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Cerebrovascular impairment represents one of the main causes of death worldwide with a mortality rate of 5.5 million per year. The disability of 50% of surviving patients has high social impacts and costs in long period treatment for national healthcare systems. For these reasons, the efficacious clinical treatment of patients, with brain ischemic stroke, remains a medical need. To this aim, a liposome nanomedicine, with monosialic ganglioside type 1 (GM1), OX26 (an anti-transferrin receptor antibody), and CDP-choline (a neurotrophic drug) (CDP-choline/OX26Lip) was prepared. CDP-choline/OX26Lip were prepared by a freeze and thaw method and then extruded through polycarbonate filters, to have narrow size distributed liposomes of ~80 nm. CDP-choline/OX26Lip were stable in human serum, they had suitable pharmacokinetic properties, and 30.0 ± 4.2% of the injected drug was still present in the blood stream 12 h after its systemic injection. The post-ischemic therapeutic effect of CDP-choline/OX26Lip is higher than CDP-choline/Lip, thus showing a significantly high survival rate of the re-perfused post-ischemic rats, i.e. 96% and 78% after 8 days. The treatment with CDP-choline/OX26Lip significantly decreased the peroxidation rate of ~5-times compared to CDP-choline/Lip; and the resulting conjugated dienes, that was 13.9 ± 1.1 mmol/mg proteins for CDP-choline/Lip and 3.1 ± 0.8 for CDP-choline/OX26Lip. OX26 increased the accumulation of GM1-liposomes in the brain tissues and thus the efficacious of CDP-choline. Therefore, this nanomedicine may represent a strategy for the reassessment of CDP-choline to treat post-ischemic events caused by brain stroke, and respond to a significant clinical need. [ABSTRACT FROM AUTHOR]

Levosulpiride (LSP) has been studied for its wide medicinal potential. One of its uses is in the treatment of schizophrenia. LSP has limited oral bioavailability because of its low permeability, dissolvability, and P-Glycoprotein (Pgp) efflux effect. Contrary to conventional methods, the intranasal route provides safe and effective treatment as well as targeted action. It can also prevent the P-gp efflux effect and increase brain bioavailability. In this research, we aimed to develop LSP-loaded Phospholipid Magnesomes (PMs), a novel vesicular nanosystem, recently fabricated for brain targeting by the Ultra-sonication method with materials including Phospholipon 90G, the combination of Propylene glycol and ethanol, magnesium sulphate (MgSO4) and water. The Box-Behnken design was utilized with 29 runs to optimize the LSP-PMs formulation. The formulation was confirmed and evaluated by the FTIR, DSC, PXRD, and TEM study. The formulation was investigated in vitro at pH 6.4, and the results showed that the formulation had improved drug release. The optimized LSP-PMs formula had a vesicle sizing of 85.035 ± 2.77 nm, a PDI of 0.392 ± 0.69, and a %EE of 76.024 %. Spherical and multilamellar morphology of LSP-PMs were visible by the TEM. The optimized LSP-PMs had the quickest medication diffusing profile, achieving 100% in one hour. The LSP-PMs formulation was stable at room temperature for 50 days when screened for the stability study. Thus, to sum up, the nano-vesicular system of LSP-PMs demonstrated to be a promising formulation for enhancing drug release of the poorly water-soluble and permeable LSP. Further investigation to analyze nasal transport to the brain, pharmacokinetic and pharmacodynamic effects, local safety, and the behavior of the developed carrier will require additional research. [ABSTRACT FROM AUTHOR]

Nanoparticles, in particular PEGylated, show great potential for in vivo brain targeted drug delivery. Nevertheless, how polyethylene glycol (PEG) length of nanoparticles affects their blood brain barrier (BBB) penetration or brain targeting is still unclear. In this study, we investigated the power of PEG chain-lengths (2, 3.4, 5, 10 kDa) in BBB penetration and brain targeting using Angiopep-2 peptide decorated liposomes. We found that PEG chain-length is critical, where the shorter PEG enabled the Angiopep-2 decorated liposomes to display more potent in vitro cell uptake via endocytosis. In contrast, their in vitro BBB penetration via transcytosis was much weaker relative to the liposomes with longer PEG chains, which result from their ineffective BBB exocytosis. Interestingly, the in vivo brain targeting aligns with the in vitro BBB penetration, as the long chain PEG-modified liposomes exerted superior brain accumulation both in normal or orthotropic glioblastoma (GBM) bearing mice, which could be ascribed to the combinational effect of prolonged circulation and enhanced BBB penetration of long chain PEG attached liposomes. These results demonstrate the crucial role of PEG length of nanoparticles for BBB penetration and brain targeting, providing guidance for PEG length selection in the design of nanocarrier for brain diseases treatment. [Display omitted] [ABSTRACT FROM AUTHOR]

Yan Yang,1,* Yiling Wang,1,* Xinran Jiang,1 Jiahao Mi,1 Dizhang Ge,2 Yuna Tong,3 Yuxuan Zhu1,2 1Department of Pharmacy, Personalized Drug Therapy Key Laboratory of Sichuan Province, Sichuan Academy of Medical Science & Sichuan Provincial People’s Hospital, University of Electronic Science and Technology of China, Chengdu, 610072, People’s Republic of China; 2Department of Pharmacy, People’s Hospital of Aba Tibetan and Qiang Autonomous Prefecture, Aba, 624000, People’s Republic of China; 3Department of Nephrology, The Third People’s Hospital of Chengdu, Chongqing Medical University, Chengdu, 610031, People’s Republic of China*These authors contributed equally to this workCorrespondence: Yuna Tong; Yuxuan Zhu, Email tongyuna1985@163.com; zhuyuxuan6688@163.comIntroduction: Alzheimer’s disease (AD), a neurodegenerative condition, stands as the most prevalent form of dementia. Its complex pathological mechanisms and the formidable blood-brain barrier (BBB) pose significant challenges to current treatment approaches. Oxidative stress is recognized as a central factor in AD, underscoring the importance of antioxidative strategies in its treatment. In this study, we developed a novel brain-targeted nanoparticle, Ce/Zr-MOF@Cur-Lf, for AD therapy.Methods: Layer-by-layer self-assembly technology was used to prepare Ce/Zr-MOF@Cur-Lf. In addition, the effect on the intracellular reactive oxygen species level, the uptake effect by PC12 and bEnd.3 cells and the in vitro BBB permeation effect were investigated. Finally, the mouse AD model was established by intrahippocampal injection of Aβ1-42, and the in vivo biodistribution, AD therapeutic effect and biosafety of the nanoparticles were researched at the animal level.Results: As anticipated, Ce/Zr-MOF@Cur-Lf demonstrated efficient BBB penetration and uptake by PC12 cells, leading to attenuation of H2O2-induced oxidative damage. Moreover, intravenous administration of Ce/Zr-MOF@Cur-Lf resulted in rapid brain access and improvement of various pathological features of AD, including neuronal damage, amyloid-β deposition, dysregulated central cholinergic system, oxidative stress, and neuroinflammation.Conclusion: Overall, Ce/Zr-MOF@Cur-Lf represents a promising approach for precise brain targeting and multi-target mechanisms in AD therapy, potentially serving as a viable option for future clinical treatment.Keywords: metal-organic frameworks, Alzheimer’s disease, drug delivery, brain targeting, oxidative stress

Abstract Background As per World Health Organization (WHO) database, neurological and psychiatric disorders constitute a significant and escalating source of morbidity, impacting over one billion lives with a staggering 9 million fatalities. Unfortunately, the magnitude of these disorders remains largely untreated, primarily due to the formidable challenge of the cerebrospinal fluid–brain barrier (CBB), blood–brain barrier (BBB), as well as the blood–cerebrospinal fluid barrier (BCSFB) compromising the central nervous system (CNS) therapies. Thus, there is a need to explore innovative drug delivery platforms capable of overcoming these barriers in order to facilitate effective delivery of therapeutic drugs. Main body of abstract Intranasal drug delivery (INDD) of nanoformulations has emerged as a promising approach, leveraging advantages such as a high surface area, nanoscale particle size, mucoadhesion, noninvasive administration with rapid, and greater drug bioavailability. In this, cubosomal drug delivery (DD) has emerged as a pivotal targeted drug delivery strategy, particularly in the therapy of neurological ailments. Nowadays, researchers and academicians have focused their efforts to tailor cubosomes (CBS) specifically for improving efficacy of central nervous system (CNS) therapies. Conclusion This review gives an idea about current status of neurological disorders (ND), the barriers that restricts CNS drug delivery (BBB), and possible nasal pathways of CBS for effective drug transport. A central focus is placed on intranasal (IN) cubosomal formulations for several NDs, elucidating their potential benefits while addressing existing challenges. In essence, this comprehensive review provides valuable insights into innovative approaches that hold promise for addressing the use and need of IN-CBS in the treatment of NDs.

Tianshu Liu, Mengfan Zhang, Jin Zhang, Naijin Kang, Linlin Zheng, Zhiying Ding School of Pharmaceutical Sciences, Jilin University, Changchun, 130021, People’s Republic of ChinaCorrespondence: Zhiying Ding, School of Pharmaceutical Sciences, Jilin University, Changchun, 130021, People’s Republic of China, Tel/Fax +86 13843180286, Email dzy@jlu.edu.cnPurpose: Ginsenoside Rg3 (Rg3) and Panax notoginseng saponins (PNS) can be used for ischemic stroke treatment, however, the lack of targeting to the ischemic region limits the therapeutic effect. To address this, we leveraged the affinity of macrophage membrane proteins for inflamed brain microvascular endothelial cells to develop a macrophage membrane-cloaked liposome loaded with Rg3 and PNS (MM-Lip-Rg3/PNS), which can precisely target brain lesion region through intranasal administration.Methods: MM-Lip-Rg3/PNS was prepared by co-extrusion method and was performed by characterization, stability, surface protein, and morphology. The cellular uptake, immune escape ability, and blood-brain barrier crossing ability of MM-Lip-Rg3/PNS were studied in vitro. The in vivo brain targeting, biodistribution and anti-ischemic efficacy of MM-Lip-Rg3/PNS were evaluated in MACO rats, and we determined the diversity of the nasal brain pathway through the olfactory nerve blockade model in rats. Finally, the pharmacokinetics and brain targeting index of MM-Lip-Rg3/PNS were investigated.Results: Our results indicated that MM-Lip-Rg3/PNS was spherical with a shell-core structure. MM-Lip-Rg3/PNS can avoid mononuclear phagocytosis, actively bind to inflammatory endothelial cells, and have the ability to cross the blood-brain barrier. Moreover, MM-Lip-Rg3/PNS could specifically target ischemic sites, even microglia, increase the cumulative number of drugs in the brain, improve the inflammatory environment of the brain, and reduce the infarct size. By comparing olfactory nerve-blocking rats with normal rats, it was found that there are direct and indirect pathways for nasal entry into the brain. Pharmacokinetics demonstrated that MM-Lip-Rg3/PNS exhibited stronger brain targeting and prolonged drug half-life.Conclusion: MM-Lip-Rg3/PNS might contribute to the accumulation of Rg3 and PNS in the ischemic brain area to improve treatment efficacy. This biomimetic nano-drug delivery system provides a new and promising strategy for the treatment of ischemic stroke. Keywords: macrophage-membrane coating, biomimetic liposome, brain targeting, ischemic stroke, intranasal delivery

Background: As per World Health Organization (WHO) database, neurological and psychiatric disorders constitute a significant and escalating source of morbidity, impacting over one billion lives with a staggering 9 million fatalities. Unfortunately, the magnitude of these disorders remains largely untreated, primarily due to the formidable challenge of the cerebrospinal fluid–brain barrier (CBB), blood–brain barrier (BBB), as well as the blood–cerebrospinal fluid barrier (BCSFB) compromising the central nervous system (CNS) therapies. Thus, there is a need to explore innovative drug delivery platforms capable of overcoming these barriers in order to facilitate effective delivery of therapeutic drugs. Intranasal drug delivery (INDD) of nanoformulations has emerged as a promising approach, leveraging advantages such as a high surface area, nanoscale particle size, mucoadhesion, noninvasive administration with rapid, and greater drug bioavailability. In this, cubosomal drug delivery (DD) has emerged as a pivotal targeted drug delivery strategy, particularly in the therapy of neurological ailments. Nowadays, researchers and academicians have focused their efforts to tailor cubosomes (CBS) specifically for improving efficacy of central nervous system (CNS) therapies. Conclusion: This review gives an idea about current status of neurological disorders (ND), the barriers that restricts CNS drug delivery (BBB), and possible nasal pathways of CBS for effective drug transport. A central focus is placed on intranasal (IN) cubosomal formulations for several NDs, elucidating their potential benefits while addressing existing challenges. In essence, this comprehensive review provides valuable insights into innovative approaches that hold promise for addressing the use and need of IN-CBS in the treatment of NDs. [ABSTRACT FROM AUTHOR]

The precise and targeted delivery of therapeutic agents to the lesion sites remains a major challenge in treating brain diseases represented by ischemic stroke. Herein, we modified liposomes with mesenchymal stem cells (MSC) membrane to construct biomimetic liposomes, termed MSCsome. MSCsome (115.99 ± 4.03 nm) exhibited concentrated accumulation in the cerebral infarcted hemisphere of mice with cerebral ischemia-reperfusion injury, while showing uniform distribution in the two cerebral hemispheres of normal mice. Moreover, MSCsome exhibited high colocalization with damaged nerve cells in the infarcted hemisphere, highlighting its advantageous precise targeting capabilities over liposomes at both the tissue and cellular levels. Leveraging its superior targeting properties, MSCsome effectively delivered Dl-3-n-butylphthalide (NBP) to the injured hemisphere, making a single-dose (15 mg/kg) intravenous injection of NBP-encapsulated MSCsome facilitate the recovery of motor functions in model mice by improving the damaged microenvironment and suppressing neuroinflammation. This study underscores that the modification of the MSC membrane notably enhances the capacity of liposomes for precisely targeting the injured hemisphere, which is particularly crucial in treating cerebral ischemia-reperfusion injury. We constructed biomimetic liposomes based on mesenchymal stem cell membrane, possessing precise brain-targeting properties at both tissue and cellular levels, which can efficiently target the infarcted hemisphere and are further internalized by damaged nerve cells. [Display omitted] • MSCsome incorporated cellular properties onto the inherent characteristics of liposomes. • MSCsome accumulated in the cerebral infarcted hemisphere, while showing non-regionally selective distribution in normal mice. • A single-dose intravenous injection of NBP-MSCsome showed superior efficacy in treating cerebral ischemia-reperfusion injury. [ABSTRACT FROM AUTHOR]

Etomidate is a general anesthetic that has shown good hemodynamic stability without significant cardiovascular or respiratory depression. Despite several kinds of dosage forms having been reported for this drug, formulation types are very limited in clinical practice, and brain-targeted formulations for this central nervous system (CNS) drug have been rarely reported. Moreover, studies on the biocompatibility, toxicity, and anesthetic effects of the etomidate preparations in vivo were inadequate. The present study was to develop lactoferrin-modified liposomal etomidate (Eto-lip-LF) for enhanced drug distribution in the brain and improved anesthetic effects. Eto-lip-LF had good stability for storage and hemocompatibility for intravenous injection. Compared with the non-lactoferrin-containing liposomes, the lactoferrin-modified liposomes had notably enhanced brain-targeting ability in vivo, which was probably realized by the binding of transferrin with the transferrin and lactoferrin receptors highly distributed in the brain. Eto-lip-LF had a therapeutic index of about 25.3, higher than that of many other general anesthetics. Moreover, compared with the commercial etomidate emulsion, Eto-lip-LF could better achieve rapid onset of general anesthesia and rapid recovery from anesthesia, probably due to the enhanced drug delivery to the brain. The above results demonstrated the potential of this lactoferrin-modified liposomal etomidate to become an alternative preparation for clinical general anesthesia. [ABSTRACT FROM AUTHOR]

The blood–brain barrier (BBB) poses a major obstacle in the treatment of all types of central nervous system (CNS) diseases. Small interfering RNA (siRNA) offers in principle a promising therapeutic approach by downregulating disease-related genes via RNA interference. However, the BBB is a formidable barrier for macromolecules such as nucleic acids. In an effort to develop a brain-targeted strategy for siRNA delivery systems formed by electrostatic interactions with cationic polymers (polyplexes (PXs)), we investigated the suitability of the well-known surfactant-based approach for Apolipoprotein E (ApoE)-functionalization of nanoparticles (NPs). The aim of this present work was to investigate if ApoE coating of siRNA PXs formed with cationic branched 25-kDa poly(ethyleneimine) (b-PEI) and nylon-3 polymers without or after precoating with polysorbate 80 (PS 80) would promote successful delivery across the BBB. We utilized highly hydrophobic NM0.2/CP0.8 nylon-3 polymers to evaluate the effects of hydrophobic cyclopentyl (CP) subunits on ApoE binding efficacy and observed successful ApoE binding with and without PS 80 precoating to the nylon-3 but not the PEI polyplexes. Accordingly, ApoE-coated nylon-3 polyplexes showed significantly increased uptake and gene silencing in U87 glioma cells but no benefit in vivo. In conclusion, further optimization of ApoE-functionalized polyplexes and more sophisticated in vitro models are required to achieve more successful in vitro-in vivo translation in future approaches. [ABSTRACT FROM AUTHOR]

Central nervous system-related disorders have become a continuing threat to human life and the current statistic indicates an increasing trend of such disorders worldwide. The primary therapeutic challenge, despite the availability of therapies for these disorders, is to sustain the drug's effective concentration in the brain while limiting its accumulation in non-targeted areas. This is attributed to the presence of the blood–brain barrier and first-pass metabolism which limits the transportation of drugs to the brain irrespective of popular and conventional routes of drug administration. Therefore, there is a demand to practice alternative routes for predictable drug delivery using advanced drug delivery carriers to overcome the said obstacles. Recent research attracted attention to intranasal-to-brain drug delivery for promising targeting therapeutics in the brain. This review emphasizes the mechanisms to deliver therapeutics via different pathways for nose-to-brain drug delivery with recent advancements in delivery and formulation aspects. Concurrently, for the benefit of future studies, the difficulties in administering medications by intranasal pathway have also been highlighted. [ABSTRACT FROM AUTHOR]

This study explored the distribution of esculin microspheres in rabbit brain tissue following intravitreal injection and investigated the possibility of direct entry of the drug into the brain through the eye, to develop a formulation with enhanced therapeutic efficacy against Parkinson's disease. Chitosan microspheres of esculin were prepared via an emulsification cross-linking method and their characteristics were evaluated, including angle of repose, bulk density, and swelling ratio. Furthermore, the pharmacokinetic parameters and brain tissue distribution in rabbits were compared among groups administered esculin eye drops, intravitreal esculin solution, and intravitreal esculin microspheres, to determine whether esculin could enter the brain through an ocular route. The results showed that the prepared esculin microspheres were spherical and had good fluidity. Notably, intravitreal administration enhanced the area under the curve (AUC) of esculin in the thalamus. Delivery through microspheres prolonged the drug retention time in both rabbit plasma and brain tissues, as well as the brain-targeting efficiency of esculin. The collective findings indicated that there may be a direct eye-brain pathway facilitating enter of esculin microspheres into brain tissue after intravitreal injection, supporting the utility of intravitreal esculin microspheres as an effective therapeutic formulation for Parkinson's disease, a long-term chronic condition. [ABSTRACT FROM AUTHOR]

Zhuoxuan Li,1 Tatyana Kovshova,2 Julia Malinovskaya,2 Julian Knoll,1 Saeed Shanehsazzadeh,1 Nadezhda Osipova,2 Anastasia Chernysheva,3 Pavel Melnikov,2 Svetlana Gelperina,2 Matthias G Wacker1 1National University of Singapore, Department of Pharmacy and Pharmaceutical Sciences, Faculty of Science, Singapore; 2Dmitry Mendeleev University of Chemical Technology of Russia, Moscow, Russia; 3V. Serbsky Federal Medical Research Centre of Psychiatry and Narcology of the Ministry of Health of the Russian Federation, Moscow, RussiaCorrespondence: Matthias G Wacker, Email matthias.g.wacker@nus.edu.sgPurpose: This study investigated the brain targeting mechanism of doxorubicin-loaded polybutyl cyanoacrylate (PBCA) nanoparticles, particularly their interactions with the blood-brain barrier (BBB). The BBB protects the brain from drugs in the bloodstream and represents a crucial obstacle in the treatment of brain cancer.Methods: An advanced computer model analyzed the brain delivery of two distinct formulations, Doxil® and surfactant-coated PBCA nanoparticles. Computational learning was combined with in vitro release and cell interaction studies to comprehend the underlying brain delivery pathways.Results: Our analysis yielded a surprising discovery regarding the brain delivery mechanism of PBCA nanoparticles. While Doxil® exhibited the expected behavior, accumulating in the brain through extravasation in tumor tissue, PBCA nanoparticles employed a unique and previously uncharacterized mechanism. They underwent cell hitchhiking, resulting in a remarkable more than 1000-fold increase in brain permeation rate compared to Doxil® (2.59 × 10− 4 vs 0.32 h− 1).Conclusion: The nonspecific binding to blood cells facilitated and intensified interactions of surfactant-coated PBCA nanoparticles with the vascular endothelium, leading to enhanced transcytosis. Consequently, the significant increase in circulation time in the bloodstream, coupled with improved receptor interactions, contributes to this remarkable uptake of doxorubicin into the brain. Keywords: BBB, brain targeting, CNS, modeling, doxorubicin, drug delivery

Cerebral malaria (CM), a severe neurological pathology caused by Plasmodium falciparum infection, poses a significant global health threat and has a high mortality rate. Conventional therapeutics cannot cross the blood–brain barrier (BBB) efficiently. Therefore, finding effective treatments remains challenging. The novelty of the treatment proposed in this study lies in the feasibility of intranasal (IN) delivery of the nanostructured lipid carrier system (NLC) combining microRNA (miRNA) and artemether (ARM) to enhance bioavailability and brain targeting. The rational use of NLCs and RNA-targeted therapeutics could revolutionize the treatment strategies for CM management. This study can potentially address the challenges in treating CM, allowing drugs to pass through the BBB. The NLC formulation was developed by a hot-melt homogenization process utilizing 3% (w/w) precirol and 1.5% (w/v) labrasol, resulting in particles with a size of 94.39 nm. This indicates an effective delivery to the brain via IN administration. The results further suggest the effective intracellular delivery of encapsulated miRNAs in the NLCs. Investigations with an experimental cerebral malaria mouse model showed a reduction in parasitaemia, preservation of BBB integrity, and reduced cerebral haemorrhages with the ARM+ miRNA-NLC treatment. Additionally, molecular discoveries revealed that nicotinamide adenine dinucleotide phosphate oxidase 2 (NOX2) and Interleukin-6 (IL-6) levels were reduced in the treated groups in comparison to the CM group. These results support the use of nanocarriers for IN administration, offering a viable method for mitigating CM through the increased bioavailability of therapeutics. Our findings have far-reaching implications for future research and personalized therapy. [ABSTRACT FROM AUTHOR]

Purpose: Receptor-mediated transcytosis (RMT) is a more specific, highly efficient, and reliable approach to crossing the blood-brain-barrier (BBB) and releasing the therapeutic cargos into the brain parenchyma. Methods: Here, we introduced and characterized a human/mouse-specific novel leptin-derived peptide using in silico , in vitro and in vivo experiments. Results: Based on the bioinformatics analysis and molecular dynamics (MD) simulation, a 14 amino acid peptide sequence (LDP 14) was introduced and its interaction with leptin-receptor (ObR) was analyzed in comparison with an well known leptin-derived peptide, Lep 30. MD simulation data revealed a significant stable interaction between ligand binding domains (LBD) of ObR with LDP 14. Analyses demonstrated suitable cellular uptake of LDP 14 alone and its derivatives (LDP 14-modified G4 PAMAM dendrimer and LDP 14-modified G4 PAMAM/pEGFP-N1 plasmid complexes) via ObR, energy and species dependent manner (preferred uptake by human/mouse cell lines compared to rat cell line). Importantly, our findings illustrated that the entry of LDP 14-modified dendrimers in hBCEC-D3 cells not only is not affected by protein corona (PC) formation, as the main reason for diminishing the cellular uptake, but also PC per se can enhance uptake rate. Finally, fluorescein labeled LDP 14-modified G4 PAMAM dendrimers efficiently accumulated in the mice brain with lower biodistribution in other organs, in our in vivo study. Conclusion: LDP 14 introduced as a novel and highly efficient ligand, which can be used for drugs/genes delivery to brain tissue in different central nervous system (CNS) disorders. [ABSTRACT FROM AUTHOR]

Background: Panax notoginseng saponins (PNS) are commonly used first-line drugs for treating cerebral thrombosis and stroke in China. However, the synchronized and targeted delivery of active ingredients in traditional Chinese medicine (TCM) poses a significant challenge for modern TCM formulations. Methods: Bovine serum albumin (BSA) was modified using 2-methacryloyloxyethyl phosphorylcholine (MPC), an analog of acetylcholine, and subsequently adsorbed the major PNS onto the modified albumin to produce MPC-BSA@PNS nanoparticles (NPs). This novel delivery system facilitated efficient and synchronized transport of PNS across the blood–brain barrier (BBB) through active transport mediated by nicotinic acetylcholine receptors. Results: In vitro experiments demonstrated that the transport rates of R1, Rg1, Rb1, and Rd across the BBB were relatively synchronous in MPC-BSA@PNS NPs compared to those in the PNS solution. Additionally, animal experiments revealed that the brain-targeting efficiencies of R1 + Rg1 + Rb1 in MPC-BSA@PNS NPs were 2.02 and 7.73 times higher than those in BSA@PNS NPs and the free PNS group, respectively. Conclusions: This study presents a simple and feasible approach for achieving the targeted delivery of complex active ingredient clusters in TCM. [ABSTRACT FROM AUTHOR]

In spite of the great advance in drug delivery systems (DDSs) for the control of the neurological disorders like Alzheimer's disease, Parkinson's disease, epilepsy and seizures, yet there is a demand for innovative DDSs for brain targeting. The biggest hurdle for directing the drug to the brain is the presence of the blood-brain barrier (BBB) which hampers the passage of medicants to the brain. Many recent approaches to allow carriage of medicaments to the brain have come out during the last twenty years. Intranasal delivery of drugs is one of these approaches which can bypass the BBB in a noninvasive way. Lipid nanocapsules (LNCs) act as an appropriate platform and novel strategy for nose to brain drug delivery due to their several advantages. They can be produced in a quick, simple, solvent-free and scalable-up process. Therefore, this review depicts mechanisms of nose-to-brain drug delivery and the several approaches for improving nasal absorption of drugs with a special emphasis on lipid nanocapsules-based approaches. It discusses the composition and method of preparation of LNCs, their advantages and their application in nose to brain drug delivery. The upcoming prospect of nasal drug delivery to the brain is also discussed. [ABSTRACT FROM AUTHOR]

Despite the increasing global incidence of brain disorders, achieving sufficient delivery towards the central nervous system (CNS) remains a formidable challenge in terms of translating into improved clinical outcomes. The brain is highly safeguarded by physiological barriers, primarily the blood-brain barrier (BBB), which routinely excludes most therapeutics from entering the brain following systemic administration. Among various strategies investigated to circumvent this challenge, intranasal administration, a noninvasive method that bypasses the BBB to allow direct access of drugs to the CNS, has been showing promising results. Nanotechnology-based drug delivery systems, in particular, have demonstrated remarkable capacities in overcoming the challenges posed by nose-to-brain drug delivery and facilitating targeted drug accumulation within the brain while minimizing side effects of systemic distribution. This review comprehensively summarizes the barriers of nose-to-brain drug delivery, aiming to enhance our understanding of potential physiological obstacles and improve the efficacy of nasal delivery in future trials. We then highlight cutting-edge nanotechnology-based studies that enhance nose-to-brain drug delivery in three key aspects, demonstrating substantial potential for improved treatment of brain diseases. Furthermore, the attention towards clinical studies will ease the regulatory approval process for nasal administration of nanomedicines targeting brain disease. [Display omitted] [ABSTRACT FROM AUTHOR]

Polyphenols are a group of naturally occurring compounds that possess a range of biological properties capable of potentially mitigating or preventing the progression of age-related cognitive decline and Alzheimer’s disease (AD). AD is a chronic neurodegenerative disease known as one of the fast-growing diseases, especially in the elderly population. Moreover, as the primary etiology of dementia, it poses challenges for both familial and societal structures, while also imposing a significant economic strain. There is currently no pharmacological intervention that has demonstrated efficacy in treating AD. While polyphenols have exhibited potential in inhibiting the pathological hallmarks of AD, their limited bioavailability poses a significant challenge in their therapeutic application. Furthermore, in order to address the therapeutic constraints, several polymer nanoparticles are being explored as improved therapeutic delivery systems to optimize the pharmacokinetic characteristics of polyphenols. Polymer nanoparticles have demonstrated advantageous characteristics in facilitating the delivery of polyphenols across the blood–brain barrier, resulting in their efficient distribution within the brain. This review focuses on amyloid-related diseases and the role of polyphenols in them, in addition to discussing the anti-amyloid effects and applications of polyphenol-based polymer nanoparticles.

Gliomas are typical malignant brain tumours affecting a wide population worldwide. Operation, as the common treatment for gliomas, is always accompanied by postoperative drug chemotherapy, but cannot cure patients. The main challenges are chemotherapeutic drugs have low blood-brain barrier passage rate and a lot of serious adverse effects, meanwhile, they have difficulty targeting glioma issues. Nowadays, the emergence of nanoparticles (NPs) drug delivery systems (NDDS) has provided a new promising approach for the treatment of gliomas owing to their excellent biodegradability, high stability, good biocompatibility, low toxicity, and minimal adverse effects. Herein, we reviewed the types and delivery mechanisms of NPs currently used in gliomas, including passive and active brain targeting drug delivery. In particular, we primarily focused on various hopeful types of NPs (such as liposome, chitosan, ferritin, graphene oxide, silica nanoparticle, nanogel, neutrophil, and adeno-associated virus), and discussed their advantages, disadvantages, and progress in preclinical trials. Moreover, we outlined the clinical trials of NPs applied in gliomas. According to this review, we provide an outlook of the prospects of NDDS for treating gliomas and summarise some methods that can enhance the targeting specificity and safety of NPs, like surface modification and conjugating ligands and peptides. Although there are still some limitations of these NPs, NDDS will offer the potential for curing glioma patients.

Abstract Current strategies to identify ligands for brain delivery select candidates based on preferential binding to cell-membrane components (CMC) on brain endothelial cells (EC). However, such strategies generate ligands with inherent brain specificity limitations, as the CMC (e.g., the transferrin receptor TfR1) are also significantly expressed on peripheral EC. Therefore, novel strategies are required to identify molecules allowing increased specificity of therapy brain delivery. Here, we demonstrate that, while individual CMC are shared between brain EC and peripheral EC, their endocytic internalization rate is markedly different. Such differential endocytic rate may be harnessed to identify molecular tags for brain targeting based on their selective retention on the surface of brain EC, thereby generating ‘artificial’ targets specifically on the brain vasculature. By quantifying the retention of labelled proteins on the cell membrane, we measured the general endocytic rate of primary brain EC to be less than half that of primary peripheral (liver and lung) EC. In addition, through bio-panning of phage-displayed peptide libraries, we unbiasedly probed the endocytic rate of individual CMC of liver, lung and brain endothelial cells. We identified phage-displayed peptides which bind to CMC common to all three endothelia phenotypes, but which are preferentially endocytosed into peripheral EC, resulting in selective retention on the surface of brain EC. Furthermore, we demonstrate that the synthesized free-form peptides are capable of generating artificial cell-surface targets for the intracellular delivery of model proteins into brain EC with increasing specificity over time. The developed identification paradigm, therefore, demonstrates that the lower endocytic rate of individual CMC on brain EC can be harnessed to identify peptides capable of generating ‘artificial’ targets for the selective delivery of proteins into the brain vasculature. In addition, our approach identifies brain-targeting peptides which would have been overlooked by conventional identification strategies, thereby increasing the repertoire of candidates to achieve specific therapy brain delivery.

AbstractBrain tumor accounts for about 1.6% of incidence and 2.5% of mortality of all tumors, and the median survival for brain tumor patients is only about 20 months. The treatment for brain tumor still faces many challenges, such as the blood-brain barrier (BBB), blood-brain tumor barrier (BBTB), the overexpressed efflux pumps, the infiltration, invasion, high heterogeneity of tumor cells, drug resistance and immune escape caused by tumor microenvironment (TME) and cancer stem cells (CSC). This review attempts to clarify the challenges for multi-functional nano drug delivery systems (NDDS) to cross the BBB and target the cancer cells or organelles, and also provides a brief description of the different types of targeted multi-functional NDDS that have shown potential for success in delivering drugs to the brain. Further, this review also summarizes the research progress of multi-functional NDDS in the combination therapy of brain tumors from the following sections, the combination of chemotherapy drugs, chemotherapy-chemodynamic combination therapy, chemotherapy-immunization combination therapy, and chemotherapy-gene combination therapy. We also provide an insight into the recent advances in designing multi-functional NDDS for combination therapy.

The unique anatomical and physiological connections between the nasal cavity and brain provide a pathway for bypassing the blood--brain barrier to allow for direct brain-targeted drug delivery through nasal administration. There are several advantages of nasal administration compared with other routes; for example, the first-pass effect that leads to the metabolism of orally administered drugs can be bypassed, and the poor compliance associated with injections can be minimized. Nasal administration can also help maximize brain-targeted drug delivery, allowing for high pharmacological activity at lower drug dosages, thereby minimizing the likelihood of adverse effects and providing a highly promising drug delivery pathway for the treatment of central nervous system diseases. The aim of this review article was to briefly describe the physiological structures of the nasal cavity and brain, the pathways through which drugs can enter the brain through the nose, the factors affecting brain-targeted nasal drug delivery, methods to improve brain-targeted nasal drug delivery systems through the application of related biomaterials, common experimental methods used in intranasal drug delivery research, and the current limitations of such approaches, providing a solid foundation for further in-depth research on intranasal brain-targeted drug delivery systems (see Graphical Abstract). [ABSTRACT FROM AUTHOR]

Several therapeutic agents are used for controlling brain diseases, but they are not successfully reaching target sites due to the complex nature of the brain. Nasal administration as an alternate administration route has been proposed for brain targeting. To solve the above limitation linked to brain targeting through the transmission of nasal products, encourage the production of novel drug delivery by the combination of nanotechnology. The present review focuses on the latest understanding of pathways underlying central nervous system intranasal transmission. Novel Drug delivery systems as important methods for targeting the brain without toxicity in the nasal mucosa and central nervous system, they have acquired the capacity of CNS. [ABSTRACT FROM AUTHOR]

Alzheimer's disease, a progressive neurodegenerative condition, is characterized by a gradual decline in cognitive functions. Current treatment approaches primarily involve the administration of medications through oral, parenteral, and transdermal routes, aiming to improve cognitive function and alleviate symptoms. However, these treatments face limitations, such as low bioavailability and inadequate permeation. Alternative invasive methods, while explored, often entail discomfort and require specialized assistance. Therefore, the development of a non-invasive and efficient delivery system is crucial. Intranasal delivery has emerged as a potential solution, although it is constrained by the unique conditions of the nasal cavity. An innovative approach involves the use of nano-carriers based on nanotechnology for intranasal delivery. This strategy has the potential to overcome current limitations by providing enhanced bioavailability, improved permeation, effective traversal of the blood–brain barrier, extended retention within the body, and precise targeting of the brain. The comprehensive review focuses on the advancements in designing various types of nano-carriers, including polymeric nanoparticles, metal nanoparticles, lipid nanoparticles, liposomes, nanoemulsions, Quantum dots, and dendrimers. These nano-carriers are specifically tailored for the intranasal delivery of therapeutic agents aimed at combatting Alzheimer's disease. In summary, the development and utilization of intranasal delivery systems based on nanotechnology show significant potential in surmounting the constraints of current Alzheimer's disease treatment strategies. Nevertheless, it is essential to acknowledge regulatory as well as toxicity concerns associated with this route; meticulous consideration is required when engineering a carrier. This comprehensive review underscores the potential to revolutionize Alzheimer's disease management and highlights the importance of addressing regulatory considerations for safe and effective implementations. Embracing this strategy could lead to substantial advancements in the field of Alzheimer's disease treatment. [ABSTRACT FROM AUTHOR]

Nanogel systems loaded with nanosuspension area promising approach tonose-to-brain delivery in order to reduce the dose and dosing frequency and also improve the bioavailability of the drug. In the present study, an attempt was made to develop a nanosuspension-loaded insitu nasal nanogel of nortriptyline HCl (NTH) to achieve effective administration through the intranasal route to reach the brain via the olfactory and trigeminal nerves to improve the therapeutic efficiency. A nanoprecipitation–ultrasonication method followed by high-pressure homogenization was elected for the preparation of the nanosuspension, which was further incorporated into the in situ gelling polymer solution. The optimized nanosuspension-loaded nanogels were prepared using gellan gum. The optimized formulation showed an average particle size of 10–100 nm, a good PDI value, an increase in solubility, a good gelation property, and the desired viscosity to adhere to the nasal mucosa after ionic interactions. In vitro drug release was found to be greater than a drug solution over a period of 60 min. Spreadability and viscosity studies showed better results in achieving a good residence time. Hence, it was proved that insitu nanogel is one of the best possible approaches for the targeting of drugs toward the brain in nanoform. [ABSTRACT FROM AUTHOR]

Current strategies to identify ligands for brain delivery select candidates based on preferential binding to cell-membrane components (CMC) on brain endothelial cells (EC). However, such strategies generate ligands with inherent brain specificity limitations, as the CMC (e.g., the transferrin receptor TfR1) are also significantly expressed on peripheral EC. Therefore, novel strategies are required to identify molecules allowing increased specificity of therapy brain delivery. Here, we demonstrate that, while individual CMC are shared between brain EC and peripheral EC, their endocytic internalization rate is markedly different. Such differential endocytic rate may be harnessed to identify molecular tags for brain targeting based on their selective retention on the surface of brain EC, thereby generating 'artificial' targets specifically on the brain vasculature. By quantifying the retention of labelled proteins on the cell membrane, we measured the general endocytic rate of primary brain EC to be less than half that of primary peripheral (liver and lung) EC. In addition, through bio-panning of phage-displayed peptide libraries, we unbiasedly probed the endocytic rate of individual CMC of liver, lung and brain endothelial cells. We identified phage-displayed peptides which bind to CMC common to all three endothelia phenotypes, but which are preferentially endocytosed into peripheral EC, resulting in selective retention on the surface of brain EC. Furthermore, we demonstrate that the synthesized free-form peptides are capable of generating artificial cell-surface targets for the intracellular delivery of model proteins into brain EC with increasing specificity over time. The developed identification paradigm, therefore, demonstrates that the lower endocytic rate of individual CMC on brain EC can be harnessed to identify peptides capable of generating 'artificial' targets for the selective delivery of proteins into the brain vasculature. In addition, our approach identifies brain-targeting peptides which would have been overlooked by conventional identification strategies, thereby increasing the repertoire of candidates to achieve specific therapy brain delivery. [ABSTRACT FROM AUTHOR]

Globally, many individuals struggle with Alzheimer's disease (AD), an unrelenting and incapacitating neurodegenerative condition. Despite notable research endeavors, effective remedies for AD remain constrained, prompting the exploration of innovative therapeutic avenues. Within this context, silica-based nanoplatforms have emerged with pronounced potential due to their unique attributes like expansive surface area, customizable pore dimensions, and compatibility with living systems. These nanoplatforms hold promise as prospective interventions for AD. This assessment provides a comprehensive overview encompassing various forms of mesoporous silica nanoparticles (MSNs), techniques for formulation, and their applications in biomedicine. A significant feature lies in their ability to precisely guide and control the transport of therapeutic agents to the brain, facilitated by the adaptability of these nanoplatforms as drug carriers. Their utility as tools for early detection and monitoring of AD is investigated. Challenges and prospects associated with harnessing MSNs are studied, underscoring the imperative of stringent safety evaluations and optimization of how they interact with the body. Additionally, the incorporation of multifunctional attributes like imaging and targeting components is emphasized to enhance their efficacy within the intricate milieu of AD. As the battle against the profound repercussions of AD persists, MSNs emerge as a promising avenue with the potential to propel the development of viable therapeutic interventions. [ABSTRACT FROM AUTHOR]

Lamotrigine. (LMT) is a triazine drug has an antiepileptic effect but with low water solubility, dissolution rate and thus therapeutic effect. Spanlastics are nano-vesicular carriers' act as site-specific drug delivery system. Intranasal route could direct the drug from nose to brain and provide a faster and more specific therapeutic effect. Therefore, this study aimed to upload lamotrigine onto nano-vesicles using spanlastic nasal insert delivery for effective epilepsy treatment via overcoming lamotrigine's low solubility and improving its bioavailability. Lamtrigine-loaded nano-spanlastic vesicles were prepared by ethanol injection method. To study different formulation factor's effect on formulations characters; particle size (PS), Zeta potential (ZP), polydispersity index (PDI), entrapment efficiency percentage (EE%) and LMT released amount after 6 h (Q6h); 2^1 and 3^1 full factorial designs were employed. Optimized formula was loaded in lyophilized nasal inserts formulation which were characterized for LMT release and mucoadhesion. Pharmacokinetics studies in plasma and brain were performed on rats to investigate drug targeting efficiency. The optimal nano-spanlastic formulation (F4; containing equal Span 60 amount (100 mg) and edge activator; Tween 80) exhibited nano PS (174.2 nm), high EE% (92.75%), and Q6h > 80%. The prepared nasal inserts (S4) containing 100 mg HPMC has a higher mucoadhesive force (9319.5 dyne/cm2) and dissolution rate (> 80% within 10 min) for rapid in vivo bio-distribution. In vivo studies showed considerable improvement brain and plasma's rate and extent absorption after intranasal administration indicating a high brain targeting efficiency. The results achieved indicate that nano-spanlastic nasal-inserts offer a promising LMT brain targeting in order to maximize its antiepileptic effect. [ABSTRACT FROM AUTHOR]

Brain tumor accounts for about 1.6% of incidence and 2.5% of mortality of all tumors, and the median survival for brain tumor patients is only about 20 months. The treatment for brain tumor still faces many challenges, such as the blood-brain barrier (BBB), blood-brain tumor barrier (BBTB), the overexpressed efflux pumps, the infiltration, invasion, high heterogeneity of tumor cells, drug resistance and immune escape caused by tumor microenvironment (TME) and cancer stem cells (CSC). This review attempts to clarify the challenges for multi-functional nano drug delivery systems (NDDS) to cross the BBB and target the cancer cells or organelles, and also provides a brief description of the different types of targeted multi-functional NDDS that have shown potential for success in delivering drugs to the brain. Further, this review also summarizes the research progress of multi-functional NDDS in the combination therapy of brain tumors from the following sections, the combination of chemotherapy drugs, chemotherapy-chemodynamic combination therapy, chemotherapy-immunization combination therapy, and chemotherapy-gene combination therapy. We also provide an insight into the recent advances in designing multi-functional NDDS for combination therapy. [ABSTRACT FROM AUTHOR]

Zolmitriptan (ZT) is a potent second generation triptan, commonly administered to alleviate migraine attacks. ZT suffers various limitations; massive hepatic first pass metabolism, P-gp efflux transporters susceptibility, and limited (≈40%) oral bioavailability. Transdermal route of administration could be explored to enhance its bioavailability. A 23.31 full factorial design was constructed to developed twenty-four ZT loaded terpesomes via thin film hydration technique. The influence of drug: phosphatidylcholine ratio, terpene type, terpene concentration and sodium deoxycholate concentration on the characterization of the developed ZT-loaded terpesomes was assessed. Particle size (PS), zeta potential (ZP), ZT entrapment efficiency (EE%), drug loading (DL%) and drug released percentages after 6 h (Q6h) were the selected dependent variables. Further morphological, crystallinity, and in-vivo histopathological studies were conducted for the optimum terpesomes (T6). 99mTc-ZT and 99mTc-ZT-T6 gel were radio-formulated for in-vivo biodistribution studies in mice following transdermal application of 99mTc-ZT-T6 gel, relative to 99mTc-ZT oral solution. T6 terpesomes [comprising ZT and phosphatidylcholine (1:15), cineole (1% w/v) and sodium deoxycholate (0.1% w/v)] were optimum with respect to spherical PS (290.2 nm), ZP (-48.9 mV), EE% (83%), DL% (3.9%) and Q6h (92.2%) with desirability value of 0.85. The safety of the developed T6 terpesomes was verified by the in-vivo histopathological studies. 99mTc-ZT-T6 gel showed maximum brain concentration (5 ± 0.1%ID/ g) with highest brain to blood ratio of 1.92 ± 0.1 at 4 h post transdermal application. Significant improvement of ZT brain relative bioavailability (529%) and high brain targeting efficiency (315%) were revealed with 99mTc-ZT-T6 gel, which confirmed successful ZT delivery to the brain. Terpesomes could be safe, successful systems capable of improving ZT bioavailability with high brain targeting efficiency. [ABSTRACT FROM AUTHOR]

Nimodipine (NMD) is a 1,4-dihydropyridine calcium antagonist that is effective in the prevention and treatment of cerebral arterial vasospasm and cerebral ischemic injury caused by subarachnoid hemorrhage. Since the drug itself is highly insoluble in water and has low oral bioavailability, while injectable formulations may cause pain and inflammation, the blood–brain barrier (BBB) prevents the effective delivery of therapeutic agents to the brain tissue. Therefore, in the present study, NMD liposomes were prepared by ethanol injection and innovatively lyophilised and loaded into temperature-sensitive in situ gels for intranasal administration as sprays to deliver drugs to brain tissues bypassing the blood–brain barrier. The optimal gel formulation was obtained by screening in which liposomes were divided into lecithin, cholesterol, and NMD in the ratio of 40:10: 1; Pluronic P407, Pluronic P188, Tween 80, polyvinyl ketone and ethyl nipagin in the ratio of (180:20:3:1:1); Pluronic P407, Pluronic P188, Tween 80, polyvinyl ketone, and ethyl nipagin in the ratio of (180:20:3:1:1). The prepared flow gel can form a solidified gel after a temperature of 31.07–32.07°C and a time of 58.51–59.89 s. Meanwhile, the NMD liposome gel formulation achieved sustained release over 56 h. The pharmacokinetic results of the developed NMD liposomal temperature-sensitive in situ gel and NMD temperature-sensitive in situ gel showed that liposomal nasal mucosal in situ gel is a more effective brain-targeted drug delivery system for NMD. [ABSTRACT FROM AUTHOR]

The number of people with Alzheimer's disease (AD) is increasing annually, with the nidus mainly concentrated in the cortex and hippocampus. Despite of numerous efforts, effective treatment of AD is still facing great challenges due to the blood brain barrier (BBB) and limited drug distribution in the AD nidus sites. Thus, in this study, using vinpocetine (VIN) as a model drug, the objective is to explore the feasibility of tackling the above bottleneck via intranasal drug delivery in combination with a brain guider, borneol (BOR), using nanoemulsion (NE) as the carrier. First of all, the NE were prepared and characterized. In vivo behavior of the NE after intranasal administration was investigated. Influence of BOR dose, BOR administration route on drug brain targeting behavior was evaluated, and the influence of BOR addition on drug brain subregion distribution was probed. It was demonstrated that all the NE had comparable size and similar retention behavior after intranasal delivery. Compared to intravenous injection, improved brain targeting effect was observed by intranasal route, and drug targeting index (DTI) of the VIN-NE group was 154.1%, with the nose-to-brain direct transport percentage (DTP) 35.1%. Especially, remarkably enhanced brain distribution was achieved after BOR addition in the NE, with the extent depending on BOR dose. VIN brain concentration was the highest in the VIN-1-BOR-NE group at BOR dose of 1 mg/kg, with the DTI reaching 596.1% and the DTP increased to 83.1%. BOR could exert better nose to brain delivery when administrated together with the drug via intranasal route. Notably, BOR can remarkably enhance drug distribution in both hippocampus and cortex, the nidus areas of AD. In conclusion, in combination with intranasal delivery and the intrinsic brain guiding effect of BOR, drug distribution not only in the brain but also in the cortex and hippocampus can be enhanced significantly, providing the perquisite for improved therapeutic efficacy of AD. [ABSTRACT FROM AUTHOR]

The prevalence of neurological illnesses, such as epilepsy, Alzheimer's disease, Parkinson's disease, glioblastoma, and multiple sclerosis, is rising globally; there is still a shortage of effective drug delivery to central nervous system (CNS). The blood-brain barrier (BBB) is directly related to restricted drug entrance to the brain and prevents the major dose of potentially effective therapeutic moieties to reaching the brain from the systemic circulation. Drugs that have minimal oral bioavailability and are active at low dosages can be delivered effectively using intranasal route of drug delivery in conjunction with nanoparticulate structures. This route facilitates the movement of therapeutic molecules through and by circumventing the BBB. The nasal route is convenient for self-medication and avoids the hepatic first-pass elimination associated with oral delivery. The critical evaluation of reported studies showed dose reduction, effectiveness, safety, stability, improved blood circulation time, controlled release characteristics, and targeting in brain for drug-loaded nanocarriers administered intranasally. The size range of nanoparticles from published works was found to be in between 70 and 200 nm. In this review, recent developments in nanocarrier-based intranasal drug delivery systems (nanostructured lipid carriers, solid lipid nanoparticles, liposomes, niosomes, polymeric nanoparticles, nanoemulsions, nanomicelles, carbon nanotubes, and metallic nanoparticles) are described, along with basic aspects of nasal drug delivery. Patent reports related to intranasal delivery of drugs through nanocarriers in brain targeting are also summarized. [ABSTRACT FROM AUTHOR]

Abstract Background Organophosphate (OP)-induced delayed neurological damage is attributed to permanent neuropathological lesions caused by irreversible OP-neurocyte interactions, without potent brain-targeted etiological antidotes to date. The development of alternative therapies to achieve intracerebral OP detoxification is urgently needed. Methods We designed a brain-targeted nanoreactor by integrating enzyme immobilization and biomimetic membrane camouflaging protocols with careful characterization, and then examined its blood–brain barrier (BBB) permeability both in vitro and in vivo. Subsequently, the oxidative stress parameters, neuroinflammatory factors, apoptotic proteins and histopathological changes were measured and neurobehavioral tests were performed. Results The well-characterized nanoreactors exerted favourable BBB penetration capability both in vitro and in vivo, significantly inhibiting OP-induced intracerebral damage. At the cellular and tissue levels, nanoreactors obviously blocked oxidative stress, cellular apoptosis, inflammatory reactions and brain histopathological damage. Furthermore, nanoreactors radically prevented the occurrence of OP-induced delayed cognitive deficits and psychiatric abnormality. Conclusion The nanoreactors significantly prevented the development of OP-induced delayed neurological damage, suggesting a potential brain-targeted etiological strategy to attenuate OP-related delayed neurological and neurobehavioral disorders. Graphical Abstract

Etomidate is a general anesthetic that has shown good hemodynamic stability without significant cardiovascular or respiratory depression. Despite several kinds of dosage forms having been reported for this drug, formulation types are very limited in clinical practice, and brain-targeted formulations for this central nervous system (CNS) drug have been rarely reported. Moreover, studies on the biocompatibility, toxicity, and anesthetic effects of the etomidate preparations in vivo were inadequate. The present study was to develop lactoferrin-modified liposomal etomidate (Eto-lip-LF) for enhanced drug distribution in the brain and improved anesthetic effects. Eto-lip-LF had good stability for storage and hemocompatibility for intravenous injection. Compared with the non-lactoferrin-containing liposomes, the lactoferrin-modified liposomes had notably enhanced brain-targeting ability in vivo, which was probably realized by the binding of transferrin with the transferrin and lactoferrin receptors highly distributed in the brain. Eto-lip-LF had a therapeutic index of about 25.3, higher than that of many other general anesthetics. Moreover, compared with the commercial etomidate emulsion, Eto-lip-LF could better achieve rapid onset of general anesthesia and rapid recovery from anesthesia, probably due to the enhanced drug delivery to the brain. The above results demonstrated the potential of this lactoferrin-modified liposomal etomidate to become an alternative preparation for clinical general anesthesia.

(-)-Epigallocatechin-3-gallate (EGCG) possesses potent antioxidant and neuroprotective properties. In this study, a novel glucose-modified EGCG encapsulated liposome (EGCG-Glu-Lip) was developed and characterized. EGCG-Glu-Lip liposome’s cytotoxicity, brain targeting ability, and its antioxidative neuroprotection were examined via bEnd.3 and PC12 cells testing. EGCG-Glu-Lip liposome particle mean size was 158.7 nm, with encapsulation efficiency 73.05 % under EGCG/lipid mass ratio 1:22 and soybean phospholipids (SPC) to cholesterol (Chol) mass ratio 3.84:1. EGCG-Glu-Lip exhibited less cytotoxicity, stronger protection to PC12 cells from H2O2 induced oxidative damage, keeping reactive oxygen species (ROS) level. Glucose modified liposome (Glu-Lip) cellular uptake in bEnd.3 and PC12 cells were 1.5-fold and 1.3-fold higher than that of Lip, supporting EGCG-Glu-Lip possessing enhanced blood–brain barrier (BBB) permeability mediated via glucose transporter protein 1 (GLUT1) and neuronal cell uptake for brain targeting. EGCG-Glu-Lip could provide an efficient nano delivery pathway to deliver sufficient EGCG to brain tissue exerting its antioxidative neuroprotection more efficiently.

Nano-structured lipid carriers containing zopiclone were prepared as a targeted drug delivery system to convey zopiclone directly to brain via nasal route. Nano-structured lipid carriers were constructed adopting hot emulsification-ultrasonication method using palmitic acid in place of the solid lipid, cod liver oil as liquid lipid, and poloxamer 407 as a surfactant. A three-factor three-level central composite face-centered design was used to optimize the formulated nano-structured lipid carriers. The independent factors were lipid amount (X1), surfactant amount (X2), and sonication time (X3). The examined responses were entrapment efficiency (EE,Y1,%), particle size (PS,Y2,nm), zeta potential(mV), polydispersity index(PDI,Y3), in vitro release(Q8h,Y4,%) and dissolution efficiency (DE,Y5,%). The optimum formula showed high entrapment efficiency of 94.31% ± 2.44, in vitro drug release of 83.89% ± 1.77 with dissolution efficiency equals 88.63% ± 2.01, small particle size of 71.27 nm ± 13.57 and low polydispersity index 0.097 ± 0.15. In vivo biodistribution in mice was evaluated by a radiobiological technique using radioiodinated zopiclone([131I]iodo-ZP). Results revealed the superiority of the intranasal route to deliver zopiclone directly to brain faster and higher brain uptake (6.9 ± 1.02%ID/g at 5 min post-administration). The current study confirmed that intranasal administration of nano-structured lipid carriers had great potential as an effective tool for targeted brain zopiclone delivery for insomnia treatment.

AbstractLamotrigine. (LMT) is a triazine drug has an antiepileptic effect but with low water solubility, dissolution rate and thus therapeutic effect. Spanlastics are nano-vesicular carriers’ act as site-specific drug delivery system. Intranasal route could direct the drug from nose to brain and provide a faster and more specific therapeutic effect. Therefore, this study aimed to upload lamotrigine onto nano-vesicles using spanlastic nasal insert delivery for effective epilepsy treatment via overcoming lamotrigine’s low solubility and improving its bioavailability. Lamtrigine-loaded nano-spanlastic vesicles were prepared by ethanol injection method. To study different formulation factor’s effect on formulations characters; particle size (PS), Zeta potential (ZP), polydispersity index (PDI), entrapment efficiency percentage (EE%) and LMT released amount after 6 h (Q6h); 2^1 and 3^1 full factorial designs were employed. Optimized formula was loaded in lyophilized nasal inserts formulation which were characterized for LMT release and mucoadhesion. Pharmacokinetics studies in plasma and brain were performed on rats to investigate drug targeting efficiency. The optimal nano-spanlastic formulation (F4; containing equal Span 60 amount (100 mg) and edge activator; Tween 80) exhibited nano PS (174.2 nm), high EE% (92.75%), and Q6h > 80%. The prepared nasal inserts (S4) containing 100 mg HPMC has a higher mucoadhesive force (9319.5 dyne/cm2) and dissolution rate (> 80% within 10 min) for rapid in vivo bio-distribution. In vivo studies showed considerable improvement brain and plasma’s rate and extent absorption after intranasal administration indicating a high brain targeting efficiency. The results achieved indicate that nano-spanlastic nasal-inserts offer a promising LMT brain targeting in order to maximize its antiepileptic effect.

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Purposes: Generalized anxiety is one of the most frequent anxiety problems. This study aimed to improve the distribution of venlafaxine HCl (Ven) in the brain by using Tween 80-coated chitosan nanoparticles made by ionic gelation. Methods: The impact of the proportion of chitosan (CS): tripolyphosphate (TPP) and surface coating on the formulations were investigated. Differential scanning calorimetry (DSC), attenuated total reflectance–Fourier transform infrared (ATR-FTIR) spectroscopy, drug release, scanning electron microscopy (SEM), and animal bio-distribution model, and cellular safety assessment were applied to investigate the characteristics, morphology, and effectiveness of the Ven nanoparticle. Results: The drug entrapment efficiency (80.69 ± 1.91%), particle size (248.066 ± 7.385 nm), polydispersity index (0.286 ± 0.012), and zeta potential (-13.93 ± 1.65 mV) of Tween 80-coated and Ven-incorporated chitosan nanoparticles were determined to be adequate. In vitro drug release from uncoated (62.758 ± 3.581%) and Tween 80-coated nanoparticles (30.682 ± 3.225%) demonstrated sustained release over 24 h compared with Ven solution. Furthermore, the cell safety of both coated and uncoated nanoparticles showed that they were nontoxic. In vivo bio-distribution investigations in mice revealed that Tween 80-coated Ven-entrapped chitosan nanoparticles had greater Ven amounts (474.393 ± 52.100 ng/ml) in the brain tissue after 1 h of oral administration than uncoated Ven-entrapped chitosan nanoparticles (357.815 ± 39.624 ng/ml) and Ven solution (122.752 ± 38.075 ng/ml). Conclusion: These findings indicated that surface-coated, Ven-loaded chitosan nanoparticles might become a viable technique for improving Ven brain uptake and ultimately opening up new pathways for generalized anxiety disorder management. [ABSTRACT FROM AUTHOR]