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.

Intranasal absorption of rivastigmine hydrogen tartrate and brain targeting evaluation / 药学学报

To investigate factors influencing the intranasal absorption of rivastigmine hydrogen tartrate (RHT), we studied the pharmacokinetics of RHT after intranasal administration and evaluated its brain targeting behavior. In situ rat nasal perfusion model was used in the study and pH impact was examined on the intranasal absorption of RHT. High performance liquid chromatography (HPLC) method was established to measure RHT concentration in the plasma and brain tissue after intranasal and intravenous administration. The pharmacokinetic parameters, drug targeting index (DTI), and nose-to-brain direct transport percentage (DTP) were calculated. It was demonstrated that the intranasal absorption mechanism of RHT was passive diffusion. The absorption rate was highest at pH 6.0. The absolute bioavailability of intranasally administrated RHT was 73.58%. Compared with that of intravenous administration, RHT absorption into the brain was faster and more efficient after intranasal delivery, and the DTI value was 195.27% of intravenous injection. Moreover, 48.79% of the drug can be absorbed directly from the nose into the brain without systematic circulation. Meanwhile, drug elimination half-time in the brain was prolonged by 1.4 fold compared to that of intravenous injection. In conclusion, intranasal administration of RHT not only improves drug absorption into the system, but also enhances drug absorption rate and content in the brain remarkably, which is an advantage in the treatment of central nervous system-related diseases.

Progress and perspectives on targeting nanoparticles for brain drug delivery

Due to the ability of the blood-brain barrier (BBB) to prevent the entry of drugs into the brain, it is a challenge to treat central nervous system disorders pharmacologically. The development of nanotechnology provides potential to overcome this problem. In this review, the barriers to brain-targeted drug delivery are reviewed, including the BBB, blood-brain tumor barrier (BBTB), and nose-to-brain barrier. Delivery strategies are focused on overcoming the BBB, directly targeting diseased cells in the brain, and dual-targeted delivery. The major concerns and perspectives on constructing brain-targeted delivery systems are discussed.

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.

Promotion of cerebral blood supply and expression of vascular endothelial growth factor by intranasal delivery of calcitonin gene-related peptide after subarachnoid hemorrhage / 中国药理学通报

Aim To investigate the influence of intranasal delivery of calcitonin gene-related peptide(CGRP)on cerebral blood supply and expression of vascular endothelial growth factor(VEGF)following experimental subarachnoid hemorrhage(SAH).Methods Wistar rats were divided into normal control group,SAH group,intranasal normal saline(NS)+SAH group and intranasal CGRP+SAH group.SAH models were produced by double injection of autologous arterial blood into cisterna magna.CGRP and NS were given by intranasal perfusion.Dynamic observations of regional cerebral blood flow(rCBF)of cerebral cortex were made using a laser Doppler flowmeter probe.On the third day after the second cisternal injection,the expression of VEGF protein in cerebral cortex was observed by immunofluorescence method combined with laser confocal microscopic observation.Results Anatomic observation revealed that SAH models were successfully manufactured.In SAH and intranasal NS+SAH groups,a drastic and persistent drop in rCBF was noted during the observed periods.The decrease of rCBF in intranasal CGRP+SAH group was slighter as compared with that in SAH and intranasal NS+SAH groups.In SAH and intranasal NS+SAH groups,increased expression of VEGF protein in cerebral cortex was observed on the third day after second cisternal injection as compared with that in normal control group.The expression of VEGF in intranasal CGRP+SAH group was more obvious than that in intranasal NS+SAH group.Conclusion Intranasal delivery of CGRP improves cerebral blood supply and promotes angiogenesis by enhancing the expression of VEGF after SAH.

Neuroprotective effects of rhG-CSF on brain given intranasal in cerebral infarct rats / 中华行为医学与脑科学杂志

Objective To explore the protective effect of rhG-CSF given intranasally on cerebral infarct rats by observing the neurological dysfunction and the expression of Fas ligand (FasL) in hippocampus of cerebral infarct rats.Methods Middle cerebral artery occlusion(MCAO) model rats were established by nylon strand,reperfuse 2 hours later,and give rhG-CSF through subcutaneous and intranasal way.The rats were divided into the nermal group,the sham-operated control group(sham),MCAO group,MCAO+NS given intranasally group(NS),MCAO + rhG-CSF given subcutaneously group,and MCAO + rhG-CSF given intranasally group each group had 6 rats. At the time of 3d after reperfusion,neurological severity scores (NSS) test was performed and the expression of FasL was detected via immunohistochemical staining in collateral hippocampus. Results Neurological dysfunction appeared in all groups except for the normal and the sham group. The dysfunction of the MCAO and the NS group was the most serious,the NSS was the highest(10.20±1.85,10.30±1.76),the number of FasL positive cells was the most(41.17±3.25,41.00±2.76),and there was no obvious difference between the two groups ( P ＞0.05);the NSS and FasL positive cells decreased in the subcutaneous group(5.67±1.32,P ＜0.01;32.67±1.97,P ＜0.01) and decreased further more in the intranasal group(4.00±0.93,P ＜0.05;19.50±1.05,P ＜0.01).Conclusions rhG-CSF given intranasally can relieve the neurological dysfunction of cerebral infarct rats,and brain cells are thereby protected by resisting the expression of FasL.

Reversed phase HPLC determination of zidovudine in rat plasma and its pharmacokinetics after a single intranasal dose administration

The development and validation of a simple and accurate method based on HPLC with ultraviolet detection for the quantification of zidovudine in rat plasma and its application to a pharmacokinetic study following a single intranasal dose zidovudine is described. Zidovudine was extracted from the plasma using a single-step deproteinization. Chromatographic separation of zidovudine from interfering components was achieved with a C-18 reverse phase column, a mobile phase consisting of a mixture of sodium acetate buffer (55mM) with pH adjusted to 7.0 and acetonitrile (91:9 v/v) and UV detection set at 265 nm. The method was linear from 100 to 10000 ng.mL"¹ (r² > 0.9995), and zidovudine had a mean recovery from plasma of 92.8 percent. The coefficient of variation of inter-day and intra-day quality control samples was less than 15 percent. After a single intranasal dose of zidovudine administered to rats, pharmacokinetic parameters (AUC0 24, Cmax, t , t1/2) were determined. The proposed method was found to be simple, specific, accurate, and precise and could be applied to the quantitative analysis of clinical pharmacokinetic studies of zidovudine in rats.

Gene Knockdown in the Olfactory Bulb, Amygdala, and Hypothalamus by Intranasal siRNA Administration / 대한해부학회지

Intranasal administration provides a method of bypassing the blood brain barrier, which separates the systemic circulating system and central interstitial fluid, and directly delivering drugs to the central nervous system. This method also circumvents first-pass elimination by the liver and gastrointestinal tract. In the present study, the authors investigated intranasal siRNA delivery efficiency by using FITC-labeled transfection control siRNA and a genespecific siRNA. The localization of fluorescence-tagged siRNA revealed that siRNA was delivered to cells in the olfactory bulb and that the level of the siRNA target gene (alpha B-crystallin) was significantly reduced in the same area. siRNA was delivered to processes as well as nuclei and cytoplasm. At 12 hrs after intranasal delivery, siRNA-mediated target gene reduction was observed in other more distally located brain regions, for example, in the amygdala, entorhinal cortex, and hypothalamus. Target gene knockdown was demonstrated by double immunohistochemistry, which demonstrated alpha B crystallin expression depletion in more than 70% of cells at 12 hrs after the intranasal delivery. siRNA-mediated target gene suppression was detected not only in neurons but in glia, for example, astrocytes. These results indicate that intranasal siRNA delivery offers an efficient means of reducing specific target genes in certain regions of the brain and of performing gene knockdown-mediated therapy.

Treatment of acute cerebral infarction by intranasal administration of nerve growth factor into central nervous system / 医学研究生学报

Objective:To study the reliability and feasibility of intranasal(IN)pathway bypassing the blood-brain barrier (BBB) and observe the potential neuroprotective effects of intranasal NGF on acute cerebral ischemia. Methods:A blinded, vehicle-controlled study of IN NGF and IV NGF administration was performed by intraluminal middle cerebral artery occlusion (MCAO) model. Experiment 1: Rats were randomly divided into IN NGF, IV NGF and untreated group (n=4). The concentration of NGF in different brain regions was measured by ELISA. Experiment 2: Rats were randomly assigned into 4 groups: IN vehicle, IN NGF, IV vehicle, IV NGF (n=8 each). Treatments was initiated 30 min after the onset of MCAO and then again 24 h later. Three neurologic behavioral tests were assessed at 24 h and 48h. Corrected infarct volumes were determined 48 h after the onset of MCAO. Results:Olfactory bulb in IN NGF group obtained the highest concentration among all tissues, arriving at 3 252 pg/g, followed by hippocampus. The NGF concentrations of olfactory bulb and hippocampus in IN NGF group were significantly higher than that in IV NGF and control group. The infarct volume in IN NGF group was reduced significantly by 38.8% as compared with IN vehicle. The vestibulomotor function of IN NGF improved significantly at 24 and 48 h (P=0.02 and P=0.04, respectively). Conclusion:Intranasal NGF could bypass BBB, reach the CNS, reduce infarct volume and improve neurological function in rats following MCAO. Intranasal delivery of NGF holds a promising treatment for stroke and other CNS disorders.