Brain Drug Delivery Research Articles

Peptide Shuttles for Blood-Brain Barrier Drug Delivery.

The blood–brain barrier (BBB) limits the delivery of therapeutics to the brain but also represents the main gate for nutrient entrance. Targeting the natural transport mechanisms of the BBB offers an attractive route for brain drug delivery. Peptide shuttles are able to use these mechanisms to increase the transport of compounds that cannot cross the BBB unaided. As peptides are a group of biomolecules with unique physicochemical and structural properties, the field of peptide shuttles has substantially evolved in the last few years. In this review, we analyze the main classifications of BBB–peptide shuttles and the leading sources used to discover them.

Effect of Slp4-a on Membrane Bending During Prefusion of Vesicles in Blood-Brain Barrier.

Vesicle exocytosis is a promising pathway for brain drug delivery through the blood-brain barrier to treat neurodegenerative diseases. In vesicle exocytosis, the membrane fusion process is initiated by the calcium sensor protein named synaptotagmin-like protein4-a (Slp4-a). Understanding conformational changes of Slp4-a during the prefusion stage of exocytosis will help to develop vesicle-based drug delivery to the brain. In this work, we use molecular dynamics (MD) simulations with a hybrid force field coupling united-atom protein model with MARTINI coarse-grained (CG) solvent to capture the conformational changes of Slp4-a during the prefusion stage. These hybrid coarse-grained simulations are more efficient than all-atom MD simulations and can capture protein interactions and conformational changes. Our simulation results show that the calcium ions play critical roles during the prefusion stage. Only one calcium ion can remain in each calcium-binding pocket of Slp4-a C2 domains. The C2B domain of calcium-unbound Slp4-a remains parallel to the endothelial membrane, while the C2B domain of calcium-bound Slp4-a rotates perpendicular to the endothelial membrane to approach the vesicular membrane. For the calcium-bound case, three Slp4-a proteins can effectively bend lipid membranes at the prefusion stage, which could later trigger lipid stalk between membranes. This work provides a better understanding how C2 domains of Slp4-a operate during vesicle exocytosis from an endothelial cell.

Drug delivery system based on nanobubbles

AbstractUltrasound (US) medical technology is widely used due to its advantages of safety, speed, and low cost. With the rapid development of biomedical nanotechnology, micro/nanobubbles, as US contrast agents, are not only valuable in US imaging diagnosis but also show broad application prospects in drug delivery. Nanobubbles (NBs) have more advantages as drug delivery systems (DDSs) due to their smaller size and longer circulation time compared with microbubbles. In this review, the fundamentals of NBs, including classification, stability mechanism, and preparation methods are summarized. Then, the strategies of a DDS based on NBs, including direct delivery, codelivery, target delivery, and stimuli‐responsive delivery are reviewed and discussed. The three main applications of NBs‐based DDSs, namely tumor theranostics, brain drug delivery, and vascular disease theranostics were highlighted. The challenges and future directions of the NBs‐based DDSs are also considered and discussed.

Oral delivery of polyester nanoparticles for brain-targeting: Challenges and opportunities

Efficient oral delivery of drugs treating brain diseases has long been a challenging topic faced by the drug delivery community. Fortunately, polyester nanoparticles offer certain solutions to this problem. This review article firstly describes the main obstacles faced by oral administered brain targeting, including: (1) instability in the gastrointestinal tract; (2) poor penetration of the intestinal mucosa and epithelium; (3) blood clearance; and (4) restriction by the BBB. Then the key factors influencing brain-targeting efficiency of orally administered polyester nanoparticles are also discussed, such as size, shape and surface properties. Finally, recent brain-targeting delivery strategies using oral polyester nanoparticles as carriers and their effects on brain drugs transport are reviewed, and the delivery ‘as a whole’ strategy of polyester nanoparticles will provide new insight for oral brain-targeting delivery. And by combination of multiple strategies, both the stability and permeability of polyester nanoparticles can be greatly improved for oral brain drug delivery.

Self-Emulsifying Drug Delivery Systems: An Alternative Approach to Improve Brain Bioavailability of Poorly Water-Soluble Drugs through Intranasal Administration.

Efforts in discovering new and effective neurotherapeutics are made daily, although most fail to reach clinical trials. The main reason is their poor bioavailability, related to poor aqueous solubility, limited permeability through biological membranes, and the hepatic first-pass metabolism. Nevertheless, crossing the blood–brain barrier is the major drawback associated with brain drug delivery. To overcome it, intranasal administration has become more attractive, in some cases even surpassing the oral route. The unique anatomical features of the nasal cavity allow partial direct drug delivery to the brain, circumventing the blood–brain barrier. Systemic absorption through the nasal cavity also avoids the hepatic first-pass metabolism, increasing the systemic bioavailability of highly metabolized entities. Nevertheless, most neurotherapeutics present physicochemical characteristics that require them to be formulated in lipidic nanosystems as self-emulsifying drug delivery systems (SEDDS). These are isotropic mixtures of oils, surfactants, and co-surfactants that, after aqueous dilution, generate micro or nanoemulsions loading high concentrations of lipophilic drugs. SEDDS should overcome drug precipitation in absorption sites, increase their permeation through absorptive membranes, and enhance the stability of labile drugs against enzymatic activity. Thus, combining the advantages of SEDDS and those of the intranasal route for brain delivery, an increase in drugs’ brain targeting and bioavailability could be expected. This review deeply characterizes SEDDS as a lipidic nanosystem, gathering important information regarding the mechanisms associated with the intranasal delivery of drugs loaded in SEDDS. In the end, in vivo results after SEDDS intranasal or oral administration are discussed, globally revealing their efficacy in comparison with common solutions or suspensions.

Computational Assessment of Different Structural Models for Claudin-5 Complexes in Blood-Brain Barrier Tight Junctions.

The blood-brain barrier (BBB) strictly regulates the exchange of ions and molecules between the blood and the central nervous system. Tight junctions (TJs) are multimeric structures that control the transport through the paracellular spaces between the adjacent brain endothelial cells of the BBB. Claudin-5 (Cldn5) proteins are essential for TJ formation and assemble into multiprotein complexes via cis-interactions within the same cell membrane and trans-interactions across two contiguous cells. Despite the relevant biological function of Cldn5 proteins and their role as targets of brain drug delivery strategies, the molecular details of their assembly within TJs are still unclear. Two different structural models have been recently introduced, in which Cldn5 dimers belonging to opposite cells join to generate paracellular pores. However, a comparison of these models in terms of ionic transport features is still lacking. In this work, we used molecular dynamics simulations and free energy (FE) calculations to assess the two Cldn5 pore models and investigate the thermodynamic properties of water and physiological ions permeating through them. Despite different FE profiles, both structures present single/multiple FE barriers to ionic permeation, while being permissive to water flux. These results reveal that both models are compatible with the physiological role of Cldn5 TJ strands. By identifying the protein-protein surface at the core of TJ Cldn5 assemblies, our computational investigation provides a basis for the rational design of synthetic peptides and other molecules capable of opening paracellular pores in the BBB.

Nose to brain delivery of nanosuspensions with first line antiviral agents is alternative treatment option to Neuro-AIDS treatment

Intranasal drug delivery is one of the uprising areas of the research in targeting drug to the brain. Nose to brain drug delivery follows the olfactory pathway and purportedly known to be more efficient to deliver neuro-therapeutics to the brain by circumventing the BBB and thereby increasing bioavailability of drugs in the brain. The advantage of this method is non-invasiveness, rapid onset of action and helps to achieve site specific delivery. In this research work nanosuspension were prepared using combination of antiretroviral agents for Neuro-AIDS treatment. Nanosuspensions were prepared by high-speed homogenization, wet milling and high-pressure homogenization techniques. Formulations were analysed by SEM, FTIR, and DSC. Morphology and stability analysis was done by analysing zeta potential, particle size, and PDI. Ex-vivo diffusion study and histopathological analysis was performed using goat nasal mucosa. High pressure homogenization was found to be best technique for formulation of nanosuspension. Antiviral drugs could be delivered successfully by optimizing nasal dosage form.

A Historical Review of Brain Drug Delivery.

The history of brain drug delivery is reviewed beginning with the first demonstration, in 1914, that a drug for syphilis, salvarsan, did not enter the brain, due to the presence of a blood–brain barrier (BBB). Owing to restricted transport across the BBB, FDA-approved drugs for the CNS have been generally limited to lipid-soluble small molecules. Drugs that do not cross the BBB can be re-engineered for transport on endogenous BBB carrier-mediated transport and receptor-mediated transport systems, which were identified during the 1970s–1980s. By the 1990s, a multitude of brain drug delivery technologies emerged, including trans-cranial delivery, CSF delivery, BBB disruption, lipid carriers, prodrugs, stem cells, exosomes, nanoparticles, gene therapy, and biologics. The advantages and limitations of each of these brain drug delivery technologies are critically reviewed.

Chrysin-Loaded Chitosan Nanoparticle-Mediated Neuroprotection in Aβ1-42-Induced Neurodegenerative Conditions in Zebrafish.

Amyloid β plaques and neurofibrillary tangles are the characteristic features of Alzheimer's disease (AD). Plaques of amyloid β play a pivotal role in affecting cognitive functions and memory. Alzheimer's disease is a progressive neurodegenerative disease and is one of the leading causes of dementia worldwide. Several treatment strategies focusing on the amyloid cascade have been implemented to treat AD. The blood-brain barrier (BBB) poses the main obstructive barrier by refraining drugs from penetrating the brain. Nanotechnology is a promising research field for brain drug delivery using nanosized particles. Zebrafish is emerging as a model of interest to elaborate on brain targeting and nanotechnology-based therapeutics for neurodegenerative diseases. In the current study, we have synthesized and characterized chrysin-loaded chitosan nanoparticles (Chr-Chi NPs) and evaluated them for neuroprotection against amyloid-β-induced toxicity. We find that treatment with Chr-Chi NPs helps to retain memory, cognition, and synaptic connections, which are otherwise compromised due to Aβ1-42 toxicity. The NPs further help in reducing aggregates of amyloid β, thus decreasing neuronal death and generation of reactive oxygen species (ROS). Taken together, our study brings to light a novel strategy for treating AD by a combined action on the neurons and amyloid aggregates mediated by chrysin and chitosan, respectively. Chr-Chi NPs, therefore, have the potential to provide a beneficial combinatorial treatment strategy for AD.

Increased/Targeted Brain (Pro)Drug Delivery via Utilization of Solute Carriers (SLCs).

Membrane transporters have a crucial role in compounds’ brain drug delivery. They allow not only the penetration of a wide variety of different compounds to cross the endothelial cells of the blood–brain barrier (BBB), but also the accumulation of them into the brain parenchymal cells. Solute carriers (SLCs), with nearly 500 family members, are the largest group of membrane transporters. Unfortunately, not all SLCs are fully characterized and used in rational drug design. However, if the structural features for transporter interactions (binding and translocation) are known, a prodrug approach can be utilized to temporarily change the pharmacokinetics and brain delivery properties of almost any compound. In this review, main transporter subtypes that are participating in brain drug disposition or have been used to improve brain drug delivery across the BBB via the prodrug approach, are introduced. Moreover, the ability of selected transporters to be utilized in intrabrain drug delivery is discussed. Thus, this comprehensive review will give insights into the methods, such as computational drug design, that should be utilized more effectively to understand the detailed transport mechanisms. Moreover, factors, such as transporter expression modulation pathways in diseases that should be taken into account in rational (pro)drug development, are considered to achieve successful clinical applications in the future.

Preparation and evaluation of niosomal chitosan-based in situ gel formulation for direct nose-to-brain methotrexate delivery

Achieving effective treatments for various brain disorders due to the blood-brain barrier existence and the brain's complex structure has become a challenging goal. To overcome these challenges, one of the non-invasive strategies aimed at direct brain drug delivery is the use of the intranasal route. Novel drug delivery systems can be used to overcome the limitations in this administration route. This study suggested niosomal methotrexate (MTX) in situ gel formulation, which could be a suitable candidate for drug delivery to the brain. Here, niosomal MTX was prepared by a modified reverse-phase evaporation method, optimized with the aid of the design expert® software, and characterized. Optimum niosomal MTX with particle size, zeta potential, and entrapment efficiency (EE%), equal to 130.5 nm, −38.5 mV, and 91.39 %, respectively, were added into the temperature-sensitive in situ gel formulation composed of chitosan and Poloxamer 407. This study demonstrates that the simultaneous use of niosome and in situ gel formulations causes long-term persistence in the nasal cavity and helps us to have a more controlled drug release system with higher brain concentration, lower plasma concentration, higher Kp, and lower side effects compared to the free drug (MTX solution), MTX-gel (MTX-loaded in situ gel), and niosomal MTX formulations.

Simultaneous Localized Brain Mild Hyperthermia and Blood-Brain Barrier Opening via Feedback-Controlled Transcranial MR-Guided Focused Ultrasound and Microbubbles.

Non-invasive methods to enhance drug delivery and efficacy in the brain have been pursued for decades. Focused ultrasound hyperthermia (HT) combined with thermosensitive therapeutics have been demonstrated promising in enhancing local drug delivery to solid tumors. We hypothesized that the presence of microbubbles (MBs) combined with transcranial MR-guided focused ultrasound (MRgFUS) could be used to reduce the ultrasound power required for HT while simultaneously increasing drug delivery by locally opening the blood-brain barrier (BBB). Transcranial HT (42 °C, 10 min) was performed in wild-type mice using a small animal MRgFUS system incorporated into a 9.4T Bruker MR scanner, with infusions of saline or Definity MBs with doses of 20 or 100 µl/kg/min (denoted as MB-20 and MB-100). MR thermometry data was continuously acquired as feedback for the ultrasound controller during the procedure. Spatiotemporally precise transcranial HT was achieved in both saline and MB groups. A significant ultrasound power reduction (-45.7%, p = 0.006) was observed in the MB-20 group compared to saline. Localized BBB opening was achieved in MB groups confirmed by CE-T1w MR images. There were no structural abnormalities, edema, hemorrhage, or acutemicroglial activation in all groups, confirmed by T2w MR imaging and histology. Our investigations showed that it is feasible and safe to achieve spatiotemporally precise brain HT at significantly reduced power and simultaneous localized BBB opening via transcranial MRgFUS and MBs. This study provides a new synergistic brain drug delivery method with clinical translation potential.

A non-invasive direct nose to brain drug delivery platform vs. invasive brain delivery approach: patient-centered care impact analysis

Current literature lacks structured methodologies for analyzing medical technologies’ impact from the patient-centered care perspective. This study introduces, applies and validates ‘Patient-Centered Care Impact Analysis’ (PCIA) as a method for identifying patient-centered care associated demands and expectations for a particular technology and assessing its compliance with these demands. PCIA involves five stages: (1) demand identification, (2) ranking demands’ impact magnitude, (3) scoring demand compliance (DC), (4) demand priority (DP) assignment based on impact magnitude and compliance, (5) generating a summative impact priority number (IPN). PCIA was performed as a comparative assessment of two central nervous system (CNS) drug-delivery platforms; SipNose, a novel noninvasive Direct-Nose-to-Brain (DNTB), vs. the standard-of-care invasive intrathecal/intracerebroventricular injection (Invasive I/I). Study participants included a ranking team (RT) without experience with the SipNose technology that based their scoring on experimental data; and a validation team (VT) experienced with the SipNose platform. All had experience with, or knowledge of, InvasiveI/I. Demand identification and impact magnitude were performed by one content and one assessment expert. Each participant assessed each technology’s DC. DP scores, IPN’s and IPN DNTB:InvasiveI/I ratios were generated for each technology, for each team, based on DC and summative DP scores, respectively. Both teams assigned DNTB higher DC scores, resulting in higher DNTB DP, IPN scores and DNTB:InvasiveI/I IPN ratios. Lack of difference between team assessments of DP and IPN ratio validate PCIA as an assessment tool capable of predicting patient-centered clinical care quality for a new technology. The significant differences between the platforms highlight SipNose’s patient-care centered advantages as an effective CNS drug-delivery platform.

Blood-brain barrier targeted delivery of lacosamide-conjugated gold nanoparticles: Improving outcomes in absence seizures

ObjectiveMost currently available antiepileptics are not fully effective in the prevention of seizures in absence epilepsy owing to the presence of blood-brain barrier (BBB). We aimed to test whether binding an antiepileptic drug, lacosamide (LCM), to glucose-coated gold nanoparticles (GNPs) enables efficient brain drug delivery to suppress the epileptic activity in WAG/Rij rats with absence epilepsy. MethodsIn these animals, intracranial-EEG recording, behavioral test, in vivo imaging of LCM and LCM-GNP conjugate distribution in the brain, inductively coupled plasma mass spectrometry analysis, immunofluorescence staining of glucose transporter (Glut)− 1, glial fibrillary acidic protein (GFAP), and p-glycoprotein (P-gp) and electron microscopy were performed. ResultsLacosamide-GNP conjugates decreased the amplitude and frequency of spike-wave-like discharges (SWDs) and alleviated the anxiety-like behavior as assessed by EEG and elevated plus-maze test, respectively (p < 0.01). The in vivo imaging system results showed higher levels of fluorescein dye tagged to LCM-GNP in the brain during the 5-day injection period (p < 0.01). Immunofluorescence staining displayed decreased P-gp, Glut-1, and GFAP expression by LCM-GNP conjugate treatment predominantly in the cerebral cortex suggesting a potential functionality of this brain region in the modulation of neuronal activity in our experimental setting (p < 0.01). SignificanceWe suggest that the conjugation of LCM to GNPs may provide a novel approach for efficient brain drug delivery in light of the effectiveness of our strategy not only in suppressing the seizure activity but also in decreasing the need to use high dosages of the antiepileptics to reduce the frequently encountered side effects in drug-resistant epilepsy.

Regulation of Blood-Brain Barrier Transporters by Transforming Growth Factor-β/Activin Receptor-Like Kinase 1 Signaling: Relevance to the Brain Disposition of 3-Hydroxy-3-Methylglutaryl Coenzyme A Reductase Inhibitors (i.e., Statins).

Our laboratory has shown that activation of transforming growth factor- β (TGF- β )/activin receptor-like kinase 1 (ALK1) signaling can increase protein expression and transport activity of organic anion transporting polypeptide 1a4 (Oatp1a4) at the blood-brain barrier (BBB). These results are relevant to treatment of ischemic stroke because Oatp transport substrates such as 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (i.e., statins) improve functional neurologic outcomes in patients. Advancement of our work requires determination if TGF- β /ALK1 signaling alters Oatp1a4 functional expression differently across brain regions and if such disparities affect central nervous system (CNS) statin disposition. Therefore, we studied regulation of Oatp1a4 by the TGF- β /ALK1 pathway, in vivo, in rat brain microvessels isolated from cerebral cortex, hippocampus, and cerebellum using the ALK1 agonist bone morphogenetic protein-9 (BMP-9) and the ALK1 inhibitor 4-[6-[4-(1-piperazinyl)phenyl]pyrazolo[1,5-a]pyrimidin-3-yl]quinoline dihydrochloride 193189. We showed that Oatp1a4 protein expression and brain distribution of three currently marketed statin drugs (i.e., atorvastatin, pravastatin, and rosuvastatin) were increased in cortex relative to hippocampus and cerebellum. Additionally, BMP-9 treatment enhanced Oatp-mediated statin transport in cortical tissue but not in hippocampus or cerebellum. Although brain drug delivery is also dependent upon efflux transporters, such as P-glycoprotein and/or Breast Cancer Resistance Protein, our data showed that administration of BMP-9 did not alter the relative contribution of these transporters to CNS disposition of statins. Overall, this study provides evidence for differential regulation of Oatp1a4 by TGF- β /ALK1 signaling across brain regions, knowledge that is critical for development of therapeutic strategies to target Oatps at the BBB for CNS drug delivery. SIGNIFICANCE STATEMENT: Organic anion transporting polypeptides (Oatps) represent transporter targets for brain drug delivery. We have shown that Oatp1a4 statin uptake is higher in cortex versus hippocampus and cerebellum. Additionally, we report that the transforming growth factor- β /activin receptor-like kinase 1 agonist bone morphogenetic protein-9 increases Oatp1a4 functional expression, but not efflux transporters P-glycoprotein and Breast Cancer Resistance Protein, in cortical brain microvessels. Overall, this study provides critical data that will advance treatment for neurological diseases where drug development has been challenging.

Identification of lamprey variable lymphocyte receptors that target the brain vasculature

The blood–brain barrier (BBB) represents a significant bottleneck for the delivery of therapeutics to the central nervous system. In recent years, the promise of coopting BBB receptor-mediated transport systems for brain drug delivery has increased in large part due to the discovery and engineering of BBB-targeting antibodies. Here we describe an innovative screening platform for identification of new BBB targeting molecules from a class of lamprey antigen recognition proteins known as variable lymphocyte receptors (VLRs). Lamprey were immunized with murine brain microvessel plasma membranes, and the resultant repertoire cloned into the yeast surface display system. The library was screened via a unique workflow that identified 16 VLR clones that target extracellular epitopes of in vivo-relevant BBB membrane proteins. Of these, three lead VLR candidates, VLR-Fc-11, VLR-Fc-30, and VLR-Fc-46 selectively target the brain vasculature and traffic within brain microvascular endothelial cells after intravenous administration in mice, with VLR-Fc-30 being confirmed as trafficking into the brain parenchyma. Epitope characterization indicates that the VLRs, in part, recognize sialylated glycostructures. These promising new targeting molecules have the potential for brain targeting and drug delivery with improved brain vascular specificity.

Copper bis(thiosemicarbazone) complexes modulate P-glycoprotein expression and function in human brain microvascular endothelial cells.

P‐glycoprotein (P‐gp) is an efflux transporter at the blood–brain barrier (BBB) that hinders brain access of substrate drugs and clears endogenous molecules such as amyloid beta (Aβ) from the brain. As biometals such as copper (Cu) modulate many neuronal signalling pathways linked to P‐gp regulation, it was hypothesised that the bis(thiosemicarbazone) (BTSC) Cu‐releasing complex, copper II glyoxal bis(4‐methyl‐3‐thiosemicarbazone) (CuII[GTSM]), would enhance P‐gp expression and function at the BBB, while copper II diacetyl bis(4‐methyl‐3‐thiosemicarbazone) (CuII[ATSM]), which only releases Cu under hypoxic conditions, would not modulate P‐gp expression. Following treatment with 25–250 nM CuII(BTSC)s for 8–48 h, expression of P‐gp mRNA and protein in human brain endothelial (hCMEC/D3) cells was assessed by RT‐qPCR and Western blot, respectively. P‐gp function was assessed by measuring accumulation of the fluorescent P‐gp substrate, rhodamine 123 and intracellular Cu levels were quantified by inductively coupled plasma mass spectrometry. Interestingly, CuII(ATSM) significantly enhanced P‐gp expression and function 2‐fold and 1.3‐fold, respectively, whereas CuII(GTSM) reduced P‐gp expression 0.5‐fold and function by 200%. As both compounds increased intracellular Cu levels, the effect of different BTSC backbones, independent of Cu, on P‐gp expression was assessed. However, only the Cu‐ATSM complex enhanced P‐gp expression and this was mediated partly through activation (1.4‐fold) of the extracellular signal‐regulated kinase 1 and 2, an outcome that was significantly attenuated in the presence of an inhibitor of the mitogen‐activated protein kinase regulatory pathway. Our findings suggest that CuII(ATSM) and CuII(GTSM) have the potential to modulate the expression and function of P‐gp at the BBB to impact brain drug delivery and clearance of Aβ.

LIPID-POLYMER HYBRID NANOCARRIERS AS A NOVEL DRUG DELIVERY PLATFORM

The main aim of my review to discuss the most prominent nanocarrier, “Lipid-Polymer Hybrid Nanoparticle” (LPHNPs) that overcomes the limitation of lipid and polymeric nanoparticles. That consists of polymeric core and lipid outer layer. The polymeric core encapsulates both hydrophilic and hydrophobic drugs and lipid shell provides a coat that gives a barrier to prevent drug leakage and easily penetrate into the skin. The LPHNPs has significant application in drug delivery, drug targeting, cancer treatment, brain drug delivery, multiple drug delivery, delivery of diagnostic imaging agent and Small interfering Ribonucleic acid (siRNA). This session is based on literature information in which LPHNPs were prepared by Two-step and Single-step method. Most of the researcher use the Single-step method by emulsification solvent evaporation and Nanoprecipitation method that are easy to prepare LPHNPs. The Polylactic Glycolic acid (PLGA), Poly € caprolactone, Chitosan, Alginate, Dextron, Sodium Alginate, etc used as polymeric core and Stearic Acid, Palmitic Acid, Cetyl Alcohol, Behenol Alcohol, etc used as lipid core. All results were analyzed by us according to the literature and authors’ expertise. The drug release depends on diffusion processes, followed by erosion, then swelling of the matrix. The lipid shell provides a biocompatible shield that acts as the phospholipid bilayer of skin and easily penetrates into the skin. That also capable to deliver the multidrug and diagnostic imaging agent for the treatment of cancer. The Lipid-Polymer Hybrid Nanoparticles are the most prominent nanocarrier for drug delivery. That is capable to deliver both Hydrophilic and Lipophilic drugs and show high bioavailability.

Bubble-vessel interactions: From physics to applications in brain disease theranostics

Focused ultrasound combined with microbubbles (FUS + MB) provides a noninvasive and spatially targeted approach for inducing blood-brain barrier (BBB) disruption. Revealing the interactions among ultrasound, bubbles, and blood vessels is fundamental toward understanding this technique's physical mechanism. These interactions in the brain induce various bioeffects, including BBB disruption. FUS + MB-induced BBB disruption enables two-way trafficking between the brain and the bloodstream. While circulating agents can enter the brain through FUS-mediated BBB disruption for the treatment of brain diseases, brain disease-derived biomarkers (e.g., DNA, RNA, and protein) can also be released into the blood circulation to improve the sensitivity of blood-based liquid biopsy. The application of FUS + MB in brain drug delivery has been translated into the clinic with more than 20 clinical trials currently ongoing. The application of FUS + MB for blood-based liquid biopsy, called sonobiopsy, has been demonstrated feasible for the diagnosis of brain cancer. This talk will cover topics ranging from the fundamental physics of bubble-vessel interactions to their applications in the diagnosis and treatment of brain diseases.

Current Chemical, Biological, and Physiological Views in the Development of Successful Brain-Targeted Pharmaceutics.

One of the greatest challenges with successful pharmaceutical treatments of central nervous system (CNS) diseases is the delivery of drugs into their target sites with appropriate concentrations. For example, the physically tight blood-brain barrier (BBB) effectively blocks compounds from penetrating into the brain, also by the action of metabolizing enzymes and efflux transport mechanisms. However, many endogenous compounds, including both smaller compounds and macromolecules, like amino acids, sugars, vitamins, nucleosides, hormones, steroids, and electrolytes, have their peculiar internalization routes across the BBB. These delivery mechanisms, namely carrier-mediated transport and receptor-mediated transcytosis have been utilized to some extent in brain-targeted drug development. The incomplete knowledge of the BBB and the smaller than a desirable number of chemical tools have hindered the development of successful brain-targeted pharmaceutics. This review discusses the recent advancements achieved in the field from the point of medicinal chemistry view and discusses how brain drug delivery can be improved in the future.