Nose-to-brain drug delivery approach：a key to easily accessing the brain for the treatment of Alzheimer＇s disease

Alzheimer＇s disease（AD）：AD,a neurodegenerative disorder and a significant cause of dementia throughout the world mostly affects the older adults but sometimes also seen in young age（early state AD）（Agrawal et al.,2017）.

Mitochondrial-targeted and ROS-responsive nanocarrier via nose-to-brain pathway for ischemic stroke treatment

Oxidative stress injury and mitochondrial dysfunction are major obstacles to neurological functional recovery after ischemic stroke.The development of new approaches to simultaneously diminish oxidative stress and resist mitochondrial dysfunction is urgently needed.Inspired by the overproduced reactive oxygen species(ROS)at ischemic neuron mitochondria,multifunctional nanoparticles with ROS-responsiveness and mitochondrial-targeted(SPNPs)were engineered,achieving specific targeting delivery and controllable drug release at ischemic penumbra.Due to the nose-to-brain pathway.SPNPs which were encapsulated in a thermo-sensitive gel by intranasal administration were directly delivered to the ischemic penumbra bypassing the blood-brain barrier(BBB)and enhancing delivery efficiency.The potential of SPNPs for ischemic stroke treatment was systematically evaluated in vitro and in rat models of middle cerebral artery occlusion(MCAO).Results demonstrated the mitochondrialtargeted and protective effects of SPNPs on H2O2-induced oxidative damage in SH-SY5Y cells.In vivo distribution analyzed by fuorescence imaging proved the rapid and enhanced active targeting of SPNPs to the ischemic area in MCAO rats.SPNPs by intranasal administration exhibited superior therapeutic efficacy by alleviating oxidative stress,diminishing infammation,repairing mitochondrial function,and decreasing apoptosis.This strategy provided a multifunctional delivery system for the effective treatment of ischemic injury,which also implies a potential application prospect for other central nervous diseases.

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.

Quantitative tracking of trans-synaptic nose-to-brain transport of nanoparticles and its modulation by odor,aging,and Parkinson’s disease

Nanoparticles(NPs)can be transported via the nose-to-brain(N_(2)B)route.Nonetheless,quantitative data on their spatiotemporal dynamics and regulation of the N_(2)B transport are largely lacking.We surveyed metal oxide/hydroxide NPs as magnetic resonance imaging(MRI)contrasts for quantitative N_(2)B tracking.NPs containing divalent transition metals were the only ones capable of N_(2)B transmission.Using T1-weighted(T1W)MRI,we showed that Mn_(3)O_(4)-NPs were readily engulfed by olfactory receptor neurons(ORNs)without disrupting olfactory sensing,we mapped their N_(2)B trajectory.Within neurons,the Mn_(3)O_(4)-NPs were localized to the cytosol,mitochondria,vesicles,moved at mixed fast and slow axonal transport velocities intraand extra-vesicularly through ORNs.The NPs’axonal transport is dependent on neuronal activity and microtubule integrity.The Mn_(3)O_(4)-NPs were trans-synaptically transmitted through at least four synapses across the olfactory tract.Trans-synaptic transmission of the NPs was dependent on N-type Ca^(2+)channels and NMDA receptors but blocked by GABAB receptor activation.A five-parameter Weibull signal increase/decrease model fitted to the T1W MRI data allowed for estimating kinetic parameters of Mn_(3)O_(4)-NP accumulation/elimination.Absolute and relative accumulation rates,but not elimination,correlated negatively with the number of synapses from ORNs,indicating a coupling of the NPs’N_(2)B transport with spontaneous neuronal activity.Accordingly,olfactory stimuli(2,5-dimethylpyrazine and acetophenone)significantly modulated and rerouted the Mn_(3)O_(4)-NP N_(2)B transport odor specifically.Finally,the NPs’trans-synaptic transmission was impaired by aging and the onset of Parkinson’s disease.These data suggest new approaches to diagnostics,functional neuroimaging,controlling N_(2)B drug delivery.

Intranasal neprilysin rapidly eliminates amyloid-beta plaques, but causes plaque compensations: the explanation why the amyloid-beta cascade may fail?

Neurodegenerative brain disorders are a major burden in our society,such as Alzheimer´s disease.In order to repair or prevent such diseases,drugs are designed which enter the brain,but the blood-brain barrier limits their entry and the search for alternative pathways is important.Recently,we reported that intranasal delivery of the amyloid-beta degrading enzyme neprilysin eliminated amyloid-beta plaques in transgenic Alzheimer´s disease mice.This review describes the anatomical structure of the intranasal pathway,explains the intranasal delivery of pure neprilysin,cell-loaded neprilysin(platelets)and collagen-embedded neprilysin to destruct amyloid-beta plaques in Alzheimer´s disease in transgenic APP_SweDI mice and hypothesizes why this may cause compensation and why the amyloid-beta cascade hypothesis may fail.

Research progress on intranasal treatment forParkinson'sdisease

Parkinson's disease(PD)is the second most prevalent neurodegenerative disorder globally,significantly affecting the quality of life of affected individuals.Systemic drug delivery to the brain is inefficient because of first-pass metabolism,the blood-brain barrier(BBB),and the blood-cerebrospinal fluid barrier.This inefficiency necessitates increased dosage as the disease progresses,leading to severe side effects that compromise the efficacy of the medication.Nose-to-brain(N2B)administration bypasses the BBB,allowing delivery of both small molecules and large protein substances to the central nervous system.Compared with systemic administration,this method enhances brain bioavailability,reduces enzymatic degradation,and minimizes systemic adverse reactions.However,the N2B delivery system is associated with several critical challenges,including mucociliary clearance,enzymatic degradation,and drug translocation via efflux mechanisms.This paper provides a comprehensive overview of the current research progress in intranasal treatment of PD,considering both preclinical and clinical studies,and discusses the physiological aspects and limitations of its delivery system.

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.