-Behnken design: In vitro and in vivo studies for brain targeting. Kumbhar Santosh Ashok,Kokare Chandrakant R,Shrivastava Birendra,Gorain Bapi,Choudhury Hira International journal of pharmaceutics The tight junctions between capillary endothelial cells of the blood-brain barrier (BBB) restricts the entry of therapeutics into the brain. Potential of the intranasal delivery tool has been explored in administering the therapeutics directly to the brain, thus bypassing BBB. The objective of this study was to develop and optimize an intranasal mucoadhesive nanoemulsion (MNE) of asenapine maleate (ASP) in order to enhance the nasomucosal adhesion and direct brain targetability for improved efficacy and safety. Box-Behnken statistical design was used to recognize the crucial formulation variables influencing droplet size, size distribution and surface charge of ASP-NE. ASP-MNE was obtained by incorporating GRAS mucoadhesive polymer, Carbopol 971 in the optimized NE. Optimized ASP-MNE displayed spherical morphology with a droplet size of 21.2 ± 0.15 nm and 0.355 polydispersity index. Improved ex-vivo permeation was observed in ASP-NE and ASP-MNE, compared to the ASP-solution. Finally, the optimized formulation was found to be safe in ex-vivo ciliotoxicity study on sheep nasal mucosa. The single-dose pharmacokinetic study in male Wistar rats revealed a significant increase in concentration of ASP in the brain upon intranasal administration of ASP-MNE, with a maximum of 284.33 ± 5.5 ng/mL. The time required to reach maximum brain concentration (1 h) was reduced compared to intravenous administration of ASP-NE (3 h). Furthermore, it has been established during the course of present study, that the brain targeting capability of ASP via intranasal administration had enhanced drug-targeting efficiency and drug-targeting potential. In the animal behavioral studies, no extrapyramidal symptoms were observed after intranasal administration of ASP-MNE, while good locomotor activity and hind-limb retraction test established its antipsychotic activity in treated animals. Thus, it can be concluded that the developed intranasal ASP-MNE could be used as an effective and safe tool for brain targeting of ASP in the treatment of psychotic disorders. 10.1016/j.ijpharm.2020.119499
    Impact of rasagiline nanoparticles on brain targeting efficiency via gellan gum based transdermal patch: A nanotheranostic perspective for Parkinsonism. Bali Nikhil R,Salve Pramod S International journal of biological macromolecules Rasagiline mesylate is used as first line agent for early management of Parkinson's disease but its water soluble nature creates hurdles to cross blood brain barrier also its low oral bioavailability and rapid elimination requires frequent dosing. Thus present study aims to prepare rasagiline mesylate-nanoparticles (RM-NPs) loaded gellan gum transdermal film for non-invasive; self-administration in elderly patients. PLGA coated RM-NPs prepared by solvent evaporation technique were incorporated into film prepared by solvent casting method. Optimized films with 1.127 g gellan gum and 1.962 % linoleic acid showed enhanced ex-vivo diffusion over a period of 72 h. Comparative pharmacokinetic study revealed increased bioavailability of rasagiline on transdermal application compared to oral route. In-vivo anti-Parkinson activity estimated by behavioural and biochemical analysis indicate reserpine to interfere with monoamine storage hence resulting in development of akinesia and PD-like symptoms in rats. Brain targeting monitored by gamma imaging showed effective brain drug uptake from transdermal film which was also supported by increased brain targeting efficiency estimated from biodistribution study. Thus, the data support efficacy of gellan gum film to target drug to brain region compared to oral route and hence can be employed as a convenient approach for long-term treatment of Parkinson's disease in elderly patients. 10.1016/j.ijbiomac.2020.06.261
    A dual-ligand fusion peptide improves the brain-neuron targeting of nanocarriers in Alzheimer's disease mice. Guo Qian,Xu Shuting,Yang Peng,Wang Pengzhen,Lu Shuai,Sheng Dongyu,Qian Kang,Cao Jinxu,Lu Wei,Zhang Qizhi Journal of controlled release : official journal of the Controlled Release Society The presence of blood-brain barrier (BBB) and specificity of neuron targeting remain two challenges in the effective delivery of nanotherapeutics for the treatment of Alzheimers disease (AD). Traditional strategy of nanocarriers for AD treatment involves co-decoration of both BBB-penetrating ligand and neuron-targeting ligand on the surface of the nanoparticles for "dual-stage" targeted delivery. Instead, we design and optimize a fusion peptide TPL comprising a BBB-penetrating peptide TGN and a neuron binding peptide Tet1 through a four-glycine linker. Compared to the mono-ligand Tet1 or CGN which is the retro-inverso isomer of TGN with higher brain targeting than TGN, the dual-ligand fusion peptide TPL has preferable blood stability and enhanced structural flexibility, resulting in higher binding affinity to either GT1b ganglioside receptor or brain capillary endothelial bEnd.3 cells. The TPL-modified nanoparticles (TPL-NP) increased the BBB-penetration and neuron-targeting efficacy than the nanoparticles co-decorated with the two mono-ligands. Encapsulation of a neuroprotective peptide NAP, TPL-NP significantly enhance reactive oxygen species scavenging ability and effectively protect microtubule from Aβ-induced neurotoxicity. Meanwhile, TPL-NP inhibit okadaic acid-induced tau aggregation and neuronal apoptosis. Administration of TPL-NP in AD mice also significantly improves the cognitive performance, down-regulates the tau phosphorylation level, promotes axonal transport and attenuates microgliosis. Taken together, this work demonstrates that the rationally designed dual-ligand fusion peptides can greatly improve the delivery of drugs to the AD lesions, thereby markedly enhancing the efficacy of AD treatment. 10.1016/j.jconrel.2020.01.039
    Active Targeting Towards and Inside the Brain based on Nanoparticles: A Review. Rabiei Morteza,Kashanian Soheila,Samavati Seyedeh S,Jamasb Shahriar,McInnes Steven J P Current pharmaceutical biotechnology BACKGROUND:Treatment of neurological diseases using systemic and non-surgical techniques presents a significant challenge in medicine. This challenge is chiefly associated with the condensation and coherence of the brain tissue. METHODS:The coherence structure of the brain is due to the presence of the blood-brain barrier (BBB), which consists of a continuous layer of capillary endothelial cells. The BBB prevents most drugs from entering the brain tissue and is highly selective, permitting only metabolic substances and nutrients to pass through. RESULTS:Although this challenge has caused difficulties for the treatment of neurological diseases, it has opened up a broad research area in the field of drug delivery. Through the utilization of nanoparticles (NPs), nanotechnology can provide the ideal condition for passing through the BBB. CONCLUSION:NPs with suitable dimensions and optimum hydrophobicity and charge, as well as appropriate functionalization, can accumulate in the brain. Furthermore, NPs can facilitate the targeted delivery of therapeutics into the brain areas involved in Alzheimer's disease, Parkinson's disease, stroke, glioma, migraine, and other neurological disorders. This review describes these methods of actively targeting specific areas of the brain. 10.2174/1389201020666191203094057
    Recent strategies and advances in the fabrication of nano lipid carriers and their application towards brain targeting. Agrawal Mukta,Saraf Swarnlata,Saraf Shailendra,Dubey Sunil Kumar,Puri Anu,Patel Ravish J,Ajazuddin ,Ravichandiran V,Murty Upadhyayula Suryanarayana,Alexander Amit Journal of controlled release : official journal of the Controlled Release Society In last two decades, the lipid nanocarriers have been extensively investigated for their drug targeting efficiency towards the critical areas of the human body like CNS, cardiac region, tumor cells, etc. Owing to the flexibility and biocompatibility, the lipid-based nanocarriers, including nanoemulsion, liposomes, SLN, NLC etc. have gained much attention among various other nanocarrier systems for brain targeting of bioactives. Across different lipid nanocarriers, NLC remains to be the safest, stable, biocompatible and cost-effective drug carrier system with high encapsulation efficiency. Drug delivery to the brain always remains a challenging issue for scientists due to the complex structure and various barrier mechanisms surrounding the brain. The application of a suitable nanocarrier system and the use of any alternative route of drug administration like nose-to-brain drug delivery could overcome the hurdle and improves the therapeutic efficiency of CNS acting drugs thereof. NLC, a second-generation lipid nanocarrier, upsurges the drug permeation across the BBB due to its unique structural properties. The biocompatible lipid matrix and nano-size make it an ideal drug carrier for brain targeting. It offers many advantages over other drug carrier systems, including ease of manufacturing and scale-up to industrial level, higher drug targeting, high drug loading, control drug release, compatibility with a wide range of drug substances, non-toxic and non-irritant behavior. This review highlights recent progresses towards the development of NLC for brain targeting of bioactives with particular reference to its surface modifications, formulations aspects, pharmacokinetic behavior and efficacy towards the treatment of various neurological disorders like AD, PD, schizophrenia, epilepsy, brain cancer, CNS infection (viral and fungal), multiple sclerosis, cerebral ischemia, and cerebral malaria. This work describes in detail the role and application of NLC, along with its different fabrication techniques and associated limitations. Specific emphasis is given to compile a summary and graphical data on the area explored by scientists and researchers worldwide towards the treatment of neurological disorders with or without NLC. The article also highlights a brief insight into two prime approaches for brain targeting, including drug delivery across BBB and direct nose-to-brain drug delivery along with the current global status of specific neurological disorders. 10.1016/j.jconrel.2020.02.020
    Targeting the transferrin receptor for brain drug delivery. Johnsen Kasper Bendix,Burkhart Annette,Thomsen Louiza Bohn,Andresen Thomas Lars,Moos Torben Progress in neurobiology Obtaining efficient drug delivery to the brain remains the biggest challenge for the development of therapeutics to treat diseases of the central nervous system. The main obstacle is the blood-brain barrier (BBB), which impedes the entrance of most molecules present in the systemic circulation, especially large molecule drugs and nanomedicines. To overcome this obstacle, targeting strategies binding to nutrient receptors present at the luminal membrane of the BBB are frequently employed. Amongst the numerous potential targets at the BBB, the transferrin receptor (TfR) remains the most common target used to ensure sufficient drug delivery to the brain. In this review, we provide a full account on the use of the TfR as a target for brain drug delivery by describing the function of the TfR in the BBB, the historical background of its use in drug delivery, and the most recent evidence suggesting TfR-targeted medicines to be efficient for brain drug delivery with a clear clinical potential. 10.1016/j.pneurobio.2019.101665
    Sequential Targeting in Crosslinking Nanotheranostics for Tackling the Multibarriers of Brain Tumors. Wu Hao,Lu Hongwei,Xiao Wenwu,Yang Jinfan,Du Hongxu,Shen Yingbin,Qu Haijing,Jia Bei,Manna Suman K,Ramachandran Mythili,Xue Xiangdong,Ma Zhao,Xu Xiaobao,Wang Zhongling,He Yixuan,Lam Kit S,Zawadzki Robert J,Li Yuanpei,Lin Tzu-Yin Advanced materials (Deerfield Beach, Fla.) The efficacy of therapeutics for brain tumors is seriously hampered by multiple barriers to drug delivery, including severe destabilizing effects in the blood circulation, the blood-brain barrier/blood-brain tumor barrier (BBB/BBTB), and limited tumor uptake. Here, a sequential targeting in crosslinking (STICK) nanodelivery strategy is presented to circumvent these important physiological barriers to improve drug delivery to brain tumors. STICK nanoparticles (STICK-NPs) can sequentially target BBB/BBTB and brain tumor cells with surface maltobionic acid (MA) and 4-carboxyphenylboronic acid (CBA), respectively, and simultaneously enhance nanoparticle stability with pH-responsive crosslinkages formed by MA and CBA in situ. STICK-NPs exhibit prolonged circulation time (17-fold higher area under curve) than the free agent, allowing increased opportunities to transpass the BBB/BBTB via glucose-transporter-mediated transcytosis by MA. The tumor acidic environment then triggers the transformation of the STICK-NPs into smaller nanoparticles and reveals a secondary CBA targeting moiety for deep tumor penetration and enhanced uptake in tumor cells. STICK-NPs significantly inhibit tumor growth and prolong the survival time with limited toxicity in mice with aggressive and chemoresistant diffuse intrinsic pontine glioma. This formulation tackles multiple physiological barriers on-demand with a simple and smart STICK design. Therefore, these features allow STICK-NPs to unleash the potential of brain tumor therapeutics to improve their treatment efficacy. 10.1002/adma.201903759
    Chemical Targeting of Voltage Sensitive Dyes to Specific Cells and Molecules in the Brain. Fiala Tomas,Wang Jihang,Dunn Matthew,Šebej Peter,Choi Se Joon,Nwadibia Ekeoma C,Fialova Eva,Martinez Diana M,Cheetham Claire E,Fogle Keri J,Palladino Michael J,Freyberg Zachary,Sulzer David,Sames Dalibor Journal of the American Chemical Society Voltage sensitive fluorescent dyes (VSDs) are important tools for probing signal transduction in neurons and other excitable cells. The impact of these highly lipophilic sensors has, however, been limited due to the lack of cell-specific targeting methods in brain tissue or living animals. We address this key challenge by introducing a nongenetic molecular platform for cell- and molecule-specific targeting of synthetic VSDs in the brain. We employ a dextran polymer particle to overcome the inherent lipophilicity of VSDs by dynamic encapsulation and high-affinity ligands to target the construct to specific neuronal cells utilizing only native components of the neurotransmission machinery at physiological expression levels. Dichloropane, a monoamine transporter ligand, enables targeting of dense dopaminergic axons in the mouse striatum and sparse noradrenergic axons in the mouse cortex in acute brain slices. PFQX in conjunction with ligand-directed acyl imidazole chemistry enables covalent labeling of AMPA-type glutamate receptors in the same brain regions. Probe variants bearing either a classical electrochromic ANEP dye or state-of-the-art VoltageFluor-type dye respond to membrane potential changes in a similar manner to the parent dyes, as shown by whole-cell patch recording. We demonstrate the feasibility of optical voltage recording with our probes in brain tissue with one-photon and two-photon fluorescence microscopy and define the signal limits of optical voltage imaging with synthetic sensors under a low photon budget determined by the native expression levels of the target proteins. This work demonstrates the feasibility of a chemical targeting approach and expands the possibilities of cell-specific imaging and pharmacology. 10.1021/jacs.0c00861
    Novel peptide-conjugated nanomedicines for brain targeting: In vivo evidence. Duskey Jason T,Ottonelli Ilaria,Da Ros Federica,Vilella Antonietta,Zoli Michele,Kovachka Sandra,Spyrakis Francesca,Vandelli Maria A,Tosi Giovanni,Ruozi Barbara Nanomedicine : nanotechnology, biology, and medicine Central nervous system (CNS) compartments remain one of the most difficult districts for drug delivery. This is due to the presence of the blood-brain barrier (BBB) that hampers 90% of drug passage, dramatically requiring non-invasive treatment strategies. Here, for the first time, the use of opioid-derived deltorphin-derivative peptides to drive biodegradable and biocompatible polymeric (i.e. poly-lactide-co-glycolide, PLGA) nanomedicines delivery across the BBB was described. Opioid-derived peptides were covalently conjugated to furnish activated polymers which were further used for fluorescently tagged nanoformulations. Beyond reporting production, formulation methodology and full physico-chemical characterization, in vivo tests generated clear proof of BBB crossing and CNS targeting by engineered nanomedicines opening the research to further applications of drug delivery and targeting in CNS disease models. 10.1016/j.nano.2020.102226
    Recent advancements in brain tumor targeting using magnetic nanoparticles. Gandhi Himanshu,Sharma Abhishek Kumar,Mahant Shikha,Kapoor Deepak N Therapeutic delivery Transport of drugs through the blood-brain barrier to the brain and the toxic effects of drugs on the healthy cells can limit the effectiveness of chemotherapeutic agents. In recent years, magnetic nanoparticles (MNPs) have received much attention as targeted therapeutic and diagnostic systems due to their simplicity, ease of preparation and ability to tailor their properties such as their composition, size, surface morphology, etc. for biomedical applications. MNPs are utilized in drug delivery, radio therapeutics, hyperthermia treatment, gene therapy, biotherapeutics and diagnostic imaging. The present review will address the challenges in brain tumor targeting and discuss the application and recent developments in brain tumor targeting using MNPs. 10.4155/tde-2019-0077
    Targeting with nanoparticles for the therapeutic treatment of brain diseases. Jin Guang-Zhen,Chakraborty Atanu,Lee Jung-Hwan,Knowles Jonathan C,Kim Hae-Won Journal of tissue engineering Brain diseases including neurodegenerative disorders and tumours are among the most serious health problems, degrading the quality of life and causing massive economic cost. Nanoparticles that load and deliver drugs and genes have been intensively studied for the treatment of brain diseases, and have demonstrated some biological effects in various animal models. Among other efforts taken in the nanoparticle development, targeting of blood brain barrier, specific cell type or local intra-/extra-cellular space is an important strategy to enhance the therapeutic efficacy of the nanoparticle delivery systems. This review underlies the targeting issue in the nanoparticle development for the treatment of brain diseases, taking key exemplar studies carried out in various in vivo models. 10.1177/2041731419897460
    Targeting nanoparticles to the brain by exploiting the blood-brain barrier impermeability to selectively label the brain endothelium. Gonzalez-Carter Daniel,Liu Xueying,Tockary Theofilus A,Dirisala Anjaneyulu,Toh Kazuko,Anraku Yasutaka,Kataoka Kazunori Proceedings of the National Academy of Sciences of the United States of America Current strategies to direct therapy-loaded nanoparticles to the brain rely on functionalizing nanoparticles with ligands which bind target proteins associated with the blood-brain barrier (BBB). However, such strategies have significant brain-specificity limitations, as target proteins are not exclusively expressed at the brain microvasculature. Therefore, novel strategies which exploit alternative characteristics of the BBB are required to overcome nonspecific nanoparticle targeting to the periphery, thereby increasing drug efficacy and reducing detrimental peripheral side effects. Here, we present a simple, yet counterintuitive, brain-targeting strategy which exploits the higher impermeability of the BBB to selectively label the brain endothelium. This is achieved by harnessing the lower endocytic rate of brain endothelial cells (a key feature of the high BBB impermeability) to promote selective retention of free, unconjugated protein-binding ligands on the surface of brain endothelial cells compared to peripheral endothelial cells. Nanoparticles capable of efficiently binding to the displayed ligands (i.e., labeled endothelium) are consequently targeted specifically to the brain microvasculature with minimal "off-target" accumulation in peripheral organs. This approach therefore revolutionizes brain-targeting strategies by implementing a two-step targeting method which exploits the physiology of the BBB to generate the required brain specificity for nanoparticle delivery, paving the way to overcome targeting limitations and achieve clinical translation of neurological therapies. In addition, this work demonstrates that protein targets for brain delivery may be identified based not on differential tissue expression, but on differential endocytic rates between the brain and periphery. 10.1073/pnas.2002016117
    Selective targeting of nanomedicine to inflamed cerebral vasculature to enhance the blood-brain barrier. Marcos-Contreras Oscar A,Greineder Colin F,Kiseleva Raisa Yu,Parhiz Hamideh,Walsh Landis R,Zuluaga-Ramirez Viviana,Myerson Jacob W,Hood Elizabeth D,Villa Carlos H,Tombacz Istvan,Pardi Norbert,Seliga Alecia,Mui Barbara L,Tam Ying K,Glassman Patrick M,Shuvaev Vladimir V,Nong Jia,Brenner Jacob S,Khoshnejad Makan,Madden Tom,Weissmann Drew,Persidsky Yuri,Muzykantov Vladimir R Proceedings of the National Academy of Sciences of the United States of America Drug targeting to inflammatory brain pathologies such as stroke and traumatic brain injury remains an elusive goal. Using a mouse model of acute brain inflammation induced by local tumor necrosis factor alpha (TNFα), we found that uptake of intravenously injected antibody to vascular cell adhesion molecule 1 (anti-VCAM) in the inflamed brain is >10-fold greater than antibodies to transferrin receptor-1 and intercellular adhesion molecule 1 (TfR-1 and ICAM-1). Furthermore, uptake of anti-VCAM/liposomes exceeded that of anti-TfR and anti-ICAM counterparts by ∼27- and ∼8-fold, respectively, achieving brain/blood ratio >300-fold higher than that of immunoglobulin G/liposomes. Single-photon emission computed tomography imaging affirmed specific anti-VCAM/liposome targeting to inflamed brain in mice. Intravital microscopy via cranial window and flow cytometry showed that in the inflamed brain anti-VCAM/liposomes bind to endothelium, not to leukocytes. Anti-VCAM/LNP selectively accumulated in the inflamed brain, providing de novo expression of proteins encoded by cargo messenger RNA (mRNA). Anti-VCAM/LNP-mRNA mediated expression of thrombomodulin (a natural endothelial inhibitor of thrombosis, inflammation, and vascular leakage) and alleviated TNFα-induced brain edema. Thus VCAM-directed nanocarriers provide a platform for cerebrovascular targeting to inflamed brain, with the goal of normalizing the integrity of the blood-brain barrier, thus benefiting numerous brain pathologies. 10.1073/pnas.1912012117
    Novel therapeutic strategies for Alzheimer's disease targeting brain cholesterol homeostasis. Samant Nikita Patil,Gupta Girdhari Lal The European journal of neuroscience Alzheimer's disease (AD) is a progressive neurodegenerative disorder and the most common cause of dementia. Aβ plaques and tauopathy are two major concerns associated with AD. Moreover, excessive Aβ accumulation can lead to other nonspecific metabolic brain abnormalities. There are various genetic, environmental, and other risk factors associated with AD. Identification of risk factors and its mechanisms by which these factors impart role in AD pathology would be helpful for the prevention of AD progression. Altered cholesterol homeostasis could be considered as a risk factor for AD progression. Brain cholesterol dysmetabolism is recognized as one of the crucial attributes for AD that affect major hallmarks of AD including neurodegeneration. To fill the gap between altered cholesterol levels in the brain and AD, the researchers started focusing on statins as re-purposing drugs for AD treatment. The various other hypothesis has been suggested due to a lack of beneficial results of statins in clinical trials, such as reduced brain cholesterol could underlie poor cognition. Unfortunately, it is still unclear, whether an increase or decrease in brain cholesterol levels responsible for Alzheimer's disease or not. Presently, scientists believed that managing the level of cholesterol in the brain may help as an alternative treatment strategy for AD. In this review, we focused on the therapeutic strategies for AD by targeting brain cholesterol levels. 10.1111/ejn.14949
    Near-infrared light-activated red-emitting upconverting nanoplatform for T-weighted magnetic resonance imaging and photodynamic therapy. Tang Xiang-Long,Wu Jun,Lin Ben-Lan,Cui Sheng,Liu Hong-Mei,Yu Ru-Tong,Shen Xiao-Dong,Wang Ting-Wei,Xia Wei Acta biomaterialia Photodynamic therapy (PDT) has increasingly become an efficient and attractive cancer treatment modality based on reactive oxygen species (ROS) that can induce tumor death after irradiation with ultraviolet or visible light. Herein, to overcome the limited tissue penetration in traditional PDT, a novel near-infrared (NIR) light-activated NaScF: 40% Yb, 2% Er@CaF upconversion nanoparticle (rUCNP) is successfully designed and synthesized. Chlorin e6, a photosensitizer and a chelating agent for Mn, is loaded into human serum albumin (HSA) that further conjugates onto rUCNPs. To increase the ability to target glioma tumor, an acyclic Arg-Gly-Asp peptide (cRGDyK) is linked to rUCNPs@HSA(Ce6-Mn). This nanoplatform enables efficient adsorption and conversion of NIR light (980 nm) into bright red emission (660 nm), which can trigger the photosensitizer Ce6-Mn complex for PDT and T-weighted magnetic resonance imaging (T-weighted MRI) for glioma diagnosis. Our in vitro and in vivo experiments demonstrate that NIR light-activated and glioma tumor-targeted PDT can generate large amounts of intracellular ROS that induce U87 cell apoptosis and suppress glioma tumor growth owing to the deep tissue penetration of irradiated light and excellent tumor-targeting ability. Thus, this nanoplatform holds potential for applications in T-weighted MRI diagnosis and PDT of glioma for antitumor therapy. STATEMENT OF SIGNIFICANCE:A near-infrared (NIR) light-activated nanoplatform for photodynamic therapy (PDT) was designed and synthesized. The Red-to-Green (R/G) ratio of NaScF: 40% Yb, 2% Er almost reached 9, a value that was much higher than that of a traditional Yb/Er-codoped upconversion nanoparticle (rUCNP). By depositing a CaF shell, the red-emission intensities of the rUCNPs were seven times strong as that of NaScF: 40% Yb, 2% Er. The enhanced red-emitting rUCNPs could be applied in many fields such as bioimaging, controlled release, and real-time diagnosis. The nanoplatform had a strong active glioma-targeting ability, and all results achieved on subcutaneous glioma demonstrated that our NIR light-activated red-emitting upconverting nanoplatform was efficient for PDT. By loading Ce6-Mn complex into rUCNPs@HSA-RGD, the nanoplatform could be used as a T-weighted magnetic resonance imaging agent for tumor diagnosis. 10.1016/j.actbio.2018.05.017
    Large Timescale Interrogation of Neuronal Function by Fiberless Optogenetics Using Lanthanide Micro-particles. Miyazaki Toh,Chowdhury Srikanta,Yamashita Takayuki,Matsubara Takanori,Yawo Hiromu,Yuasa Hideya,Yamanaka Akihiro Cell reports Optogenetics requires implantation of light-delivering optical fibers, as current light-sensitive opsins are activated by visible light, which cannot effectively penetrate biological tissues. Insertion of optical fibers and subsequent photostimulation inherently damages brain tissue, and fiber tethering can restrict animal behavior. To overcome these technical limitations, we developed minimally invasive "fiberless" optogenetics using lanthanide micro-particles (LMPs), which emit up-conversion luminescence in the visible spectrum in response to irradiation with tissue-penetrating near-infrared light. Depolarizing (C1V1) and hyperpolarizing (ACR1) opsins were strongly activated by up-conversion luminescence from green-emitting LMPs both in vitro and in vivo. Using this technique, we successfully manipulated locomotive behavior of mice by activating and inhibiting neurons in the dorsal striatum, at a depth of 2 mm from the brain surface. LMPs were retained and remained functional for >8 weeks at the injection site. Fiberless optogenetics offers opportunities to control neuronal function over longer time frames using freely behaving animals. 10.1016/j.celrep.2019.01.001
    Potential Application of Upconverting Nanoparticles for Brain Photobiomodulation. Meynaghizadeh-Zargar Reza,Salehpour Farzad,Hamblin Michael R,Mahmoudi Javad,Sadigh-Eteghad Saeed Photobiomodulation, photomedicine, and laser surgery Brain photobiomodulation (PBM) describes the use of visible to near-infrared light for modulation or stimulation of the central nervous system in both healthy individuals and diseased conditions. Although the transcranial approach to delivering light to the head is the most common technique to stimulate the brain, delivery of light to deeper structures in the brain is still a challenge. The science of nanoparticle engineering in combination with biophotonic excitation could provide a way to overcome this problem. Upconversion is an anti-Stokes process that is capable of transforming low energy photons that penetrate tissue well to higher energy photons with a greater biological effect, but poor tissue penetration. Wavelengths in the third optical window are optimal for light penetration into brain tissue, followed by windows II, IV, and I. The combination of trivalent lanthanide ions within a crystalline host provides a nanostructure that exhibits the upconversion phenomenon. Upconverting nanoparticles (UCNPs) have been successfully used in various medical fields. Their ability to cross the brain-blood barrier and their low toxicity make them a good candidate for application in brain disorders. It is possible that delivery of UCNPs to the brainstem or deeper parts of the cerebral tissue, followed by irradiation using light wavelengths with good tissue penetration properties, could allow more efficient PBM of the brain. 10.1089/photob.2019.4659
    Targeted Delivery of Functionalized Upconversion Nanoparticles for Externally Triggered Photothermal/Photodynamic Therapies of Brain Glioblastoma. Tsai Yuan-Chung,Vijayaraghavan Priya,Chiang Wen-Hsuan,Chen Hsin-Hung,Liu Te-I,Shen Ming-Yin,Omoto Ayumu,Kamimura Masao,Soga Kohei,Chiu Hsin-Cheng Theranostics Therapeutic efficacy of glioblastoma multiforme (GBM) is often severely limited by poor penetration of therapeutics through blood-brain barrier (BBB) into brain tissues and lack of tumor targeting. In this regard, a functionalized upconversion nanoparticle (UCNP)-based delivery system which can target brain tumor and convert deep tissue-penetrating near-infrared (NIR) light into visible light for precise phototherapies on brain tumor was developed in this work. : The UCNP-based phototherapy delivery system was acquired by assembly of oleic acid-coated UCNPs with angiopep-2/cholesterol-conjugated poly(ethylene glycol) and the hydrophobic photosensitizers. The hybrid nanoparticles (ANG-IMNPs) were characterized by DLS, TEM, UV/vis and fluorescence spectrophotometer. Cellular uptake was examined by laser scanning confocal microscopy and flow cytometry. The PDT/PTT effect of ANG-IMNPs was evaluated using MTT assay. Tumor accumulation of NPs was determined by a non-invasive imaging system (IVIS). The anti-glioma effect of ANG-IMNPs was evaluated by immunohistochemical (IHC) examination of tumor tissues and Kaplan-Meier survival analysis. : data demonstrated enhanced uptake of ANG-IMNPs by murine astrocytoma cells (ALTS1C1) and pronounced cytotoxicity by combined NIR-triggered PDT and PTT. In consistence with the increased penetration of ANG-IMNPs through endothelial monolayer , the NPs have also shown significantly enhanced accumulation at brain tumor by IVIS. The IHC tissue examination confirmed prominent apoptotic and necrotic effects on tumor cells in mice receiving targeted dual photo-based therapies, which also led to enhanced median survival (24 days) as compared to the NP treatment without angiopep-2 (14 days). : and data strongly indicate that the ANG-IMNPs were capable of selectively delivering dual photosensitizers to brain astrocytoma tumors for effective PDT/PTT in conjugation with a substantially improved median survival. The therapeutic efficacy of ANG-IMNPs demonstrated in this study suggests their potential in overcoming BBB and establishing an effective treatment against GBM. 10.7150/thno.22482
    Upconversion Nanoparticle-Based Strategy for Crossing the Blood-Brain Barrier to Treat the Central Nervous System Disease. Fu Libing,Chung Roger,Shi Bingyang Methods in molecular biology (Clifton, N.J.) The blood-brain barrier (BBB) is a major challenge for the treatment of central nervous system (CNS) diseases. The BBB strictly regulates the movement of molecules into and out of the brain, and therefore protects the brain from noxious agents. However, for this reason the BBB also acts as a major obstacle that prevents most therapeutic molecules from getting into the target site of the brain. Therefore, it is essential to develop an efficient and general approach to overcome the BBB and transport the drug to the targeted region. Nanoparticle-based drug delivery systems are emerging as a promising drug delivery platform, due to their distinct advantages of tunable biophysical properties such as surface chemistry, size, and shape leading to various biological actions (like clearance, biodistribution, and biocompatibility) in the body. Therefore, it was hypothesized that the surface and shape of nanoparticles will influence their BBB permeation efficiency. Here, we describe a series of upconversion nanoparticles with different surfaces (oleic acid-free, DNA-modified, Silica coating, and PEG-encapsulated), PEGylated UCNPs with various shapes were generated (including sphere and rod). The cellular uptake ability, biodistribution, and BBB penetration of those UCNPs were assessed in cultured cells (NSC-34 neuron- like cells) and in vivo (zebrafish models). 10.1007/978-1-4939-9769-5_17
    808 nm near-infrared light controlled dual-drug release and cancer therapy in vivo by upconversion mesoporous silica nanostructures. Dai Yunlu,Bi Huiting,Deng Xiaoran,Li Chunxia,He Fei,Ma Ping'an,Yang Piaoping,Lin Jun Journal of materials chemistry. B The design of stimuli-responsive drug delivery systems has attracted much attention to improve therapeutic efficacy for clinical applications. Here an 808 nm NIR light responsive dual-drug system was designed for cancer treatment both in vitro and in vivo. Mesoporous silica coated NaYF:Yb/Tm@NaGdF:Yb@NaNdF:Yb (UCNPs) with a core-shell structure (labeled as UCNPs@mSiO) was prepared and loaded with the antitumor drug doxorubicin (DOX). The surface of the composite was functionalized with β-cyclodextrin rings bridged by the light cleavable platinum(iv) pro-drug, thus blocking DOX inside the mesopores of silica. When excited by 808 nm NIR light, the emitted UV light from the UCNPs was used to activate the platinum(iv) pro-drug to gain higher toxicity platinum(ii) complexes and open the mesopores of silica (at the same time) to release DOX molecules. Both DOX and platinum(ii) complexes can kill cancer cells. This dual-drug delivery system may represent a new avenue for the application of UCNPs in photoactivated cancer therapy. 10.1039/c7tb00224f
    Synthesis of Core-shell Lanthanide-doped Upconversion Nanocrystals for Cellular Applications. Ai Xiangzhao,Lyu Linna,Mu Jing,Hu Ming,Wang Zhimin,Xing Bengang Journal of visualized experiments : JoVE Lanthanide-doped upconversion nanocrystals (UCNs) have attracted much attention in recent years based on their promising and controllable optical properties, which allow for the absorption of near-infrared (NIR) light and can subsequently convert it into multiplexed emissions that span over a broad range of regions from the UV to the visible to the NIR. This article presents detailed experimental procedures for high-temperature co-precipitation synthesis of core-shell UCNs that incorporate different lanthanide ions into nanocrystals for efficiently converting deep-tissue penetrable NIR excitation (808 nm) into a strong blue emission at 480 nm. By controlling the surface modification with biocompatible polymer (polyacrylic acid, PAA), the as-prepared UCNs acquires great solubility in buffer solutions. The hydrophilic nanocrystals are further functionalized with specific ligands (dibenzyl cyclooctyne, DBCO) for localization on the cell membrane. Upon NIR light (808 nm) irradiation, the upconverted blue emission can effectively activate the light-gated channel protein on the cell membrane and specifically regulate the cation (e.g., Ca) influx in the cytoplasm. This protocol provides a feasible methodology for the synthesis of core-shell lanthanide-doped UCNs and subsequent biocompatible surface modification for further cellular applications. 10.3791/56416
    Integration of IR-808 Sensitized Upconversion Nanostructure and MoS Nanosheet for 808 nm NIR Light Triggered Phototherapy and Bioimaging. Xu Jiating,Gulzar Arif,Liu Yuhui,Bi Huiting,Gai Shili,Liu Bin,Yang Dan,He Fei,Yang Piaoping Small (Weinheim an der Bergstrasse, Germany) Near infrared (NIR) light triggered phototherapy including photothermal therapy (PTT) and photodynamic therapy (PDT) affords superior outcome in cancer treatment. However, the reactive oxygen species (ROS) generated by NIR-excited upconversion nanostructure is limited by the feeble upconverted light which cannot activate PDT agents efficiently. Here, an IR-808 dye sensitized upconversion nanoparticle (UCNP) with a chlorin e6 (Ce6)-functionalized silica layer is developed for PDT agent. The two booster effectors (dye-sensitization and core-shell enhancement) synergistically amplify the upconversion efficiency, therefore achieving superbright visible emission under low 808 nm light excitation. The markedly amplified red light subsequently triggers the photosensitizer (Ce6) to produce large amount of ROS for efficient PDT. After the silica is endowed with positive surface, these PDT nanoparticles can be easily grafted on MoS nanosheet. As the optimal laser wavelength of UCNPs is consistent with that of MoS nanosheet for PTT, the invented nanoplatform generates both abundant ROS and local hyperthermia upon a single 808 nm laser irradiation. Both the in vitro and in vivo assays validate that the innovated nanostructure presents excellent cancer cell inhibition effectiveness by taking advantages of the synergistic PTT and PDT, simultaneously, posing trimodal (upconversion luminescence/computed tomography (CT)/magnetic resonance imaging (MRI) imaging capability. 10.1002/smll.201701841
    Near-Infrared Light Triggered Upconversion Optogenetic Nanosystem for Cancer Therapy. Zheng Bin,Wang Hanjie,Pan Huizhuo,Liang Chao,Ji Wanying,Zhao Li,Chen Hongbin,Gong Xiaoqun,Wu Xiaoli,Chang Jin ACS nano In vivo the application of optogenetic manipulation in deep tissue is seriously obstructed by the limited penetration depth of visible light that is continually applied to activate a photoactuator. Herein, we designed a versatile upconversion optogenetic nanosystem based on a blue-light-mediated heterodimerization module and rare-earth upconversion nanoparticles (UCNs). The UCNs worked as a nanotransducer to convert external deep-tissue-penetrating near-infrared (NIR) light to local blue light to noninvasively activate photoreceptors for optogenetic manipulation in vivo. In this, we demonstrated that deeply penetrating NIR light could be used to control the apoptotic signaling pathway of cancer cells in both mammalian cells and mice by UCNs. We believe that this interesting NIR-light-responsive upconversion optogenetic nanotechnology has significant application potentials for both basic research and clinical applications in vivo. 10.1021/acsnano.7b06395
    Upconversion Nanoparticles-Based Multiplex Protein Activation to Neuron Ablation for Locomotion Regulation. Zhang Yan,Zhang Wanmei,Zeng Kanghua,Ao Yanxiao,Wang Mengdie,Yu Zhongzheng,Qi Fukang,Yu Weiwei,Mao Heng,Tao Louis,Zhang Cuntai,Tan Timothy Thatt Yang,Yang Xiangliang,Pu Kanyi,Gao Shangbang Small (Weinheim an der Bergstrasse, Germany) The optogenetic neuron ablation approach enables noninvasive remote decoding of specific neuron function within a complex living organism in high spatiotemporal resolution. However, it suffers from shallow tissue penetration of visible light with low ablation efficiency. This study reports a upconversion nanoparticle (UCNP)-based multiplex proteins activation tool to ablate deep-tissue neurons for locomotion modulation. By optimizing the dopant contents and nanoarchitecure, over 300-fold enhancement of blue (450-470 nm) and red (590-610 nm) emissions from UCNPs is achieved upon 808 nm irradiation. Such emissions simultaneously activate mini singlet oxygen generator and Chrimson, leading to boosted near infrared (NIR) light-induced neuronal ablation efficiency due to the synergism between singlet oxygen generation and intracellular Ca elevation. The loss of neurons severely inhibits reverse locomotion, revealing the instructive role of neurons in controlling motor activity. The deep penetrance NIR light makes the current system feasible for in vivo deep-tissue neuron elimination. The results not only provide a rapidly adoptable platform to efficient photoablate single- and multiple-cells, but also define the neural circuits underlying behavior, with potential for development of remote therapy in diseases. 10.1002/smll.201906797
    Near-infrared boosted ROS responsive siRNA delivery and cancer therapy with sequentially peeled upconversion nano-onions. He Yuling,Guo Shuwen,Wu Lina,Chen Pengwen,Wang Leyong,Liu Ying,Ju Huangxian Biomaterials RNA interference (RNAi) therapy has become an appealing approach for cancer treatment, while the specificity and efficiency of controlled small interference RNA (siRNA) release remain challenging due to the heterogeneity of tumor environment. Herein, upconversion nano-onions (UCNOs) with stacked polymer coating layers are constructed to decompose sequentially in response to extracellular environment and NIR stimulation. The UCNOs (UCNPs-PEIRB-PEISeSe/siRNA-R8-HA) are composed of upconversion nanoparticles (UCNPs) core functionalized with inner coating layer of photosensitizer rose bengal (RB) conjugated PEI 600, middle coating layer of singlet oxygen (O) sensitive diselenide linked PEI 600 with therapeutic siRNA loading and cell-penetrating peptide R8 modification, and outer coating layer of negatively charged hyaluronic acid (HA). HA prevents siRNA leakage during delivery process and specifically targets tumor cells with overexpressed CD44 membrane receptors, and digested by cell secreted hyaluronidase (HAase). Upon the subsequent irradiation at 808 nm, UCNPs core generates emissions around 540 nm, which activate RB to boost ROS generation for complete PEI-SeSe decompose. The NIR boosted decompose of UCNOs induces a fast and efficient siRNA release, which effectively improves the gene silencing efficiency in vitro and suppresses tumor growth in vivo. The proposed sequentially responsive UCNOs have promising potential application in precision medicine. 10.1016/j.biomaterials.2019.119501
    AIEgen-coupled upconversion nanoparticles eradicate solid tumors through dual-mode ROS activation. Mao Duo,Hu Fang,Yi Zhigao,Kenry Kenry,Xu Shidang,Yan Shuangqian,Luo Zichao,Wu Wenbo,Wang Zhihong,Kong Deling,Liu Xiaogang,Liu Bin Science advances Reactive oxygen species (ROS) are essential for the regulation of antitumor immune responses, where they could induce immunogenic cell death, promote antigen presentation, and activate immune cells. Here, we report the development of near-infrared (NIR)-driven immunostimulants, based on coupling upconversion nanoparticles with aggregation-induced emission luminogens (AIEgens), to integrate the immunological effects of ROS for enhanced adaptive antitumor immune responses. Intratumorally injected AIEgen-upconversion nanoparticles produce high-dose ROS under high-power NIR irradiation, which induces immunogenic cell death and antigen release. These nanoparticles can also capture the released antigens and deliver them to lymph nodes. Upon subsequent low-power NIR treatment of lymph nodes, low-dose ROS are generated to further trigger efficient T cell immune responses through activation of dendritic cells, preventing both local tumor recurrence and distant tumor growth. The utility of dual-mode pumping power on AIEgen-coupled upconversion nanoparticles offers a powerful and controllable platform to activate adaptive immune systems for tumor immunotherapy. 10.1126/sciadv.abb2712
    Designing Stimuli-Responsive Upconversion Nanoparticles that Exploit the Tumor Microenvironment. Ovais Muhammad,Mukherjee Sudip,Pramanik Arindam,Das Devlina,Mukherjee Anubhab,Raza Abida,Chen Chunying Advanced materials (Deerfield Beach, Fla.) Tailoring personalized cancer nanomedicines demands detailed understanding of the tumor microenvironment. In recent years, smart upconversion nanoparticles with the ability to exploit the unique characteristics of the tumor microenvironment for precise targeting have been designed. To activate upconversion nanoparticles, various bio-physicochemical characteristics of the tumor microenvironment, namely, acidic pH, redox reactants, and hypoxia, are exploited. Stimuli-responsive upconversion nanoparticles also utilize the excessive presence of adenosine triphosphate (ATP), riboflavin, and Zn in tumors. An overview of the design of stimulus-responsive upconversion nanoparticles that precisely target and respond to tumors via targeting the tumor microenvironment and intracellular signals is provided. Detailed understanding of the tumor microenvironment and the personalized design of upconversion nanoparticles will result in more effective clinical translation. 10.1002/adma.202000055