Application of exosomes in brain-targeted delivery / 药学学报

Brain-targeted delivery plays an important role in the diagnosis and treatment of neurological diseases, but the existence of blood brain barrier (BBB) limits the development of brain-targeted delivery. As cell-derived nanovesicles, exosomes can participate in the transportation of substances between cells to mediate the communication between cells to play a biological regulatory role in vivo. Due to the low immunogenicity, low toxicity, high engineering and natural crossing over BBB, exosomes play an important role in brain-targeted delivery. In this paper, the composition of exosomes, the mechanism of brain targeted delivery and its role in various brain diseases are systematically described.

Glyceryl behenate-based solid lipid nanoparticles as a carrier of haloperidol for nose to brain delivery: formulation development, in-vitro, and in-vivo evaluation

Abstract This study was aimed to develop the haloperidol (HPL) loaded solid lipid nanoparticles (SLNs) for brain targeting through the intranasal route. SLNs were fabricated by the emulsification diffusion technique using glyceryl behenate as lipid and tween 80 as a surfactant. SLNs were evaluated for particle size, zeta potential, structure, entrapment efficiency, solid state characterization by differential scanning calorimetry (DSC), and in-vitro release. In-vivo biological evaluation was performed on albino Wistar rats for the determination of pharmacokinetic as well as brain targeting parameters. Particle size, PDI, zeta potential, and entrapment efficiency of optimized formulation (HPL-SLNs 6) were found to be 103±09 nm, 0.190±0.029, -23.5±1.07 mV, and 79.46±1.97% respectively. In-vitro drug release studies exhibited that 87.21± 3.63% of the entrapped drug was released from the SLNs within 24 h. DSC curves confirmed that during entrapment in SLNs, the drug was solubilized in the lipid matrix and converted into the amorphous form. Enhanced HPL targeting to the brain was observed from HPL-SLNs as compared to HPL-Sol when administered intranasally. The value of AUC 0-∞ in the brain for HPL-SLNs i.n. was found to be nearly 2.7 times higher than that of HPL-Sol i.v., whereas 3.66 times superior to HPL-Sol administered i.n. Stability studies revealed that the formulation remains unchanged when stored at 4±2 °C (refrigerator) and 25±2 °C /60 ±5% RH up to six months. Finally, it could be concluded that SLN is a suitable carrier for HPL with enhanced brain targeting through i.n administration, as compared to the HPL-Sol, administered i.n. and i.v.

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-

Strategies for enhancing nanoscale brain targeting drug delivery / 药学学报

The blood brain barrier can selectively block the uptake of xenobiotics from peripheral blood into the brain. Although this is important for maintaining the stability of the brain environment and normal function of the central nervous system, it presents a challenge for delivery of therapeutic drugs to the brain. Passive brain-targeting drug carrier is able to increase the drug concentration in the brain by enhancing the affinity to blood-brain barrier and/or inhibiting the efflux absorbed drug via P-glycoprotein. The active brain-targeting drug carrier can be obtained by linking specific ligands or antibodies onto passive target carriers to achieve precise delivery of drugs to the brain. Dual targeting drug carriers obtained by combining tumor cell targeting with brain targeting have shown their advantages for treatment of brain tumors. The targeted drug delivery to brain will provide a unique manner for the treatment of brain diseases such as Alzheimer's, Parkinson's, brain tumors, and stroke. Among the drug delivery systems of passive brain-targeting, active brain-targeting and dual brain-targeting, we evaluated the strategies to improve brain drug delivery efficiency, such as by reducing carrier size, opening tight junctions between cells at the blood-brain barrier, incorporating hydrophilic groups on the surface of the carrier, and alternative intranasal drug administration.

Emerging transporter-targeted nanoparticulate drug delivery systems

Transporter-targeted nanoparticulate drug delivery systems (nano-DDS) have emerged as promising nanoplatforms for efficient drug delivery. Recently, great progress in transporter-targeted strategies has been made, especially with the rapid developments in nanotherapeutics. In this review, we outline the recent advances in transporter-targeted nano-DDS. First, the emerging transporter-targeted nano-DDS developed to facilitate oral drug delivery are reviewed. These include improvements in the oral absorption of protein and peptide drugs, facilitating the intravenous-to-oral switch in cancer chemotherapy. Secondly, the recent advances in transporter-assisted brain-targeting nano-DDS are discussed, focusing on the specific transporter-based targeting strategies. Recent developments in transporter-mediated tumor-targeting drug delivery are also discussed. Finally, the possible transport mechanisms involved in transporter-mediated endocytosis are highlighted, with special attention to the latest findings of the interactions between membrane transporters and nano-DDS.

Menthol-modified casein nanoparticles loading 10-hydroxycamptothecin for glioma targeting therapy

Chemotherapy outcomes for the treatment of glioma remains unsatisfactory due to the inefficient drug transport across the blood-brain barrier (BBB) and insufficient drug accumulation in the tumor region. Although many approaches, including various nanosystems, have been developed to promote the distribution of chemotherapeutics in the brain tumor, the delivery efficiency and the possible damage to the normal brain function still greatly restrict the clinical application of the nanocarriers. Therefore, it is urgent and necessary to discover more safe and effective BBB penetration and glioma-targeting strategies. In the present study, menthol, one of the strongest BBB penetration enhancers screened from traditional Chinese medicine, was conjugated to casein, a natural food protein with brain targeting capability. Then the conjugate self-assembled into the nanoparticles to load anti-cancer drugs. The nanoparticles were characterized to have appropriate size, spheroid shape and high loading drug capacity. Tumor spheroid penetration experiments demonstrated that penetration ability of menthol-modified casein nanoparticles (M-CA-NP) into the tumor were much deeper than that of unmodified nanoparticles. imaging further verified that M-CA-NPs exhibited higher brain tumor distribution than unmodified nanoparticles. The median survival time of glioma-bearing mice treated with HCPT-M-CA-NPs was significantly prolonged than those treated with free HCPT or HCPT-CA-NPs. HE staining of the organs indicated the safety of the nanoparticles. Therefore, the study combined the advantages of traditional Chinese medicine strategy with modern delivery technology for brain targeting, and provide a safe and effective approach for glioma therapy.

Eight-arm polyethylene glycol nanoconjugates for brain targeted delivery of photosensitizer / 中国药科大学学报

@#The aim of this study was to prepare the nanoconjugates for targeted photodynamic therapy of brain cancer by using eight-arm polyethylene glycol(8PEG)as the carrier and cRGD as the targeting ligand, and to investigate the antitumor effect and its mechanism. UV-Vis spectra and confocal microscopy were used for characterization and cellular uptake behavior of nanoconjugates respectively. Alamar Blue assay and Calcein AM/PI staining were applied to investigate the cytotoxocity of nanoconjugates against tumor cells, and tumor spheroid growth curve was used to assess the tumor growth suppression effect. In addition, the generation of reactive oxygen species(ROS), apoptosis and spheroid permeability test was used to reveal the antitumor mechanism of nanoconjugates. The results showed that cRGD-8PEG-IR700 was taken up efficiently by integrin overexpressed U87MG cells, while almost no uptake was found in integrin free NIH/3T3 cells. Remarkable photokilling effect against U87MG cells was only shown in cRGD-8PEG-IR700 group due to the light-induced ROS generation and apoptosis, whereas growth suppression effect was also observed in U87MG spheroids treated with cRGD-8PEG-IR700 plus light owing to the superior penetration ability of targeted nanoconjugates. Hence, tumor-targeted PEG nanoconjugates may provide a promising drug delivery system for photodynamic therapy of cancers.

Surface modification of PGP for a neutrophil-nanoparticle co-vehicle to enhance the anti-depressant effect of baicalein

Exploiting cells as vehicles combined with nanoparticles combined with therapy has attracted increasing attention in the world recently. Red blood cells, leukocytes and stem cells have been used for tumor immunotherapy, tissue regeneration and inflammatory disorders, and it is known that neutrophils can accumulate in brain lesions in many brain diseases including depression. -Acetyl Pro-Gly-Pro (PGP) peptide shows high specific binding affinity to neutrophils through the CXCR2 receptor. In this study, PGP was used to modify baicalein-loaded solid lipid nanoparticles (PGP-SLNs) to facilitate binding to neutrophils . Brain-targeted delivery to the basolateral amygdala (BLA) was demonstrated by enhanced concentration of baicalein in the BLA. An enhanced anti-depressant effect was observed and The mechanism involved inhibition of apoptosis and a decrease in lactate dehydrogenase release. Behavioral evaluation carried out with rats demonstrated that anti-depression outcomes were achieved. The results indicate that PGP-SLNs decrease immobility time, increase swimming time and climbing time and attenuate locomotion in olfactory-bulbectomized (OB) rats. In conclusion, PGP modification is a strategy for targeting the brain with a cell-nanoparticle delivery system for depression therapy.

Construction of the brain-targeting drug carrier through imprinting of nicotinic acetylcholine receptor α7 / 药学学报

In this study, a novel brain-targeting carrier was made via conformational epitope imprinting. Acrylamide and N,N'-methylene bisacrylamide was used as carrier materials and the N-terminal epitope of nicotinic acetylcholine receptor α7 (nAchR α7) was tested as a template molecule, and the polymer nanoparticles were obtained after polymerization and template removal. The nanoparticles were investigated by particle size analyzer and transmission electron microscopy (TEM). Their targeting capabilities were investigated with a cell uptake assay in vitro and fluorescence imaging in vivo. The results suggest that the nanoparticles had a small particle size (42.1±4.3 nm) with a homogeneous distribution, and good targeting properties in vitro and in vivo. We have made the molecularly imprinted polymer nanoparticles with brain targeting capability, which represents a new tool in the treatment of brain diseases.

Angiopep-2 conjugated brain targeting system:research advances / 国际药学研究杂志

The key factor of chemotherapy for brain disorders is to penetrate brain blood barrier(BBB). Receptor mediated en-docytosis is one of the mechanisms for drug carriers to cross the BBB. Angiopep-2(ANG)can specifically bind to low density lipopro-tein receptor-related proteins 1(LRP-1)overexpressed on BBB and glioma cells,thus exhibits a higher LRP-mediated BBB penetra-tion capability. Its targeting efficiency is higher than that of other targeting molecules such as transferrin and(TF)lactoferrin(LF). This paper introduces the structure and function of ANG,and its application in brain targeting delivery systems,in order to provide references for research and development of brain targeting preparations and guidance for therapy of brain diseases.

Advances of polypeptide fragment of rabiesvirus glycoprotein as a brain-targeting carrier / 中国药理学通报

Polypeptide fragment of rabies virus glycoprotein(RVG)has become one of the most popular polypeptides in drug delivery field,because of its advantages of neurotropiam,penetration of blood-brain barrier and biosafety.Polypeptide fragment of RVG can directly deliver proteins and nucleic acids into brain.Additionally,when polypeptide fragment of RVG couples with drug-loading polymers,nanoparticles or liposomes,it can mediate the latters into brain.The application of the RVG polypeptide fragment provides a safe and effective approach for the treatment of brain diseases with biomolecules,such as chemicals,proteins.plasmids,siRNA,miRNA.

Effect of Danshensu borneol esteron P-glycoprotein expression level in rat brain / 中国药理学通报

Aim To investigate the relationship between the brain targeting effect and P-glycoprotein(P-gp)expression level of Danshensu borneol ester(DBE)and the combination use of sodium Danshensu and borneol(SDSS-B).Methods The liquid chromatography mass spectrometry(LC-MS)method was applied to investigate the accumulation of Danshensu(DSS)in rat brain tissues after intravenous injection of DBE,SDSS-B and SDSS.Also their effect on regulating the expression level of P-gp in rat hippocampus was investigated using Western blot.Results The brain targeting effect of DBE,SDSS-B was qualitatively analyzed through the brain distribution of DSS,and the result was DBE(SDSS-B)>SDSS(P0.05 at 5,15,45,60 min,vs control group).Conclusion An attenuated expression level of P-gp can be realized by DBE and SDSS-B,which is advantageous to their brain targeting.

Pharmacokinetics and Brain-targeting Ability of Gastrodin Nasal in Situ Gel in Rats / 中国药师

Objective:To study the pharmacokinetic parameters of gastrodin nasal in situ gel ( ISG) with the base of TMC-P407-P188-carbomer, and evaluate its brain-targeting ability preliminarily. Methods:Rats were used as the model animals. The experiment group was treated with gastrodin nasal in situ gel, and the control group was treated with gastrodin solution with intravenous administra-tion. The plasma sample and brain tissue ( cerebrum and cerebellum) were taken out at the predetermined time points, and the concen-tration of gastrodin in plasma and gastrodigenin in brain tissues were determined by HPLC to draw the curve of concentration vs time. The pharmacokinetic parameters such as MRT and AUC were calculated by 3P97 software. The bioavailability F (%) and the brain-targeting index BTI were compared between the groups. Results:The concentration of gastrodigenin in the brain tissues of grastrodin in situ gel was higher than that of gastrodin solution with intravenous administration (P<0. 05). AUC of cerebrum and cerebellum both increased significantly with BTI of 2. 38 and 1. 93, respectively. MRT increased by nearly two-fold in the gel group when compared with that in the control group, and F(%) increased significantly in cerebrum and cerebellum as well. Conclusion:Gastrodin nasal in situ gel with the base of TMC-P407-P188-carbomer has promising effectiveness. Meanwhile, it can improve the brain-targeting ability of gastrodin with sustained release.

Study on the Pharmacokinetics and Brain Targeting of Toutongning Nasal Spray in Rats in vivo / 中国药房

OBJECTIVE:To study the pharmacokinetics and brain targeting of Toutongning nasal spray in rats in vivo. METH-ODS:84 SD rats were divided into nasal administration group and vein administration group,42 in each group,with dose of 1.2 mL/kg. 5 mL sample blood was taken in abdominal aorta after 5,10,15,30,60,90,120 min of administration,and brain tissue was taken (6 rats in each time point). HPLC-MS was adopted to determine the concentration of prim-o-glucosylcimifugin and 5-O-methylvisammioside in plasma and brain tissue of rats in each group,and DAS 2.0 software was used to calculate the pharma-cokinetic parameters and brain targeting indexes. RESULTS:The cmax of prim-o-glucosylcimifugin and 5-O-methylvisammioside in plasma of rats in nasal administration group were(0.2024±0.0158),(0.3738±0.0857)μg/mL;tmax were(10.0000±0.0000) min;and AUC0-∞ were (16.5429 ± 2.1103),(27.4527 ± 5.5721)μg·h/mL,respectively. The cmax of prim-o-glucosylcimifugin and 5-O-methylvisammioside in brain tissue of rats were (0.1802 ± 0.0384),(0.3204 ± 0.0277)μg/g;tmax were (10.0000 ± 0.0000)min;and AUC0-∞ were(17.1053±2.4329),(24.5416±3.7534)μg·h/g,respectively. The cmax of prim-o-glucosylcimi-fugin and 5-O-methylvisammioside in plasma of rats in vein administration group were (0.3002 ± 0.0161),(0.5267 ± 0.0441)μg/mL;tmax were(10.0000±0.0000)min;and AUC0-∞ were(28.0105±4.1128),(60.2941±11.2902)μg·h/mL,respective-ly. The cmax of prim-o-glucosylcimifugin and 5-O-methylvisammioside in brain tissue of rats were(0.1498±0.0315),(0.1998± 0.0401)μg/g;tmax were(15.0000±0.0000)min;and AUC0-∞were(22.6434±2.8831),(36.7218±14.8856)μg·h/g,respec-tively. The brain targeting indexes of prim-o-glucosylcimifugin and 5-O-methylvisammioside were 2.3870 and 2.1761,respective-ly. CONCLUSIONS:After nasal administration of Toutongning nasal spray,parts of drugs can directly transport to the brian by na-sal absorption. It is scientific and reasonable to make nasal spray.

Pharmacokinetics of α-asarone after intranasal and intravenous administration with PLA-α-asarone nanoparticles / 中国中药杂志

PLA-α-asarone nanoparticles were prepared by using organic solvent evaporation method, and their in vivo distribution and brain targeting after intranasal administration were studied as compared with intravenous administration. The results showed that brain targeting coefficient of PLA-α-asarone nanoparticles after intranasal and intravenous administration was 1.65 and 1.16 respectively. The absolute bioavailability, brain-targeting efficiency and the percentage of nasal-brain delivery of PLA-α-asarone nanoparticles were 74.2%, 142.24 and 29.83%, respectively after intranasal administration. The results of fluorescence labeling showed that the fluorescent intensity of coumarin-6 in the brain tissue was the highest after intranasal administration of PLA-α-asarone fluorescent nanoparticles, achieving the purpose of brain-targeted drug delivery. The fluorescent intensity of coumarin-6 in liver tissue after intravenous administration of PLA-α-asarone nanoparticles was much higher than that after intranasal administration, indicating that intranasal administration of PLA-α-asarone nanoparticles could decrease drug-induced hepatotoxicity. In addition, the fluorescent intensity of coumarin-6 in lung tissue was weaker after intranasal administration, which solved the shortcomings of intranasal administration of α-asarone dry powder prepared by airflow pulverization method. In vivo studies indicated that PLA-α-asarone nanoparticles after intranasal administration had a stronger brain targeting as compared with intravenous administration.

Development of a new HPLC method for in vitro and in vivo studies of haloperidol in solid lipid nanoparticles

ABSTRACT A simple and sensitive HPLC method was developed and validated for the quantification of haloperidol in solid lipid nanoparticles (SLNs). The developed method was used for detection of shelf life of haloperidol in SLNs. Calibration curve of haloperidol was also constructed in rat plasma using loratidine as internal standard. In vivo studies were performed on rats and concentration of haloperidol in brain and blood was measured for the determination of various pharmacokinetic and hence brain targeting parameters. Chromatogram separation was achieved using C18 column as stationary phase. The mobile phase consisted of 100 mM/L potassium dihydrogen phosphate-acetonitrile-TEA (10:90:0.1, v/v/v) and the pH was adjusted with o-phosphoric acid to 3.5. Flow rate of mobile phase was 2 mL/minute and eluents were monitored at 230 nm using UV/VIS detector. The method was validated for linearity, precision, accuracy, reproducibility, limit of detection (LOD) and limit of quantification (LOQ). Linearity for haloperidol was in the range of 1-16 µg/mL. The value of LOD and LOQ was found to be 0.045 and 0.135 μg/mL respectively. The shelf life of SLNs formulation was found to be 2.31 years at 4 oC. Various parameters like drug targeting index (DTI), drug targeting efficiency (DTE) and nose-to-brain direct transport (DTP) were determined for HP-SLNs & HP-Sol administered intranasally to evaluate the extent of nose-to-brain delivery. The value of DTI, DTE and DTP for HP-SLNs was found to be 23.62, 2362.43 % and 95.77% while for HP-Sol, values were 11.28, 1128.61 % and 91.14 % respectively.

Comparison of different administration routes of saikosaponin in plasma pharmacokinetics and brain pharmacokinetics / 中国中药杂志

To evaluate the optimum administration routes of saikosaponin in the treatment of epilepsy by comparing the plasma pharmacokinetics and the brain pharmacokinetics after different administration routes of saikosaponin. After receiving saikosaponin in different administration routes, the mice were sacrificed to collect the blood and brain tissues. The acetonitrile and methanol (9∶1) were used to precipitate the plasma protein. The concentration of the SSa in mice plasma and brain was determined by UPLC-MS/MS, and the pharmacokinetic parameters, bioavailability, the brain targeting coefficient (Re) and the brain drug targeting index (DTI) were calculated with Kinetica software. The relative brain Re was 142.17% by intranasal administration, with DTI of 3.06, significantly higher than those by the injections; in addition, the brain DTI was 1.25 by gavage administration. The brain drug targeting of saikosaponin by intranasal administration was higher than that by injection and gavage administration, indicating the advantages of the intranasal administration on medicine absorption into the brain.

Pharmacokinetics and Brain Targeting Characteristics of Risperidone Nasal Gel in Rats / 中国药学杂志

OBJECTIVE: To study the pharmacokinetics of risperidone (RIS) nasal gel and its brain targeting effect and related mechanisms in rats. METHODS: The concentrations of RIS in rat plasma and brain tissues were determined by HPLC method. The pharmacokinetics and relative bioavailability to oral RIS preparation of RIS nasal gel and the drug distribution in various brain tissues such as olfactory bulb (OB), olfactory tract (OT), cerebellum (CL) and cerebrum (CR) were investigated in rats. RESULTS: The main pharmacokinetic parameters of RIS following nasal and oral administration such as tmax and ρmax were 5 and 20 min, 9.89 and 1.93 μg·mL-1, respectively. The relative bioavailability of nasally administered RIS was up to 4 730%. Furthermore, the AUC values of RIS nasal gel for different brain tissues such as OB, OT, CL and CR were found to be 45.3, 9.9, 1.5 and 1.1 folds of those of oral drug suspension, respectively. CONCLUSION: The in vivo absorption rate and bioavailability of RIS following nasal administration are obviously increased and improved. Additionally, the significant brain targeting characteristics of the drug nasal gel is also confirmed.

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.

Brain-targeted nasal drug delivery systems for the treatment of neurodegenerative diseases / 国际药学研究杂志

Incidence of neurodegenerative diseases has been increasing year by year in the current aging society which inter?feres the living quality of the patients severely. Pathological changes in neurodegenerative diseases appeare in central nervous system (CNS). The administration route of drugs to treat neurodegenerative diseases becomes a very important scientific research field. Part of drugs may cross over blood-brain barrier(BBB)to CNS by oral or injection administration. But most of drugs are distributed in the oth?er tissues and might cause adverse reactions ,such as gastrointestinal side-effects and arrhythmia. Moreover ,the compliance of the aging patients is poor. They cannot adhere to administer multi-dose drugs for sereral times a day. Nasal drug delivery systems could de?liver drugs to brains directly by nasal-brain route,avoiding BBB with high targeting ratio,high drug availability and good patients′compliance. The review summarizes the major types of neurodegenerative diseases and their current therapeutic methods. The impor?tant obstacles for brain-targeted drug delivery ,nose-brain routes and the factors influencing nasal absorption are introduced. More importantly,the principal formulations,recent research progress and the unsolved problems of brain-targeted nasal drug delivery sys?tems are also reviewed.