Exploring the potential to enhance drug distribution in the brain subregion via intranasal delivery of nanoemulsion in combination with borneol as a guider

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.

Protective effects of resveratrol nanosuspensions loaded in situ hydrogel on Alzheimer disease model mice after intranasal administration

OBJECTIVE To evaluate the protective effects of resveratrol nanosuspensions loaded in situ hydrogel on Alzheimer disease model mice after intranasal administration. METHODS Resveratrol nanosuspensions were fabricated by antisolvent nano-precipitation method,and then dispersed into0.5% gellan gum to form resveratrol nanosuspenisons loaded ionic sensitive in situ hydrogel. The Alzheimer′s disease models were induced by lateral ventricle injection of Aβ_(25~35)and the protection and treatment effects of resveratrol nanosuspensions loaded in situ hydrogel on study and memory capability were performed after intranasal administration in water maze experiments. The analyses of the changes of cholinergic neurotransmitters in the brain were also determined according to the contents of acetylcholine(ACh),choline acetyltransferase(ChAT) and acetylcholinesterase(AChE). RESULTS Behavior assessment disclosed that in position navigation,escape latency test,each of experimental animals showed a decreased trend with swim training days increase,indicating that in the training process they had the ability of learning and memory in looking for the platform. Compared with the control group,average latency of model group significantly increased. While compared with the model group,treatment group′s average latency was significantly shorter. Space exploration experiment results showed that the times of model group across target quadrant of the platform is less than that of control group. But the crossing times of treatment group with resveratrol increased compared with the model group. As for the changes of cholinergic neurotransmitters,in AD mice brain ACh content decreased; the Ch AT activity decreased,while the activity of ACh E with the ability to hydrolysis acetylcholine increased. The administration of resveratrol can decrease the activity of ACh enzymes but increase Ch AT activity and the levels of acetylcholine. CONCLUSION Resveratrol nanosuspension loaded in situ gel can ameliorate the declining ability of learning and memory of AD model mice after intranasal administration. As a promising approach for the treatment of central nervous system(CNS) disease,intranasal administration route can effectively deliver to the brain and thus enhance the therapeutic effect.

Hypothalamic circuits and aging:keeping the circadian clock updated

Over the past century,age-related diseases,such as cancer,type-2 diabetes,obesity,and mental illness,have shown a significant increase,negatively impacting overall quality of life.Studies on aged animal models have unveiled a progressive discoordination at multiple regulatory levels,including transcriptional,translational,and post-translational processes,resulting from cellular stress and circadian derangements.The circadian clock emerges as a key regulator,sustaining physiological homeostasis and promoting healthy aging through timely molecular coordination of pivotal cellular processes,such as stem-cell function,cellular stress responses,and inter-tissue communication,which become disrupted during aging.Given the crucial role of hypothalamic circuits in regulating organismal physiology,metabolic control,sleep homeostasis,and circadian rhythms,and their dependence on these processes,strategies aimed at enhancing hypothalamic and circadian function,including pharmacological and non-pharmacological approaches,offer systemic benefits for healthy aging.Intranasal brain-directed drug administration represents a promising avenue for effectively targeting specific brain regions,like the hypothalamus,while reducing side effects associated with systemic drug delivery,thereby presenting new therapeutic possibilities for diverse age-related conditions.

Determination of the ED95 of intranasal sufentanil combined with intranasal dexmedetomidine for moderate sedation during endoscopic ultrasonography

BACKGROUND Sedation during endoscopic ultrasonography(EUS)poses many challenges and moderate-to-deep sedation are often required.The conventional method to preform moderate-to-deep sedation is generally intravenous benzodiazepine alone or in combination with opioids.However,this combination has some limitations.Intranasal medication delivery may be an alternative to this sedation regimen.AIM To determine,by continual reassessment method(CRM),the minimal effective dose of intranasal sufentanil(SUF)when combined with intranasal dexmedetomidine(DEX)for moderate sedation of EUS in at least 95%of patients(ED95).METHODS Thirty patients aged 18-65 and scheduled for EUS were recruited in this study.Subjects received intranasal DEX and SUF for sedation.The dose of DEX(1μg/kg)was fixed,while the dose of SUF was assigned sequentially to the subjects using CRM to determine ED95.The sedation status was assessed by modified observer’s assessment of alertness/sedation(MOAA/S)score.The adverse events and the satisfaction scores of patients and endoscopists were recorded.RESULTS The ED95 was intranasal 0.3μg/kg SUF when combined with intranasal 1μg/kg DEX,with an estimated probability of successful moderate sedation for EUS of 94.9%(95%confidence interval:88.1%-98.9%).When combined with intranasal 1μg/kg DEX,probabilities of successful moderate sedation at each dose level of intranasal SUF were as follows:0μg/kg SUF,52.8%;0.1μg/kg SUF,75.4%;0.2μg/kg SUF,89.9%;0.3μg/kg SUF,94.9%;0.4μg/kg SUF,98.0%;0.5μg/kg SUF,99.0%.CONCLUSION The ED95 needed for moderate sedation for EUS is intranasal 0.3μg/kg SUF when combined with intranasal 1μg/kg DEX,based on CRM.

Intranasal administration nanosystems for brain-targeted drug delivery

The existence of the blood-brain barrier(BBB)restricts the entry of drugs from the circulation into the central nervous system(CNS),which severely affects the treatment of neurological diseases,including glioblastoma,Parkinson’s disease(PD),and Alzheimer’s disease(AD).With the advantage of bypassing the BBB and avoiding systemic distribution,intranasal administration has emerged as an alternative method of delivering drugs to the brain.Drug delivery directly to the brain using intranasal nanosystems represents a new paradigm for neurological disease treatment because of its advantages in improving drug solubility and stability in vivo,enabling targeted drug delivery and controlled release,and reducing non-specific toxicity.And it has shown efficacy in animal models and clinical applications.Herein,this review describes the mechanisms of intranasal delivery of brain-targeted drugs,the properties of nanosystems for intranasal administration(e.g.,liposomes,nanoemulsions,and micelles),and strategies for intranasal drug delivery to enhance brain-targeted drug delivery.Recent applications of nanosystems in intranasal drug delivery and disease treatment have been comprehensively reviewed.Although encouraging results have been reported,significant challenges still need to be overcome to translate these nanosystems into clinics.Therefore,the future prospects of intranasal drug delivery nanosystems are discussed in depth,expecting to provide useful insights and guidance for effective neurological disease treatment.

HR121 targeting HR2 domain in S2 subunit of spike protein can serve as a broad-spectrum SARS-CoV-2 inhibitor via intranasal administration

The continuously emerging SARS-CoV-2 variants pose a great challenge to the efficacy of current drugs,this necessitates the development of broad-spectrum antiviral drugs.In the previous study,we designed a recombinant protein,heptad repeat(HR)121,as a variant-proof vaccine.Here,we found it can act as a fusion inhibitor and demonstrated broadly neutralizing activities against SARS-CoV-2 and its main variants.Structure analysis suggested that HR121 targets the HR2 domain in SARS-CoV-2 spike(S)2 subunit to block virus-cell fusion.Functional experiments demonstrated that HR121 can bind HR2 at serological-pH and endosomal-pH,highlighting its inhibition capacity when SARS-CoV-2 enters via either cellular membrane fusion or endosomal route.Importantly,HR121 can effectively inhibit SARS-CoV-2 and Omicron variant pseudoviruses entering the cells,as well as block authentic SARSCoV-2 and Omicron BA.2 replications in human pulmonary alveolar epithelial cells.After intranasal administration to Syrian golden hamsters,it can protect hamsters from SARS-CoV-2 and Omicron BA.2 infection.Together,our results suggest that HR121 is a potent drug candidate with broadly neutralizing activities against SARS-CoV-2 and its variants.

Human umbilical cord-derived mesenchymal stem cells promote repair of neonatal brain injury caused by hypoxia/ischemia in rats

Administration of human umbilical cord-derived mesenchymal stem cells(hUC-MSCs)is believed to be an effective method for treating neurodevelopmental disorde rs.In this study,we investigated the possibility of hUC-MSCs treatment of neonatal hypoxic/ischemic brain injury associated with maternal immune activation and the underlying mechanism.We established neonatal rat models of hypoxic/ischemic brain injury by exposing pregnant rats to lipopolysaccharide on day 16 or 17 of pregnancy.Rat offspring were intranasally administe red hUC-MSCs on postnatal day 14.We found that polypyrimidine tract-binding protein-1(PTBP-1)participated in the regulation of lipopolysaccharide-induced maternal immune activation,which led to neonatal hypoxic/ischemic brain injury.Intranasal delive ry of hUC-MSCs inhibited PTBP-1 expression,alleviated neonatal brain injury-related inflammation,and regulated the number and function of glial fibrillary acidic protein-positive astrocytes,there by promoting plastic regeneration of neurons and im p roving brain function.These findings suggest that hUC-MSCs can effectively promote the repair of neonatal hypoxic/ischemic brain injury related to maternal immune activation through inhibition of PTBP-1 expression and astrocyte activation.

Preventive effect of nasal Timosaponin BII-loaded temperature-/ionsensitive in situ hydrogels on Alzheimer’s disease

Objective:To study the preventive effect of Timosaponin BII(T-BII)-loaded temperature/ion-sensitive nasal in situ hydrogels(ISGs)on Alzheimer's disease(AD),its preparation technology,characteristics and in vivo effects were evaluated.Methods:The morphological and rheological properties were evaluated.The preventive effects of T-BII ISG on scopolamine-induced AD in mice were determined with the index of muscarinicreceptor 1(M1)expression and pathological changes.Results:Results revealed that T-BII ISG significantly increased the content of M1 choline receptors in the hippocampus of mice and ameliorated the damage incurred to the hippocampal cornu ammonis 1(CA1)area.Conclusion:T-BII ISGs is a reasonable and convenient method of exerting an obvious preventive effect on mice with AD induced by scopolamine.This,thereby,lays forth a new treatment option for preventing AD.

A micro-sized vaccine based on recombinant Lactiplantibacillus plantarum fights against SARS-CoV-2 infection via intranasal immunization

COVID-19 has globally spread to burden the medical system.Even with a massive vaccination,a mucosal vaccine offering more comprehensive and convenient protection is imminent.Here,a micro-sized vaccine based on recombinant Lactiplantibacillus plantarum(rLP)displaying spike or receptor-binding domain(RBD)was characterized as microparticles,and its safety and protective effects against SARS-CoV-2 were evaluated.We found a 66.7%mortality reduction and 100%protection with rLP against SARS-CoV-2 in a mouse model.The histological analysis showed decreased hemorrhage symptoms and increased leukocyte infiltration in the lung.Especially,rLP:RBD significantly decreased pulmonary viral loads.For the first time,our study provides a L.plantarum-vectored vaccine to prevent COVID-19 progress and transmission via intranasal vaccination.

Intranasal delivery of nanostructured lipid carriers,solid lipid nanoparticles and nanoemulsions:A current overview of in vivo studies

The management of the central nervous system(CNS)disorders is challenging,due to the need of drugs to cross the blood-brain barrier(BBB)and reach the brain.Among the various strategies that have been studied to circumvent this challenge,the use of the intranasal route to transport drugs from the nose directly to the brain has been showing promising results.In addition,the encapsulation of the drugs in lipid-based nanocarriers,such as solid lipid nanoparticles(SLNs),nanostructured lipid carriers(NLCs)or nanoemulsions(NEs),can improve nose-to-brain transport by increasing the bioavailability and site-specifc delivery.This review provides the state-of-the-art of in vivo studies with lipid-based nanocarriers(SLNs,NLCs and NEs)for nose-to-brain delivery.Based on the literature available from the past two years,we present an insight into the different mechanisms that drugs can follow to reach the brain after intranasal administration.The results of pharmacokinetic and pharmacodynamics studies are reported and a critical analysis of the differences between the anatomy of the nasal cavity of the different animal species used in in vivo studies is carried out.Although the exact mechanism of drug transport from the nose to the brain is not fully understood and its effectiveness in humans is unclear,it appears that the intranasal route together with the use of NLCs,SLNs or NEs is advantageous for targeting drugs to the brain.These systems have been shown to be more effective for nose-to-brain delivery than other routes or formulations with non-encapsulated drugs,so they are expected to be approved by regulatory authorities in the coming years.

Intranasal temperature-sensitive hydrogels of cannabidiol inclusion complex for the treatment of post-traumatic stress disorder

Post-traumatic stress disorder(PTSD)is a psychiatric disease that seriously affects brain function.Currently,selective serotonin reuptake inhibitors(SSRIs)are used to treat PTSD clinically but have decreased efficiency and increased side effects.In this study,nasal cannabidiol inclusion complex temperature-sensitive hydrogels(CBD TSGs)were prepared and evaluated to treat PTSD.Mice model of PTSD was established with conditional fear box.CBD TSGs could significantly improve the spontaneous behavior,exploratory spirit and alleviate tension in open field box,relieve anxiety and tension in elevated plus maze,and reduce the freezing time.Hematoxylin and eosin and c-FOS immunohistochemistry slides showed that the main injured brain areas in PTSD were the prefrontal cortex,amygdala,and hippocampus CA1.CBD TSGs could reduce the level of tumor necrosis factor-a caused by PTSD.Western blot analysis showed that CBD TSGs increased the expression of the 5-HT1 A receptor.Intranasal administration of CBD TSGs was more efficient and had more obvious brain targeting effects than oral administration,as evidenced by the pharmacokinetics and brain tissue distribution of CBD TSGs.Overall,nasal CBD TSGs are safe and effective and have controlled release.There are a novel promising option for the clinical treatment of PTSD.

Polymeric nanocarriers for nose-to-brain drug delivery in neurodegenerative diseases and neurodevelopmental disorders

Neurodegenerative diseases are progressive conditions that affect the neurons of the central nervous system(CNS)and result in their damage and death.Neurodevelopmental disorders include intellectual disability,autism spectrum disorder,and attention-deficit/hyperactivity disorder and stem from the disruption of essential neurodevelopmental processes.The treatment of neurodegenerative and neurodevelopmental conditions,together affecting~120 million people worldwide,is challenged by the blood—brain barrier(BBB)and the blood—cerebrospinal fluid barrier that prevent the crossing of drugs from the systemic circulation into the CNS.The nose-to-brain pathway that bypasses the BBB and increases the brain bioavailability of intranasally administered drugs is promising to improve the treatment of CNS conditions.This pathway is more efficient for nanoparticles than for solutions,hence,the research on intranasal nano-drug delivery systems has grown exponentially over the last decade.Polymeric nanoparticles have become key players in the field owing to the high design and synthetic flexibility.This review describes the challenges faced for the treatment of neurodegenerative and neurodevelopmental conditions,the molecular and cellular features of the nasal mucosa and the contribution of intranasal nano-drug delivery to overcome them.Then,a comprehensive overview of polymeric nanocarriers investigated to increase drug bioavailability in the brain is introduced.

鼻内联合用药

变应性鼻炎（AR）已经成为人类第5个最常见的慢性疾病,据估计在美国有10%～30%成年人和高达40%的儿童患病[1～5]。中国2007年在11个中心城市调查的数据表明,AR发病率为12%,并且呈上升趋势。虽然,AR并不是威胁生命的疾病,但是其症状和并发症可以明显影响到生活质量[6]。

Neutralization of SARS-CoV-2 pseudovirus using ACE2-engineered extracellular vesicles

The spread of coronavirus disease 2019(COVID-19)throughout the world has resulted in stressful healthcare burdens and global health crises.Developing an effective measure to protect people from infection is an urgent need.The blockage of interaction between angiotensin-converting enzyme 2(ACE2)and S protein is considered an essential target for anti-severe acute respiratory syndrome coronavirus 2(SARS-Co V-2)drugs.A full-length ACE2 protein could be a potential drug to block early entry of SARS-Co V-2 into host cells.In this study,a therapeutic strategy was developed by using extracellular vesicles(EVs)with decoy receptor ACE2 for neutralization of SARS-Co V-2.The EVs embedded with engineered ACE2(EVs-ACE2)were prepared;the EVs-ACE2 were derived from an engineered cell line with stable ACE2 expression.The potential effect of the EVs-ACE2 on anti-SARS-Co V-2 was demonstrated by both in vitro and in vivo neutralization experiments using the pseudovirus with the S protein(S-pseudovirus).EVs-ACE2 can inhibit the infection of S-pseudovirus in various cells,and importantly,the mice treated with intranasal administration of EVs-ACE2 can suppress the entry of S-pseudovirus into the mucosal epithelium.Therefore,the intranasal EVs-ACE2 could be a preventive medicine to protect from SARS-Co V-2 infection.This EVs-based strategy offers a potential route to COVID-19 drug development.