Intranasal delivery of paeoniflorin nanocrystals for brain targeting

Paeoniflorin(PA) is an anti-Parkinson Chinese medicine with inferior bioavailability and difficulty in delivery to the brain. This research is to develop an efficacious PA nanocrystal formulation(PA-NCs) that is suitable for intranasal administration to treat Parkinson’s disease(PD). PA-NCs were fabricated through an antisolvent precipitation method using TPGS as the stabilizer. The rod-shaped PA-NCs had particle size of 139.6 ± 1.3 nm and zeta potential of-23.2 ± 0.529 mV. A molecular dynamics simulation indicated that van der Waals forces are the primary drivers of interactions between PA and TPGS. In the ex vivo nasal mucosa permeation assay, the cumulative drug release at 24 h was 87.14% ± 5.34%,which was significantly higher than that of free PA. PA-NCs exhibited substantially improved cellular uptake as well as permeability on Calu-3 cells as compared to PA alone. FRET imaging analysis demonstrated that intact NCs could be internalized into Calu-3 cells.Moreover, PA-NCs conferred desirable protective effect against MPP+-induced SH-SY5Y cellular damage. Pharmacokinetic studies revealed a higher PA concentration in the brain following intranasal delivery of PA-NCs. In summary, the intranasal administration of PANCs is a promising treatment strategy for PD.

A pan-coronavirus peptide inhibitor prevents SARS-CoV-2 infection in mice by intranasal delivery

Coronaviruses(Co Vs)have brought serious threats to humans,particularly severe acute respiratory syndrome coronavirus 2(SARS-Co V-2),which continually evolves into multiple variants.These variants,especially Omicron,reportedly escape therapeutic antibodies and vaccines,indicating an urgent need for new antivirals with pan-SARS-Co V-2 inhibitory activity.We previously reported that a peptide fusion inhibitor,P3,targeting heptad repeated-1(HR1)of SARS-Co V-2 spike(S)protein,could inhibit viral infections.Here,we further designed multiple derivatives of the P3 based on structural analysis and found that one derivative,the P315V3,showed the most efficient antiviral activity against SARS-Co V-2 variants and several other sarbecoviruses,as well as other human-Co Vs(HCo Vs).P315V3 also exhibited effective prophylactic efficacy against the SARS-Co V-2 Delta and Omicron variants in mice via intranasal administration.These results suggest that P315V3,which is in PhaseⅡclinical trial,is promising for further development as a nasal pan-SARS-Co V-2 or pan-Co Vs inhibitor to prevent or treat CoV diseases.

Intranasal nerve growth factor for prevention and recovery of the outcomes of traumatic brain injury

Traumatic brain injury is one of the main causes of mortality and disability worldwide.Traumatic brain injury is characterized by a primary injury directly induced by the impact,which progresses into a secondary injury that leads to cellular and metabolic damages,starting in the first few hours and days after primary mechanical injury.To date,traumatic brain injury is not targetable by therapies aimed at preventing and/or limiting the outcomes of secondary damage but only by palliative therapies.Nerve growth factor is a neurotrophin targeting neuronal and non-neuronal cells,potentially useful in preventing/limiting the outcomes of secondary damage in traumatic brain injury.This potential has further increased in the last two decades since the possibility of reaching neurotrophin targets in the brain through its intranasal delivery has been exploited.Indeed,molecules intranasally delivered to the brain parenchyma may easily bypass the blood-brain barrier and reach their therapeutic targets in the brain,with favorable kinetics,dynamics,and safety profile.In the first part of this review,we aimed to report the traumatic brain injury-induced dysfunctional mechanisms that may benefit from nerve growth factor treatment.In the second part,we then exposed the experimental evidence relating to the action of nerve growth factor(both in vitro and in vivo,after administration routes other than intranasal)on some of these mechanisms.In the last part of the work,we,therefore,discussed the few manuscripts that analyze the effects of treatment with nerve growth factor,intranasally delivered to the brain parenchyma,on the outcomes of traumatic brain injury.

Topical delivery of nerve growth factor for treatment of ocular and brain disorders

Neurotrophins are a family of proteins that support neuronal proliferation, survival, and differentiation in the central and peripheral nervous systems, and are regulators of neuronal plasticity. Nerve growth factor is one of the best-described neurotrophins and has advanced to clinical trials for treatment of ocular and brain diseases due to its trophic and regenerative properties. Prior trials over the past few decades have produced conflicting results, which have principally been ascribed to adverse effects of systemic nerve growth factor administration, together with poor penetrance of the blood-brain barrier that impairs drug delivery. Contrastingly, recent studies have revealed that topical ocular and intranasal nerve growth factor administration are safe and effective, suggesting that topical nerve growth factor delivery is a potential alternative to both systemic and invasive intracerebral delivery. The therapeutic effects of local nerve growth factor delivery have been extensively investigated for different ophthalmic diseases, including neurotrophic keratitis, glaucoma, retinitis pigmentosa, and dry eye disease. Further, promising pharmacologic effects were reported in an optic glioma model, which indicated that topically administered nerve growth factor diffused far beyond where it was topically applied. These findings support the therapeutic potential of delivering topical nerve growth factor preparations intranasally for acquired and degenerative brain disorders. Preliminary clinical findings in both traumatic and non-traumatic acquired brain injuries are encouraging, especially in pediatric patients, and clinical trials are ongoing. The present review will focus on the therapeutic effects of both ocular and intranasal nerve growth factor delivery for diseases of the brain and eye.

Localized delivery of nanomedicine and antibodies for combating COVID-19

The severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)pandemic has been a major health burden in the world.So far,many strategies have been investigated to control the spread of COVID-19,including social distancing,disinfection protocols,vaccines,and antiviral treatments.Despite the significant achievement,due to the constantly emerging new variants,COVID-19 is still a great challenge to the global healthcare system.It is an urgent demand for the development of new therapeutics and technologies for containing the wild spread of SARS-CoV-2.Inhaled administration is useful for the treatment of lung and respiratory diseases,and enables the drugs to reach the site of action directly with benefits of decreased dose,improved safety,and enhanced patient compliance.Nanotechnology has been extensively applied in the prevention and treatment of COVID-19.In this review,the inhaled nanomedicines and antibodies,as well as intranasal nanodrugs,for the prevention and treatment of COVID-19 are summarized.

Comparative pharmacokinetics of tetramethylpyrazine phosphate in rat plasma and extracellular fluid of brain after intranasal,intragastric and intravenous administration

The purpose of this study was to compare the pharmacokinetic profiles of tetramethylpyrazine phosphate(TMPP)in plasma and extracellular fluid of the cerebral cortex of rats via three delivery routes:intranasal(i.n.),intragastric(i.g.)and intravenous(i.v.)administration.After i.n.,i.g.and i.v.administration of a single-dose at 10 mg/kg,cerebral cortex dialysates and plasma samples drawn from the carotid artery were collected at timed intervals.The concentration of TMPP in the samples was analyzed by HPLC.The area under the concentration-time curve(AUC)and the ratio of the AUCbrain to the AUCplasma(drug targeting efficiency,DTE)was calculated to evaluate the brain targeting efficiency of the drug via these different routes of administration.After i.n.administration,TMPP was rapidly absorbed to reach its peak plasma concentration within 5 min and showed a delayed uptake into cerebral cortex(t_(max)=15 min).The ratio of the AUCbrain dialysates value between i.n.route and i.v.injection was 0.68,which was greater than that obtained after i.g.administration(0.43).The systemic bioavailability obtained with i.n.administration was greater than that obtained by the i.g.route(86.33%vs.50.39%),whereas the DTE of the nasal route was 78.89%,close to that of oral administration(85.69%).These results indicate that TMPP is rapidly absorbed from the nasal mucosa into the systemic circulation,and then crosses the blood-brain barrier(BBB)to reach the cerebral cortex.Intranasal administration of TMPP could be a promising alternative to intravenous and oral approaches.