Brain Drug Delivery Research Articles

Revolutionizing Brain Drug Delivery: Buccal Transferosomes on the Verge of a Breakthrough.

The buccal cavity, also known as the oral cavity, is a complex anatomical structure that plays a crucial role in various physiological processes. It serves as a gateway to the digestive system and facilitates the initial stages of food digestion and absorption. However, its significance extends beyond mere digestion as it presents a promising route for drug delivery, particularly to the brain. Transferosomes are lipid-based vesicles that have gained significant attention in the field of drug delivery due to their unique structure and properties. These vesicles are composed of phospholipids that form bilayer structures capable of encapsulating both hydrophilic and lipophilic drugs. Strategies for the development of buccal transferosomes for brain delivery have emerged as promising avenues for pharmaceutical research. This review aims to explore the various approaches and challenges associated with harnessing the potential of buccal transferosomes as a means of enhancing drug delivery to the brain. By understanding the structure and function of both buccal tissue and transferosomes, researchers can develop effective formulation methods and characterization techniques to optimize drug delivery. Furthermore, strategic approaches and success stories in buccal transferosome development are highlighted, showcasing inspiring examples that demonstrate their potential to revolutionize brain delivery.

Brain Drug Delivery- An Updated Review Article for Mechanism and Recent Technologies

Brain Drug Delivery- An Updated Review Article for Mechanism and Recent Technologies

EXTH-57. EXPLORING NOVEL ROUTES FOR NON-INVASIVE DRUG ADMINISTRATION: INTRADERMAL DELIVERY FOR THE TREATMENT OF BRAIN TUMORS

Abstract Effective non-invasive drug delivery to brain tumors remains challenging, despite extensive exploration of these methods, due to the blood-brain barrier (BBB). Intranasal drug delivery has emerged as a promising alternative approach, as it circumvents limitations on tumor access imposed by the BBB when administering therapeutics systemically and limits the occurrence of systemic toxic responses to treatment. The intranasal route of administration allows therapeutic access to brain tumors through pathways involving the olfactory and trigeminal nerves (TNs) that connect the nasal passage to the brain. However, effective nose-to-brain delivery is impeded by rapid mucosal drug clearance in the nasal cavity, drug aspiration, and ingestion. Since the TN arises from the brainstem and its branches innervate the facial skin, in addition to muscles, meninges, and respiratory mucosa, we tested the hypothesis that facial intradermal administration targeting the V2 branch of the TN could be an alternative strategy to harness TN-mediated brain delivery to bypass the BBB. Here, we developed Spherical Nucleic Acids (SNAs) consisting of a 15nm spherical gold nanoparticle core functionalized with radially oriented fluorophore-tagged ssDNA as a model therapeutic. We observed the delivery of the SNAs to the brain starting 4 hours post intradermal injection, with the SNA accumulation in the tumor persisting over time. Using ex vivo fluorescent imaging, comprehensive immunofluorescence microscopy, and flow cytometry we confirmed the SNA accumulation in the brain, dura, TN, and cervical lymph nodes. In particular, we demonstrated that SNAs were enriched in the neuronal cell bodies of the trigeminal ganglia and within the epineurium and perineurium of the TN. The SNAs were also enriched in CD45-positive immune cells. In conclusion, this study credentialed facial intradermal administration of SNAs as a promising non-invasive method for brain drug delivery to target intracranial tumors.

Brain drug delivery from the nasal olfactory region is enhanced using lauroylcholine chloride: An estimation using in vivo PET imaging

IntroductionIntranasal (IN) administration, often referred to as nose-to-brain (N2B) drug delivery, is an attractive approach for delivering drugs to the central nervous system. However, the efficacy of this method is limited because of the small size of the nasal olfactory region, which limits the drug dosage. Using permeation enhancers could improve drug delivery from this region to the brain, though their effects are not fully understood. We therefore investigated the effects of co-administration of permeation enhancers on N2B drug delivery of a model drug domperidone, a peripherally acting dopamine D2 receptor (D2R) blocker. MethodsWe conducted in vitro permeability assays to evaluate the effects of sodium lauryl sulfate (SLS), a classical permeation enhancer, and lauroylcholine chloride (LCC) on domperidone permeation in human nasal mucosa-derived cells. We also used the D2R ligand [11C]raclopride to assess the in vivo effects of LCC on domperidone delivery in the rat brain using a positron emission tomography (PET) competition paradigm. In comparative PET experiments, we tested the effects of intravenously administered domperidone without LCC co-administration. ResultsLCC effectively improved nasal mucosal permeation of domperidone in vitro compared to SLS. In rat IN administration experiments, striatal [11C]raclopride uptake was significantly decreased by the addition of LCC to domperidone. On the other hand, intravenously administered domperidone with or without intranasally administered LCC did not decrease [11C]raclopride brain uptake, suggesting a lesser influence of peripheral domperidone on [11C]raclopride brain uptake. PET studies showed that striatal D2R occupancy of domperidone was increased 2.4-fold by co-administration of LCC. ConclusionLCC effectively enhances the domperidone delivery from the rat olfactory region to the brain, probably not via a circulating blood. The combination of permeation enhancers and olfactory region-selective drug administration could be effective for N2B drug delivery.

Systematic Approach in the Development of Chitosan Functionalized Iloperidone Nanoemulsions for Transnasal Delivery, In Vitro and In Vivo Studies.

Iloperidone, a second-generation USFDA approved antipsychotic and BCS class II drug shows poor oral bioavailability of 28%. The present research deals with optimization of transnasal nanoemulsions of Iloperidone using Design Expert (Version 11) and further surface functionalization with chitosan for potentiating nose to brain delivery. Chitosan functionalized transnasal Iloperidone nanoemulsions were developed using oleic acid, charge inducer, Tween 80, TranscutolHP and chitosan using ultrasonication technique and evaluated. Droplet size, polydispersity index and zeta potential of Iloperidone nanoemulsions was found to be 173 ± 0.5nm, 0.413 ± 0.2 and - 22.5 ± 0.1mV while that of chitosan functionalized Iloperidone nanoemulsions was 146.4 ± 0.5nm, 0.291 ± 0.02 and + 23.6 ± 0.3mV respectively. Ninhydrin assay, TEM and FTIR studies confirmed surface functionalization of Iloperidone nanoemulsion droplets with chitosan. In vitro release of Iloperidone from nanoemulsions and chitosan functionalized nanoemulsions was 90.41 ± 2.1% and 72.02 ± 0.21% while ex vivo permeation of Iloperidone across goat nasal mucosa was 1270.58 ± 0.023μg/cm2 and 1096.13 ± 0.043μg/cm2 respectively at the end of 8h. Studies in RPMI 2650 nasal and Neuro2A brain cell line lines indicated safety of chitosan functionalized transnasal Iloperidone nanoemulsions. Studies in Wistar rats showed increased cataleptic effects, reduced cognitive impairment and anxiety-related behaviour with greater brain accumulation indicating promising potential of this approach in nose to brain drug delivery.

Optimizing Brain Drug Delivery: The Role of Nanosuspension in Enhancing Therapeutic Efficacy and Bioavailability

Optimizing Brain Drug Delivery: The Role of Nanosuspension in Enhancing Therapeutic Efficacy and Bioavailability

Exploiting the mechanical effects of ultrasound for noninvasive therapy.

Focused ultrasound is a platform technology capable of eliciting a wide range of biological responses with high spatial precision deep within the body. Although focused ultrasound is already in clinical use for focal thermal ablation of tissue, there has been a recent growth in development and translation of ultrasound-mediated nonthermal therapies. These approaches exploit the physical forces of ultrasound to produce a range of biological responses dependent on exposure conditions. This review discusses recent advances in four application areas that have seen particular growth and have immense clinical potential: brain drug delivery, neuromodulation, focal tissue destruction, and endogenous immune system activation. Owing to the maturation of transcranial ultrasound technology, the brain is a major target organ; however, clinical indications outside the brain are also discussed.

In Vitro Drug Delivery through the Blood–Brain Barrier Using Cold Atmospheric Plasma

This study explores the potential of cold atmospheric plasma (CAP) to facilitate the delivery of large-molecule drugs to the brain. The blood–brain barrier (BBB) restricts the passage of most drugs, hindering treatment for neurological disorders. CAP generates reactive oxygen and nitrogen species (RONS) that may disrupt the BBB’s tight junctions, potentially increasing drug permeability. An in vitro BBB model and an immortalized cell line (bEND.3) were used in this experiment. Fluorescein isothiocyanate dextran (FD-4), a model drug, was added to the cells to determine drug permeability. Custom microplasma was used to produce reactive oxygen species (ROS). Trans-endothelial electrical resistance (TEER) measurements assessed the integrity of the BBB after the CAP treatment. A decrease in TEER was observed in the CAP-treated group compared to the controls, suggesting increased permeability. Additionally, fluorescence intensity measurements from the basal side of the trans-well plate indicated higher drug passage in the CAP-treated group. Moreover, the higher presence of ROS in the plasma-treated cells confirmed the potential of CAP in drug delivery. These findings suggest that CAP may be a promising approach for enhancing brain drug delivery.

Key Challenges, Influencing Factors, and Future Perspectives of Nanosuspensions in Enhancing Brain Drug Delivery.

Many brain diseases pose serious challenges to human life. Alzheimer's Disease (AD) and Parkinson's Disease (PD) are common neurodegenerative diseases that seriously threaten human health. Glioma is a common malignant tumor. However, drugs cannot cross physiological and pathological barriers and most therapeutic drugs cannot enter the brain because of the presence of the Blood-brain Barrier (BBB) and Bloodbrain Tumor Barrier (BBTB). How to enable drugs to penetrate the BBB to enter the brain, reduce systemic toxicity, and penetrate BBTB to exert therapeutic effects has become a challenge. Nanosuspension can successfully formulate drugs that are difficult to dissolve in water and oil by using surfactants as stabilizers, which is suitable for the brain target delivery of class II and IV drugs in the Biopharmaceutical Classification System (BCS). In nanosuspension drug delivery systems, the physical properties of nanostructures have a great impact on the accumulation of drugs at the target site, such as the brain. Optimizing the physical parameters of the nanosuspension can improve the efficiency of brain drug delivery and disease treatment. Therefore, the key challenges, influencing factors, and future perspectives of nanosuspension in enhancing brain drug delivery are summarized and reviewed here. This article aims to provide a better understanding of nanosuspension formulation technology used for brain delivery and strategies used to overcome various physiological barriers.

Metal-Organic Frameworks for Overcoming the Blood-Brain Barrier in the Treatment of Brain Diseases: A Review.

The blood-brain barrier (BBB) plays a vital role in safeguarding the central nervous system by selectively controlling the movement of substances between the bloodstream and the brain, presenting a substantial obstacle for the administration of therapeutic agents to the brain. Recent breakthroughs in nanoparticle-based delivery systems, particularly metal-organic frameworks (MOFs), provide promising solutions for addressing the BBB. MOFs have become valuable tools in delivering medications to the brain with their ability to efficiently load drugs, release them over time, and modify their surface properties. This review focuses on the recent advancements in molecular-based approaches for treating brain disorders, such as glioblastoma multiforme, stroke, Parkinson's disease, and Alzheimer's disease. This paper highlights the significant impact of MOFs in overcoming the shortcomings of conventional brain drug delivery techniques and provides valuable insights for future research in the field of neurotherapeutics.

Dose-Dependent Attenuation of the Efficacy of Clitoria ternatea by Cobalt Oxide Nanoparticles Against Diabetes-Induced Cognitive Impairment.

Diabetes mellitus is a metabolic disorder caused by insulin deficiency, insulin resistance, genetic alterations, and oxidative stress. The high glucose levels may impair the functioning of nerve cells, leading to neurodegenerative diseases, including cognitive impairment. Clitoria ternatea has various pharmacological activities, including antioxidant, anti-inflammatory, antidiabetic, and neuroprotective effects. The present study evaluates the efficacy of fresh flower aqueous extract of Clitoria ternatea against diabetes-induced cognitive impairment. The challenges in delivering drugs targeting the brain possess the limitations of crossing the blood-brain barrier. Metal nanoparticles are considered the most reliable brain drug delivery systems. Considering the neurotoxicity of cobalt oxide, whether it can be used to improve brain delivery is also evaluated. Cobalt oxide nanoparticles (Co3O4 NPs) of fresh flower aqueous extract of Clitoria ternatea are prepared by green synthesis and characterized. The effect of these nanoparticles is compared with Clitoria ternatea extract against Streptozotocin (STZ)-induced cognitive impairment. The behavioral, biochemical, in vivo antioxidant, total thiol content, estimation of proinflammatory cytokines, acetylcholine esterase, and nitrite levels in the brain of STZ-induced diabetic rats revealed that cobalt oxide nanoparticles showed neurotoxicity, whereas C. ternatea showed neuroprotective effect and also improved the cognitive function. The lower dose of cobalt oxide nanoparticles of C. ternatea (2mg/kg) exhibited a neuroprotective and cognition improvement effect. However, the higher dose (4mg/kg) of cobalt oxide nanoparticles of C. ternatea showed a neurotoxic effect. Since Co3O4 NPs are neuroprotective at low doses, they can be used for neuroprotective actions. However, dose optimization studies are required.

Advanced Noninvasive Strategies for the Brain Delivery of Therapeutic Proteins and Peptides.

Recent years have witnessed rapid progress in the discovery of therapeutic proteins and peptides for the treatment of central nervous system (CNS) diseases. However, their clinical applications have been considerably hindered by challenges such as low biomembrane permeability, poor stability, short circulation time, and the formidable blood-brain barrier (BBB). Recently, substantial improvements have been made in understanding the dynamics of the BBB and developing efficient approaches for delivering proteins and peptides to the CNS, especially by using various nanoparticles. Herein, we present an overview of the up-to-date understanding of the BBB under physiological and pathological conditions, emphasizing their effects on brain drug delivery. We summarize advanced strategies and elucidate the underlying mechanisms for delivering proteins and peptides to the brain. We highlight the developments and applications of nanocarriers in treating CNS diseases via BBB crossing. We also provide critical opinions on the limitations and obstacles of the current strategies and put forward prospects for future research.

Nanotechnology-based Drug Delivery for Alzheimer's and Parkinson's Diseases.

The delivery of drugs to the brain is quite challenging in the treatment of the central nervous system (CNS) diseases due to the blood-brain barrier and the blood-cerebrospinal fluid barrier. However, significant developments in nanomaterials employed by nanoparticle drug-delivery systems have substantial potential to cross or bypass these barriers leading to enhanced therapeutic efficacies. Advances in nanoplatform, nanosystems based on lipids, polymers and inorganic materials have been extensively studied and applied in treating Alzheimer's and Parkinson's diseases. In this review, various types of brain drug delivery nanocarriers are classified, summarized, and their potential as drug delivery systems in Alzheimer's and Parkinson's diseases is discussed. Finally, challenges facing the clinical translation of nanoparticles from bench to bedside are highlighted.

Small Scale, Big Impact: Nanotechnology-Enhanced Drug Delivery for Brain Diseases.

Central nervous system (CNS) diseases, ranging from brain cancers to neurodegenerative disorders like dementia and acute conditions such as strokes, have been heavily burdening healthcare and have a direct impact on patient quality of life. A significant hurdle in developing effective treatments is the presence of the blood-brain barrier (BBB), a highly selective barrier that prevents most drugs from reaching the brain. The tight junctions and adherens junctions between the endothelial cells and various receptors expressed on the cells make the BBB form a nonfenestrated and highly selective structure that is crucial for brain homeostasis but complicates drug delivery. Nanotechnology offers a novel pathway to circumvent this barrier, with nanoparticles engineered to ferry drugs across the BBB, protect drugs from degradation, and deliver medications to the designated area. After years of development, nanoparticle optimization, including sizes, shapes, surface modifications, and targeting ligands, can enable nanomaterials tailored to specific brain drug delivery settings. Moreover, smart nano drug delivery systems can respond to endogenous and exogenous stimuli that control subsequent drug release. Here, we address the importance of the BBB in brain disease treatment, summarize different delivery routes for brain drug delivery, discuss the cutting-edge nanotechnology-based strategies for brain drug delivery, and further offer valuable insights into how these innovations in nanoparticle technology could revolutionize the treatment of CNS diseases, presenting a promising avenue for noninvasive, targeted therapeutic interventions.

Emerging Trends in Targeted Magnetic Nanoparticle Imaging for Precision Medicine in Oncology

In cancer care's dynamic landscape, targeted imaging is pivotal for advancing precision medicine. This review focuses on the role of magnetic nanoparticles (MNPs), particularly magnetic iron oxide nanoparticles (MIONPs) and superparamagnetic iron oxide nanoparticles (SPIONs), in personalized diagnostics and treatments for oncology. Current trends and future directions in MNP imaging, addressing challenges like biocompatibility, toxicity, and regulatory considerations, are discussed. The review explores MIONPs' theranostic potential, especially in brain drug delivery monitoring through magnetic resonance imaging (MRI) or magnetic particle imaging (MPI). Variousnanoparticle types, including SPIONs as MRI contrast agents, are highlighted. The article covers challenges in nanoparticle modification, including methoxy- polyethylene glycol (mPEG), and discusses gold nanoparticles (AuNPs) for photoacoustic imaging, as well as insights into fluorescent semiconductor quantum dots (QDs). The conclusion emphasizes rapid and accurate tumoridentification, introduces carbon nanotubes (CNTs) for cancer therapy and diagnosis, and underscores the transformative role of lipid-based nanocarriers incancer research. The multifaceted applications of nanotechnology in cancer diagnostics and treatment are discussed throughout, showcasing a paradigm shift.Crucial challenges in unlocking nanotechnology's full potential in cancer care, such as safety concerns, robust clinical trials, synthesis methods standardization, regulatory approval, biodegradability, tailoring nanotherapies, economic viability, ethical considerations, and interdisciplinary collaboration, are addressed. Addressing these challenges holds the promise of elevating nanotechnology into a potent force in the ongoing battle against cancer.

Virus-Shaped Mesoporous Silica Nanostars to Improve the Transport of Drugs across the Blood-Brain Barrier.

Conditions affecting the brain are the second leading cause of death globally. One of the main challenges for drugs targeting brain diseases is passing the blood-brain barrier (BBB). Here, the effectiveness of mesoporous silica nanostars (MSiNSs) with two different spike lengths to cross an in vitro BBB multicellular model was evaluated and compared to spherical nanoparticles (MSiNP). A modified sol-gel single-micelle epitaxial growth was used to produce MSiNS, which showed no cytotoxicity or immunogenicity at concentrations of up to 1 μg mL-1 in peripheral blood mononuclear and neuronal cells. The nanostar MSiNS effectively penetrated the BBB model after 24 h, and MSiNS-1 with a shorter spike length (9 ± 2 nm) crossed the in vitro BBB model more rapidly than the MSiNS-2 with longer spikes (18 ± 4 nm) or spherical MSiNP at 96 h, which accumulated in the apical and basolateral sides, respectively. Molecular dynamic simulations illustrated an increase in configurational flexibility of the lipid bilayer during contact with the MSiNS, resulting in wrapping, whereas the MSiNP suppressed membrane fluctuations. This work advances an effective brain drug delivery system based on virus-like shaped MSiNS for the treatment of different brain diseases and a mechanism for their interaction with lipid bilayers.

The Influence of Size on the Intracranial Distribution of Biomedical Nanoparticles Administered by Convection-enhanced Delivery in Minipigs.

Because of the blood-brain barrier (BBB), successful drug delivery to the brain has long been a key objective for the medical community, calling for pioneering technologies to overcome this challenge. Convection-enhanced delivery (CED), a form of direct intraparenchymal microinfusion, shows promise but requires optimal infusate design and real-time distribution monitoring. The size of the infused substances appears to be especially critical, with current knowledge being limited. Herein, we examined the intracranial administration of polyethylene glycol (PEG)-coated nanoparticles (NPs) of various sizes using CED in groups of healthy minipigs (n = 3). We employed stealth liposomes (LIPs, 130 nm) and two gold nanoparticle designs (AuNPs) of different diameters (8 and 40 nm). All were labeled with copper-64 for quantitative and real-time monitoring of the infusion via positron emission tomography (PET). NPs were infused via two catheters inserted bilaterally in the putaminal regions of the animals. Our results suggest CED with NPs holds promise for precise brain drug delivery, with larger LIPs exhibiting superior distribution volumes and intracranial retention over smaller AuNPs. PET imaging alongside CED enabled dynamic visualization of the process, target coverage, timely detection of suboptimal infusion, and quantification of distribution volumes and concentration gradients. These findings may augment the therapeutic efficacy of the delivery procedure while mitigating unwarranted side effects associated with nonvisually monitored delivery approaches. This is of vital importance, especially for chronic intermittent infusions through implanted catheters, as this information enables informed decisions for modulating targeted infusion volumes on a catheter-by-catheter, patient-by-patient basis.

Fabrication and Optimisation of Alumina Nanoporous Membranes for Drug Delivery Applications: A Comparative Study.

Neurodegenerative disorders cause most physical and mental disabilities, and therefore require effective treatment. The blood-brain barrier (BBB) prevents drug molecules from crossing from the blood to the brain, making brain drug delivery difficult. Implantable devices could provide sustained and regulated medication to solve this problem. Two electrolytes (0.3 M oxalic acid and 0.3 M sulphuric acid) were used to anodise Al2O3 nanoporous membranes, followed by a third anodisation in concentrated H2SO4 to separate the through-hole membranes from the aluminium substrate. FTIR, AFM, and SEM/EDX were used to characterise the membranes' structure and morphology. The effects of the anodisation time and electrolyte type on the AAO layer pore density, diameter, interpore distance, and thickness were examined. As a model drug for neurodegenerative disorders, donepezil hydrochloride (DHC) was loaded onto thin alumina nanoporous membranes. The DHC release profiles were characterised at two concentrations using a UV-Vis spectrophotometer. Oxalic acid membranes demonstrated an average pore diameter of 39.6-32.5 nm, which was two times larger than sulphuric acid membranes (22.6-19.7 nm). After increasing the anodisation time from 3 to 5 h, all of the membranes showed a reduction in pore diameter that was stable regardless of the electrolyte type or period. Drug release from oxalic acid-fabricated membranes was controlled and sustained for over 2 weeks. Thus, nanoporous membranes as implantable drug delivery systems could improve neurodegenerative disease treatment.

Cerebro-spinal fluid (CSF) targeting through intra-nasal route by using nanotechnology emerging as a powerful technique for different brain diseases

The human brain, a highly sensitive organ, functions as the body's central control unit and is naturally protected to preserve neurological health. The Blood-Brain Barrier (BBB) presents a significant challenge to the delivery of drugs into the brain. Oral medications face low bioavailability and restricted brain exposure, compounded by rapid metabolism, elimination, unwanted side effects, and the necessity for high doses. These factors lead to inconvenience for patients and substantial costs for patients, their families, and society. The primary obstacle to effective brain penetration of these compounds is the BBB, which safeguards the brain from xenobiotics. Consequently, treating brain diseases such as Alzheimer's, Parkinson's, dementia, mood disorders, and bacterial infections is more complex. The intranasal route of administration offers a promising alternative for bypassing the BBB in brain drug delivery, facilitating drug transport from the nasal cavity to the brain via the olfactory and trigeminal nerves.

Development and characterization of lipid nanocapsules loaded with iron oxide nanoparticles for magnetic targeting to the blood–brain barrier

Brain drug delivery is severely hindered by the presence of the blood–brain barrier (BBB). Its functionality relies on the interactions of the brain endothelial cells with additional cellular constituents, including pericytes, astrocytes, neurons, or microglia. To boost brain drug delivery, nanomedicines have been designed to exploit distinct delivery strategies, including magnetically driven nanocarriers as a form of external physical targeting to the BBB. Herein, a lipid-based magnetic nanocarrier prepared by a low-energy method is first described. Magnetic nanocapsules with a hydrodynamic diameter of 256.7 ± 8.5 nm (polydispersity index: 0.089 ± 0.034) and a ξ-potential of -30.4 ± 0.3 mV were obtained. Transmission electron microscopy-energy dispersive X-ray spectroscopy analysis revealed efficient encapsulation of iron oxide nanoparticles within the oily core of the nanocapsules. Both thermogravimetric analysis and phenanthroline-based colorimetric assay showed that the iron oxide percentage in the final formulation was 12 wt.%, in agreement with vibrating sample magnetometry analysis, as the specific saturation magnetization of the magnetic nanocapsules was 12% that of the bare iron oxide nanoparticles. Magnetic nanocapsules were non-toxic in the range of 50–300 μg/mL over 72 h against both the human cerebral endothelial hCMEC/D3 and Human Brain Vascular Pericytes cell lines. Interestingly, higher uptake of magnetic nanocapsules in both cell types was evidenced in the presence of an external magnetic field than in the absence of it after 24 h. This increase in nanocapsules uptake was also evidenced in pericytes after only 3 h. Altogether, these results highlight the potential for magnetic targeting to the BBB of our formulation.Graphical