Brain Targeting Ability Research Articles

Preparation and Pharmacokinetics of Brain-Targeted Nanoliposome Loaded with Rutin

Rutin is a flavonoid compound with potential for treating Alzheimer’s disease, preventing brain damage, mitigating cerebral ischemia–reperfusion injury, and exhibiting anti-glioblastoma activity. However, its efficacy is limited by its low solubility, poor bioavailability, and limited permeability across the blood–brain barrier (BBB). To enhance the bioavailability and brain-targeting ability of Rutin, transferrin-modified Rutin liposome (Tf-Rutin-Lip) was developed using liposomes as a delivery system. Rutin liposomes were prepared using the thin-film dispersion method, and the preparation conditions were optimized using the response surface methodology. Then, transferrin (Tf) was incorporated into the liposomes through covalent modification, yielding Tf-Rutin liposomes. The toxicity of these liposomes on bEnd.3 cells, as well as their impact on the tight junctions of these cells, was rigorously evaluated. Additionally, in vitro and in vivo experiments were conducted to validate the brain-targeting efficacy of the Tf-Rutin liposomes. A susceptible detection method was developed to characterize the pharmacokinetics of Tf-Rutin-Lip further. The optimized conditions for the preparation of Tf-Rutin-Lip were determined as follows: a lipid-to-cholesterol ratio of 4.63:1, a drug-to-lipid ratio of 1:45.84, a preparation temperature of 42.7 °C, a hydration volume of 20 mL, a sonication time of 10 min, a surfactant concentration of 80 mg/mL, a DSPE-MPEG-2000 concentration of 5%, and a DSPE-PEG2000-COOH to DSPE-MPEG-2000 molar ratio of 10%. The liposomes did not affect the cell activity of bEnd.3 cells at 24 h and did not disrupt the tight junction of the blood–brain barrier. Tf-modified liposomes were taken up by bEnd.3 cells, which, in turn, passed through the BBB, thus improving liposomal brain targeting. Furthermore, the results of pharmacokinetic experiments showed that the Cmax, AUC0-∞, AUC0-t, MRT0-∞, and t1/2 of Tf-Rutin-Lip increased 1.99-fold, 2.77-fold, 2.58-fold, 1.26-fold, and 1.19-fold compared to those of free Rutin solution, respectively. These findings suggest that Tf-Rutin-Lip is brain-targeted and may enhance the efficacy of Rutin in the treatment of brain disorders.

Key Lipoprotein Receptor Targeted Echinacoside-Liposomes Effective Against Parkinson's Disease in Mice Model.

Parkinson's disease (PD) is a common neurodegenerative disorder characterized by the degeneration of dopaminergic neurons in the substantia nigra. The precise molecular mechanisms underlying neuronal loss in PD remain unknown, and there are currently no effective treatments for PD-associated neurodegeneration. Echinacoside (ECH) is known for its neuroprotective effects, which include scavenging cellular reactive oxygen species and promoting mitochondrial fusion. However, the blood-brain barrier (BBB) limits the bioavailability of ECH in the brain, posing a significant challenge to its use in PD treatment. We synthesized and characterized PEGylated ECH liposomes (ECH@Lip) and peptide angiopep-2 (ANG) modified liposomes (ECH@ANG-Lip). The density of ANG in ANG-Lip was optimized using bEnd.3 cells. The brain-targeting ability of the liposomes was assessed in vitro using a transwell BBB model and in vivo using an imaging system and LC-MS. We evaluated the enhanced neuroprotective properties of this formulation in a the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced PD model. The ECH@ANG-Lip demonstrated significantly higher whole-brain uptake compared to ECH@Lip and free ECH. Furthermore, ECH@ANG-Lip was more effective in mitigating MPTP-induced behavioral impairment, oxidative stress, dopamine depletion, and dopaminergic neuron death than both ECH@Lip and free ECH. The formulation used in our study significantly enhanced the neuroprotective efficacy of ECH in the MPTP-induced PD model. Thus, ECH@ANG-Lip shows considerable potential for improving the bioavailability of ECH and providing neuroprotective effects in the brain.

In Vitro and In Vivo Evaluation of Lactoferrin-Modified Liposomal Etomidate with Enhanced Brain-Targeting Effect for General Anesthesia.

Etomidate is a general anesthetic that has shown good hemodynamic stability without significant cardiovascular or respiratory depression. Despite several kinds of dosage forms having been reported for this drug, formulation types are very limited in clinical practice, and brain-targeted formulations for this central nervous system (CNS) drug have been rarely reported. Moreover, studies on the biocompatibility, toxicity, and anesthetic effects of the etomidate preparations in vivo were inadequate. The present study was to develop lactoferrin-modified liposomal etomidate (Eto-lip-LF) for enhanced drug distribution in the brain and improved anesthetic effects. Eto-lip-LF had good stability for storage and hemocompatibility for intravenous injection. Compared with the non-lactoferrin-containing liposomes, the lactoferrin-modified liposomes had notably enhanced brain-targeting ability in vivo, which was probably realized by the binding of transferrin with the transferrin and lactoferrin receptors highly distributed in the brain. Eto-lip-LF had a therapeutic index of about 25.3, higher than that of many other general anesthetics. Moreover, compared with the commercial etomidate emulsion, Eto-lip-LF could better achieve rapid onset of general anesthesia and rapid recovery from anesthesia, probably due to the enhanced drug delivery to the brain. The above results demonstrated the potential of this lactoferrin-modified liposomal etomidate to become an alternative preparation for clinical general anesthesia.

Intranasal delivery of phenytoin loaded layered double hydroxide nanoparticles improves therapeutic effect on epileptic seizures

Improving the efficiency of antiseizure medication entering the brain is the key to reducing its peripheral toxicity. A combination of intranasal administration and nanomedicine presents a practical approach for treating epileptic seizures via bypassing the blood-brain barrier. In this study, phenytoin (PHT) loaded layered double hydroxide nanoparticles (BSA-LDHs-PHT) were fabricated via a coprecipitation − hydrothermal method for epileptic seizure control. In this study, we expound on the preparation method and characterization of BSA-LDHs-PHT. In-vitro drug release experiment shows both rapid and continuous drug release from BSA-LDHs-PHT, which is crucial for acute seizure control and chronic epilepsy therapy. In-vivo biodistribution assays after intranasal administration indicate excellent brain targeting ability of BSA-LDHs. Compared to BSA-Cyanine5.5, BSA-LDHs-Cyanine5.5 were associated with a higher brain/peripheral ratio across all tested time points. Following intranasal delivery with small doses of BSA-LDHs-PHT, the latency of seizures in the pentylenetetrazole-induced mouse models was effectively improved. Collectively, the present study successfully designed and applied BSA-LDHs-PHT as a promising strategy for treating epileptic seizures with an enhanced therapeutic effect.

Curcumin/TGF-β1 siRNA loaded solid lipid nanoparticles alleviate cerebral injury after intracerebral hemorrhage by transnasal brain targeting

Intracerebral hemorrhage (ICH) is a prevalent cerebrovascular disorder. The inflammation induced by cerebral hemorrhage plays a crucial role in the secondary injury of ICH and often accompanied by a poor prognosis, leading to disease exacerbation. However, blood-brain barrier (BBB) limiting the penetration of therapeutic drugs to the brain. In this paper, our primary objective is to develop an innovative, non-invasive, safe, and targeted formulation. This novel approach aims to synergistically harness the combined therapeutic effects of drugs to intervene in inflammation via a non-injectable route, thereby significantly mitigating the secondary damage precipitated by inflammation following ICH. Thus, a novel “anti-inflammatory” cationic solid lipid nanoparticles (SLN) with targeting ability were constructed, which can enhance the stability of curcumin(CUR) and siRNA. We successfully developed SLN loaded with TGF-β1 siRNA and CUR (siRNA/CUR@SLN) that adhere to the requirements of drug delivery system by transnasal brain targeting. Through the characterization of nanoparticle properties, cytotoxicity assessment, in vitro pharmacological evaluation, and brain-targeting evaluation after nasal administration, siRNA/CUR@SLN exhibited a nearly spherical structure with a particle size of 125.0±1.93 nm, low cytotoxicity, high drug loading capacity, good sustained release function and good stability. In vitro anti-inflammatory results showcasing its remarkable anti-inflammatory activity. Moreover, in vivo pharmacological studies revealed that siRNA/CUR@SLN can be successfully delivered to brain tissue. Furthermore, it also elicited an effective anti-inflammatory response, alleviating brain inflammation. These results indicated that favorable brain-targeting ability and anti-inflammatory effects of siRNA/CUR@SLN in ICH model mice. In conclusion, our designed siRNA/CUR@SLN showed good brain targeting and anti-inflammatory effect ability after nasal administration, which lays the foundation for the treatment of inflammation caused by ICH and offers a novel approach for brain-targeted drug delivery and brings new hope.

Preparation of a novel brain-targeted EGCG liposome and its antioxidative neuroprotection

(-)-Epigallocatechin-3-gallate (EGCG) possesses potent antioxidant and neuroprotective properties. In this study, a novel glucose-modified EGCG encapsulated liposome (EGCG-Glu-Lip) was developed and characterized. EGCG-Glu-Lip liposome’s cytotoxicity, brain targeting ability, and its antioxidative neuroprotection were examined via bEnd.3 and PC12 cells testing. EGCG-Glu-Lip liposome particle mean size was 158.7 nm, with encapsulation efficiency 73.05 % under EGCG/lipid mass ratio 1:22 and soybean phospholipids (SPC) to cholesterol (Chol) mass ratio 3.84:1. EGCG-Glu-Lip exhibited less cytotoxicity, stronger protection to PC12 cells from H2O2 induced oxidative damage, keeping reactive oxygen species (ROS) level. Glucose modified liposome (Glu-Lip) cellular uptake in bEnd.3 and PC12 cells were 1.5-fold and 1.3-fold higher than that of Lip, supporting EGCG-Glu-Lip possessing enhanced blood–brain barrier (BBB) permeability mediated via glucose transporter protein 1 (GLUT1) and neuronal cell uptake for brain targeting. EGCG-Glu-Lip could provide an efficient nano delivery pathway to deliver sufficient EGCG to brain tissue exerting its antioxidative neuroprotection more efficiently.

Development of an apolipoprotein E mimetic peptide–lipid conjugate for efficient brain delivery of liposomes

Liposomes are versatile carriers that can encapsulate various drugs; however, for delivery to the brain, they must be modified with a targeting ligand or other modifications to provide blood–brain barrier (BBB) permeability, while avoiding rapid clearance by reticuloendothelial systems through polyethylene glycol (PEG) modification. BBB-penetrating peptides act as brain-targeting ligands. In this study, to achieve efficient brain delivery of liposomes, we screened the functionality of eight BBB-penetrating peptides reported previously, based on high-throughput quantitative evaluation methods with in vitro BBB permeability evaluation system using Transwell, in situ brain perfusion system, and others. For apolipoprotein E mimetic tandem dimer peptide (ApoEdp), which showed the best brain-targeting and BBB permeability in the comparative evaluation of eight peptides, its lipid conjugate with serine–glycine (SG)5 spacer (ApoEdp-SG-lipid) was newly synthesized and ApoEdp-modified PEGylated liposomes were prepared. ApoEdp-modified PEGylated liposomes were effectively associated with human brain capillary endothelial cells via the ApoEdp sequence and permeated the membrane in an in vitro BBB model. Moreover, ApoEdp-modified PEGylated liposomes accumulated in the brain 3.9-fold higher than PEGylated liposomes in mice. In addition, the ability of ApoEdp-modified PEGylated liposomes to localize beyond the BBB into the brain parenchyma in mice was demonstrated via three-dimensional imaging with tissue clearing. These results suggest that ApoEdp-SG-lipid modification is an effective approach for endowing PEGylated liposomes with the brain-targeting ability and BBB permeability.

Biopharmaceutical, preclinical pharmacokinetic and pharmaco-dynamic investigations of an orally administered novel 3-nbutylphthalide prodrug for ischemic stroke treatment

Ischemic stroke (IS) has been contributing in leading causes of disability and death worldwide and the cases are still increasing. In China, naturally sourced compound 3-n-butylphthalide (NBP) is widely applied in clinical practice for IS treatment with established evidences of efficacy and safety. However, NBP is an oily liquid at room temperature and has no active brain targeting ability, quite limiting its broader application in clinical practice. Via intravenous injection (i.v.) a prodrug compound (DB1) we previously developed deriving from NBP had dramatically enhanced the pharmacological effects, where however, this i.v. route still discount future patient compliance. As druggability of DB1 in oral administration has yet to be elaborated, the current study intended to systemically investigate its biopharmaceutical properties, so as to further consider clinical applicability of DB1 oral preparations. Additionally, pharmacokinetics and pharmacodynamics of DB1 via oral administered route were also studied, illustrating broad potential of further DB1 medicine development. After the derivation, aqueous solubility of DB1 improved 3∼400 folds compared with NBP in various pH media, and n-octanol/water partition coefficient kept in the range of 0∼2. In situ single-pass intestinal perfusion on rats showed effective permeability coefficient of DB1 over 10-2 cm/s. In contrast to NBP, oral administration of DB1 could display significant enhanced bioavailability in rats and achieve increased accumulation in brain tissues. As expected, DB1 effectively alleviated oxidative stress damage and reduced infarct volume on ischemia/reperfusion (I/R) modeled rats, resulting in reduced mortality. Additionally, this new prodrug did not add any safety concerns based on NBP. Therefore, biopharmaceutical results and preclinical pharmacodynamic evidences support the conclusion that an oral administration of DB1 may have a good potential for clinical IS treatment.

Synthesis and evaluation of glycosylated quercetin to enhance neuroprotective effects on cerebral ischemia-reperfusion

Quercetin (Que), a polyphenolic flavonoid compound with antioxidant properties has been explicated to have neuroprotective effects on neuronal injury/neurodegenerative diseases. However, low water-solubility, instability and inability to cross the blood–brain barrier (BBB) imped its application. To enhance the neuroprotective effects and improve the potential application of quercetins as a nutraceutical or medicine, we designed and synthesized two types of glycosylated quercetins——Glu-Que and 2Glu-Que through click reaction. Glu-Que and 2Glu-Que improved the water solubility and stability of quercetin, as well as alleviating H2O2-induced neurotoxicity by increasing the cell viability of PC12 cells and reducing the ROS generation. What’s more, glycosylated quercetins enhanced neuroprotective effects on cerebral ischemia–reperfusion (I/R). Among the two types of glycosylated quercetin, 2Glu-Que displayed higher neuroprotective potential than Glu-Que. In conclusion, the glycosylated quercetin 2Glu-Que, with better water solubility, bioavailability and brain-targeting ability, significantly enhanced the neuroprotective effects of quercetin, making it a promising nutraceutical or candidate drug in neuroprotection.

Investigation of the "Nose-to-Brain" Pathways in Intranasal HupA Nanoemulsions and Evaluation of Their in vivo Pharmacokinetics and Brain-Targeting Ability.

PurposeWhile developing huperzine A (HupA) to explore new approaches to treating Alzheimer’s disease (AD), intranasal administration was proposed as an alternative route to deliver drugs into the brain. This study aimed to prepare nanoemulsions (NEs) of HupA to investigate their potential “nose-to-brain” pathways and to evaluate their pharmacokinetic and brain-targeting parameters.MethodsHupA-NE and Lf-HupA-NE that underwent surface modification with lactoferrin (Lf) were characterized to determine various physicochemical properties, such as their size, PDI, zeta potential, pH, and loading efficiency; in addition, transmission electron microscopy and stability assessments were performed. We utilized an aggregation-caused quenching (ACQ) probe to monitor intact NEs in the brains of olfactory nerve transection model and normal rats. Immunohistochemistry, pharmacokinetic and targeting index analyses were performed to investigate the in vivo effects of HupA-NE and Lf-HupA-NE.ResultsBased on the live imaging results, HupA-NE and Lf-HupA-NE could be transported into the brain via nerve and blood circulation pathways. Immunohistochemical staining tests demonstrated that the efflux proteins P-gp, MRP1, and BCRP were expressed in brain tissue. NEs can inhibit efflux pumps to improve drug concentrations in the brain. The findings of this study showed that NEs (especially Lf-HupA-NE) had better pharmacokinetic profiles and a better nose-to-brain drug transport efficiency than free HupA.ConclusionThe newly designed formulations might contribute to the transport and accumulation of HupA to achieve therapeutic results. The delivery system may be a promising strategy for the brain-targeted delivery of HupA.

Preparation of baicalin-loaded ligand-modified nanoparticles for nose-to-brain delivery for neuroprotection in cerebral ischemia

Neuroprotection in cerebral ischemia (CI) has received increasing attention. However, efficient delivery of therapeutic agents to the brain remains a major challenge due to the complex environment of the brain. Nose-to-brain-based delivery is a promising approach. Here, we optimized a nanocarrier formulation of neuroprotective agents that can be used for nose-to-brain delivery by obtaining RVG29 peptide-modified polyethylene glycol–polylactic acid-co-glycolic acid nanoparticles (PEG–PLGA RNPs) that have physicochemical properties that lead to stable and sustained drug release and thereby improve the bioavailability of neuroprotective agents. The brain-targeting ability of PEG–PLGA RNPs administered through nasal inhalation was verified in a rat model of CI. It was found that delivery to the whole brain can be achieved with little delivery to the peripheral circulation. Baicalin (BA) was selected as the neuroprotective agent for delivery. After intranasal administration of BA–PEG–PLGA RNPs, the neurological dysfunction of rats with ischemic brain injury was significantly alleviated, the cerebral infarction area was reduced, and nerve trauma and swelling were relieved. Furthermore, it was demonstrated that the neuroprotective effects of BA in a rat model of CI may be mediated by inhibition of inflammation and alleviation of oxidative stress. The immunohistochemical results obtained after treatment with nanoparticles loaded with BA showed that Nrf2/HO-1 was activated in the area in which ischemic brain damage had occurred and that its expression was significantly higher in the group treated with BA–PEG–PLGA RNPs than in the other groups. The ELISA results showed that the levels of IL-1β, IL-6, and TNF-α were abnormally increased in the serum of rats with cerebral ischemia. After treatment with BA-loaded nanoparticles, IL-1β, IL-6, and TNF-α levels decreased significantly. Oxidative stress was alleviated; the levels of glutathione and superoxide dismutase increased; and the levels of reactive oxygen species and malondialdehyde decreased, in animals to which BA–PEG–PLGA RNPs were delivered by intranasal inhalation. In conclusion, BA–PEG–PLGA RNPs can effectively deliver BA to rats and thereby exert neuroprotective effects against CI.

PH-redox responsive cascade-targeted liposomes to intelligently deliver doxorubicin prodrugs and lonidamine for glioma

To synergistically treat glioma with a combination chemotherapy, we design and prepare novel cascade-targeted liposomes (Lip-TPGS) using glucose and triphenylphosphonium (TPP) as targeting moieties, which could intelligently deliver redox-sensitive doxorubicin (DOX) prodrugs (SDOX) and chemotherapeutic sensitizer lonidamine (LND). The pH-responsive ligand Chol-TPG modified by PEGylated glucose can overcome the blood-brain barrier and reach tumor cells. Combined with the modification of mitochondria targeting ligand (Chol-TPP), Lip-TPGS are endowed with pH-responsive charge regulation function and multi-stage targeting abilities. After triggered by the excessive glutathione in tumor cells, Lip-TPGS could sufficiently release the parent drugs DOX, which would significantly reduce side effects without compromising anti-glioma efficacy. Therefore, Lip-TPGS possess these characteristics: good pharmacokinetic behavior, superior brain targeting ability, specific tumor recognition and internalization capability, and strong endo/lysosome escaping and mitochondria targeting potential. Furthermore, Lip-TPGS exhibit significant advantages on anti-glioma by inhibiting proliferation, promoting apoptosis, inducing mitochondria dysfunction, inhibiting migration and invasion, prolonging the survival time, narrowing tumor areas, limiting lung metastasis, and reducing toxicity to normal organs. In summary, Lip-TPGS, with cascade targeting abilities from tissue/cell to organelle levels and highly controlled drug release properties, would become a promising drug delivery system for glioma treatment.

Enhanced activity of AZD5582 and SM-164 in rabies virus glycoprotein-lactoferrin-liposomes to downregulate inhibitors of apoptosis proteins in glioblastoma

Upregulated proliferation of neoplastic cells from suppressing apoptotic signals associated with the inhibitors of apoptosis proteins (IAP) makes difficult the achievement of therapeutic efficiency against glioblastoma multiforme. Studies in the last few years have witnessed a paradigm focusing on targeting IAP using its antagonists, such as Smac mimetics, to restrain tumor malignancy. A Smac mimetic compound needs to penetrate the blood-brain barrier (BBB), and must be internalized into cerebral tumor for improved chemotherapy. Rabies virus glycoprotein (RVG) and lactoferrin (Lf)-grafted liposomes were developed in this study to carry two IAP antagonists, AZD5582 and SM-164, across the BBB and to induce apoptosis in U87 MG and human brain cancer stem cells (HBCSCs). Liposomes modified with RVG slightly reduced BBB tightness and enhanced capability of AZD5582 and SM-164 for traversing the barrier because of their brain-targeting ability. Immunofluorescence and western-blot results revealed that AZD5582- and SM-164-encapsulated liposomes facilitated mutual curative intensity, effectively triggered apoptosis of U87 MG and HBCSCs, reduced the expression of cellular IAP 1 (cIAP1) and X-linked IAP (XIAP), and enhanced the expression of caspase-3. Hence, RGV-Lf-liposomes carrying AZD5582 and SM-164 can be promising formulations to activate apoptosis of U87 MG and HBCSCs, and this functionalized drug delivery system targeting cIAP and XIAP is a potential strategy to cure glioblastoma in clinical cancer management.

Synchronizing In Silico, In Vitro, and In Vivo Studies for the Successful Nose to Brain Delivery of an Anticancer Molecule.

Sesamol is a sesame seed constituent with reported activity against many types of cancer. In this work, two types of nanocarriers, solid lipid nanoparticles (SLNs) and polymeric nanoparticles (PNs), were exploited to improve sesamol efficiency against the glioma cancer cell line. The ability of the proposed systems for efficient brain targeting intranasally was also inspected. By the aid of two docking programs, the virtual loading pattern inside these nanocarriers was matched to the real experimental results. Interactions involved in sesamol-carrier binding were also assessed, followed by a discussion of how different scoring functions account for these interactions. The study is an extension of the computer-assisted drug formulation design series, which represents a promising initiative for an upcoming industrial innovation. The results proved the power of combined in silico tools in predicting members with the highest sesamol payload suitable for delivering a sufficient dose to the brain. Among nine carriers, glyceryl monostearate (GMS) and polycaprolactone (PCL) scored the highest sesamol payload practically and computationally. The EE % was 66.09 ± 0.92 and 61.73 ± 0.47 corresponding to a ΔG (binding energy) of -8.85 ± 0.16 and -5.04 ± 0.11, respectively. Dynamic light scattering evidenced the formation of 215.1 ± 7.2 nm and 414.25 ± 1.6 nm nanoparticles, respectively. Both formulations demonstrated an efficient cytotoxic effect and brain-targeting ability compared to the sesamol solution. This was evidenced by low IC50 (38.50 ± 10.37 μM and 27.81 ± 2.76 μM) and high drug targeting efficiency (7.64 ± 1.89-fold and 13.72 ± 4.1-fold) and direct transport percentages (86.12 ± 3.89 and 92.198 ± 2.09) for GMS-SLNs and PCL-PNs, respectively. The results also showed how different formulations, having different compositions and characteristics, could affect the cytotoxic and targeting ability.

Biomimetic silibinin-loaded macrophage-derived exosomes induce dual inhibition of Aβ aggregation and astrocyte activation to alleviate cognitive impairment in a model of Alzheimer's disease

Alzheimer's disease (AD) is a common neurodegenerative disease of the central nervous system. Due to its complex pathogenesis and the difficulty of drugs to cross the blood brain barrier (BBB), no effective clinical drugs are currently available that prevent the development of the course of AD. Silibinin (Slb) is known to exert dual therapeutic effects on reducing amyloid-β (Aβ) aggregation and deactivating astrocytes to improve behaviour and cognitive performance in subjects with Alzheimer's disease (AD). However, the poor brain targeting ability and low bioavailability limit its wide application. We aimed to encapsulate Slb in macrophage-derived exosomes (Exo-Slb) to improve its brain targeting ability. After entering the brain, exosomal Slb selectively interacted with Aβ monomers to reduce its aggregation. At the same time, Exo-Slb was internalized in astrocytes to inhibit their activation and alleviate astrocyte inflammation-mediated neuronal damage. Finally, Exo-Slb potently ameliorated cognitive deficits in AD mice.

Glucose and Triphenylphosphonium Co-Modified Redox-Sensitive Liposomes to Synergistically Treat Glioma with Doxorubicin and Lonidamine.

Glioma is one of the most lethal and complex tumors, and thus, an effective drug delivery system must selectively target the tumor sites and release its cargos in a controlled manner. For the first time, we combined chemotherapeutic agent doxorubicin (DOX) and chemosensitizer lonidamine (LND) to synergistically treat glioma. We also designed and prepared multitargeted redox-sensitive liposomes (Lip-SPG) co-modified with glucose and triphenylphosphonium (TPP) to effectively deliver DOX and LND for anti-glioma therapy. The anti-glioma evaluation shows that DOX and LND have a synergistic effect and Lip-SPG could further enhance their cooperation. In vitro, Lip-SPG could increase the cellular uptake and mitochondrial uptake on bEnd.3 cells and C6 cells with multitargeting ability on the brain, tumor, and mitochondria mediated by glucose and TPP. Lip-SPG can also escape from lysosomes before entering the mitochondria. The anti-glioma efficacy in vitro shows that Lip-SPG can inhibit tumor cell proliferation and induce apoptosis. In addition, Lip-SPG have a remarkable interference to mitochondria, such as reducing intracellular ATP production, inducing ROS generation, and promoting mitochondrial membrane potential depolarization. Furthermore, in vivo, the introduction of PEGylation via glutathione-sensitive disulfide bonds endows Lip-SPG with favorable pharmacokinetic properties, brain targeting ability, low toxicity to normal tissues, and great anti-glioma efficacy with the survival time extended from 19 to 39 days. In conclusion, Lip-SPG are an effective delivery system for synergistically treating glioma with DOX and LND.

Assessment of brain-to-blood drug distribution using liquid chromatography.

Delivery of already existing and new drugs under development to the brain necessitates passage across the blood-brain barrier (BBB) with its tight intercellular junctions, molecular components and transporter systems. Consequently, it is critical to identify the extent of brain permeation and the partitioning across the BBB. The interpretation of brain-to-blood ratios is considered to be a significant and fundamental approach for estimating drug penetration through BBB, the brain-targeting ability and central nervous system (CNS) pharmacokinetics. Among the different bioanalytical techniques, liquid chromatography with various detectors has been widely used for determination of these ratios. This review defines the different approaches for sample preparation, extraction techniques and liquid chromatography procedures concerned with the determination of drugs in blood and brain tissues and the assessment of brain-to-blood levels. These approaches are expanded to cover the analysis of several drug classes such as CNS-acting drugs, chemotherapeutics, antidiabetics, herbal medicinal products, radiopharmaceuticals, antibiotics and antivirals. Accordingly, stability in biological matrices and matrix effects are investigated. The different administration/formulation effects and the possible deviations in these ratios are also disscussed.

Baicalin-loaded macrophage-derived exosomes ameliorate ischemic brain injury via the antioxidative pathway

Baicalin (BA), a strong free radical scavenger, has been demonstrated to exert neuroprotective effects in the treatment of ischemic stroke. However, its clinical application has been limited due to its inability to target the brain and its poor solubility. In this study, we designed novel brain-targeted BA-loaded macrophage-derived exosomes (Exo-BA) to induce neuroprotection against ischemic stroke in animal models. The results revealed that with the help of Exo, the solubility of BA was significantly enhanced. In addition, Exo-BA displayed better brain targeting ability than free BA, as they induced the transfer of more BA into the brain, in a transient middle cerebral artery occlusion/reperfusion (tMCAO) model and permanent middle cerebral artery occlusion (pMCAO) model. Compared with free BA, Exo-BA significantly reduced the generation of reactive oxygen species (ROS) and activated the Nrf2/HO-1 pathway in neurons, thus significantly alleviating cerebral ischemic injury in a stroke model.

Chondroitin sulfate conjugation facilitates tumor cell internalization of albumin nanoparticles for brain-targeted delivery of temozolomide via CD44 receptor-mediated targeting

In the present investigation, temozolomide (TMZ) loaded chondroitin sulfate conjugated albumin nanoparticles (CS-TNPs) were fabricated bydesolvation method were chondroitin sulfate (CS) was used as the surface exposed ligand to achieve CD44 receptor mediated targeting of brain tumor.The developed CS-TNPs were characterized for particle size, zeta potential, entrapment efficiency and drug loading and evaluated by FTIR, DSC, XRD and TEM analysis. BBB (blood brain barrier) passage study using in vitro BBB model indicated that CS-TNPs were able to efficiently cross the BBB. Cell viability assay data demonstrated higher cytotoxicity of CS-TNPs as compared with pure TMZ. The CD44 receptor blocking assay and receptor poisoning assay in U87 MG cells confirmed the CD44 receptor and endocytosis-mediated (caveolae pathway) uptake of CS-TNPs. CS-TNPs were able to generate ROS in U87 MG cells. In vivo pharmacokinetic and biodistribution studies were performed in Wistar rats. In vivo results revealed significant enhancement in pharmacokinetic profile of CS-TNPs as compared with TMZ alone. Biodistribution results demonstrated higher accumulation of TMZ in the brain by CS-TNPs as compared with thepure drug that confirmed the brain targeting ability of nanoparticles.From all obtained results, it may be concluded that CS-TNPs are promising carrier to deliver TMZ to the brain for targeted therapy of brain tumor. Graphical abstract.

Lactose-appended β-cyclodextrin as an effective nanocarrier for brain delivery

The blood-brain barrier (BBB) prevents the permeability of drugs into the brain, and as such limits the management of various brain diseases. To overcome this barrier, drug-encapsulating nanoparticles or vesicles, drug conjugates, and other types of drug delivery systems (DDSs) have been developed. However, the brain-targeting ability of nanoparticles or vesicles is still insufficient. Recently, among the various brain-targeting ligands previously studied for facilitating transcellular BBB transport, several sugar-appended nanocarriers for brain delivery were identified. Meanwhile, cyclodextrins (CyDs) have been used as nanocarriers for drug delivery since they can encapsulate hydrophobic compounds with high biocompatibility. Therefore, in this study, we created various sugar-appended β-cyclodextrins (β-CyDs) to discover novel brain-targeting ligands. As a result, of the six sugar-appended CyDs, lactose-appended β-CyD (Lac-β-CyD) showed greater cellular uptake in hCMEC/D3 cells, human brain microvascular endothelial cells, than other sugar-appended β-CyDs did. In addition, the permeability of Lac-β-CyD within the in vitro human BBB model was greater than that of other sugar-appended β-CyDs. Moreover, Lac-β-CyD significantly accumulated in the mouse brain after intravenous administration. Thus, Lac-β-CyD efficiently facilitated the accumulation of the model drug into the mouse brain. These findings suggest that Lac-β-CyD has the potential to be a novel carrier for drugs across the BBB.