The blood-brain barrier and brain drug delivery

The present report encompasses a thorough review of drug delivery to the brain with a particular focus on using drug carriers such as liposomes and nanoparticles. Challenges in brain drug delivery arise from the presence of one of the strictest barriers in vivo-the blood-brain barrier (BBB). This barrier exists at the level of endothelial cells of brain vasculature and its role is to maintain brain homeostasis. To better understand the principles of brain drug delivery, relevant knowledge of the blood-brain barrier anatomy and physiology is briefly reviewed. Several approaches to overcome the BBB have been reviewed including the use of carrier systems. In addition, strategies to enhance brain drug delivery by specific brain targeting are discussed.     

Nanoneurotherapeutics approach intended for direct nose to brain delivery

Abstract

Context: Brain disorders remain the world's leading cause of disability, and account for more hospitalizations and prolonged care than almost all other diseases combined. The majority of drugs, proteins and peptides do not readily permeate into brain due to the presence of the blood–brain barrier (BBB), thus impeding treatment of these conditions.

Objective: Attention has turned to developing novel and effective delivery systems to provide good bioavailability in the brain.

Methods: Intranasal administration is a non-invasive method of drug delivery that may bypass the BBB, allowing therapeutic substances direct access to the brain. However, intranasal administration produces quite low drug concentrations in the brain due limited nasal mucosal permeability and the harsh nasal cavity environment. Pre-clinical studies using encapsulation of drugs in nanoparticulate systems improved the nose to brain targeting and bioavailability in brain. However, the toxic effects of nanoparticles on brain function are unknown.

Result and conclusion: This review highlights the understanding of several brain diseases and the important pathophysiological mechanisms involved. The review discusses the role of nanotherapeutics in treating brain disorders via nose to brain delivery, the mechanisms of drug absorption across nasal mucosa to the brain, strategies to overcome the blood brain barrier, nanoformulation strategies for enhanced brain targeting via nasal route and neurotoxicity issues of nanoparticles.     

Transferrin-conjugated, fluorescein-loaded magnetic nanoparticles for targeted delivery across the blood–brain barrier

The blood–brain barrier (BBB) restricts the delivery of many potentially important therapeutic agents for the treatment of brain disorders. An efficient strategy for brain targeted delivery is the utilization of the targeting ligand conjugated nanoparticles to trigger the receptor-mediated transcytosis. In this study, transferrin (Tf) was employed as a brain targeting ligand to functionalize the fluorescein-loaded magnetic nanoparticles (FMNs). The Tf conjugated FMNs (Tf-FMNs) were characterized by transmission electron microscopy, thermal gravimetric analysis, Fourier transform infrared spectroscopy, and X-ray photoelectron spectroscopy. Using fluorescein as an optical probe, the potential of Tf-FMNs as brain targeting drug carriers was explored in vivo. It was demonstrated that Tf-FMNs were able to cross the intact BBB, diffuse into brain neurons, and distribute in the cytoplasm, dendrites, axons, and synapses of neurons. In contrast, magnetic nanoparticles without Tf conjugation cannot cross the BBB efficiently under the same conditions. Therefore, Tf-FMNs hold great potential in serving as an efficient multifunctional platform for the brain-targeted theranostics.     

Overcoming blood–brain barrier transport: Advances in nanoparticle-based drug delivery strategies

The blood–brain barrier (BBB), a unique structure in the central nervous system (CNS), protects the brain from bloodborne pathogens by its excellent barrier properties. Nevertheless, this barrier limits therapeutic efficacy and becomes one of the biggest challenges in new drug development for neurodegenerative disease and brain cancer. Recent breakthroughs in nanotechnology have resulted in various nanoparticles (NPs) as drug carriers to cross the BBB by different methods. This review presents the current understanding of advanced NP-mediated non-invasive drug delivery for the treatment of neurological disorders. Herein, the complex compositions and special characteristics of BBB are elucidated exhaustively. Moreover, versatile drug nanocarriers with their recent applications and their pathways on different drug delivery strategies to overcome the formidable BBB obstacle are briefly discussed. In terms of significance, this paper provides a general understanding of how various properties of nanoparticles aid in drug delivery through BBB and usher the development of novel nanotechnology-based nanomaterials for cerebral disease therapies.     

Nanoparticulate strategies for the treatment of polyglutamine diseases by halting the protein aggregation process†

Polyglutamine (polyQ) diseases are a class of neurodegenerative disorders that cause cellular dysfunction and, eventually, neuronal death in specific regions of the brain. Neurodegeneration is linked to the misfolding and aggregation of expanded polyQ-containing proteins, and their inhibition is one of major therapeutic strategies used commonly. However, successful treatment has been limited to date because of the intrinsic properties of therapeutic agents (poor water solubility, low bioavailability, poor pharmacokinetic properties), and difficulty in crossing physiological barriers, including the blood–brain barrier (BBB). In order to solve these problems, nanoparticulate systems with dimensions of 1–1000?nm able to incorporate small and macromolecules with therapeutic value, to protect and deliver them directly to the brain, have recently been developed, but their use for targeting polyQ disease-mediated protein misfolding and aggregation remains scarce. This review provides an update of the polyQ protein aggregation process and the development of therapeutic strategies for halting it. The main features that a nanoparticulate system should possess in order to enhance brain delivery are discussed, as well as the different types of materials utilized to produce them. The final part of this review focuses on the potential application of nanoparticulate system strategies to improve the specific and efficient delivery of therapeutic agents to the brain for the treatment of polyQ diseases.     

High melting lipid based approach for drug delivery: Solid lipid nanoparticles

Poor solubility of newly developed drug molecules is the main problem in recent drug discovery research, so novel drug delivery approaches are being used to deliver these molecular entities for pharmacological action. Colloidal carriers (emulsion, suspensions, liposomes, polymer nanoparticles and solid lipid nanoparticles) have been used to administer poorly soluble drugs, but solid lipid nanoparticles are found to be the most reliable carriers for this type of drugs due to its advantages over other carriers. Solid lipid nanoparticles have the potential to solve the drug delivery problems with safe excipients used in its formulation. In this review all the aspects of solid lipid nanoparticles production, stability, characterization, differentiation based on route, preservation and storage have been discussed.     

Sequential Targeting in Crosslinking Nanotheranostics for Tackling the Multibarriers of Brain Tumors

The efficacy of therapeutics for brain tumors is seriously hampered by multiple barriers to drug delivery, including severe destabilizing effects in the blood circulation, the blood–brain barrier/blood–brain tumor barrier (BBB/BBTB), and limited tumor uptake. Here, a sequential targeting in crosslinking (STICK) nanodelivery strategy is presented to circumvent these important physiological barriers to improve drug delivery to brain tumors. STICK nanoparticles (STICK-NPs) can sequentially target BBB/BBTB and brain tumor cells with surface maltobionic acid (MA) and 4-carboxyphenylboronic acid (CBA), respectively, and simultaneously enhance nanoparticle stability with pH-responsive crosslinkages formed by MA and CBA in situ. STICK-NPs exhibit prolonged circulation time (17-fold higher area under curve) than the free agent, allowing increased opportunities to transpass the BBB/BBTB via glucose-transporter-mediated transcytosis by MA. The tumor acidic environment then triggers the transformation of the STICK-NPs into smaller nanoparticles and reveals a secondary CBA targeting moiety for deep tumor penetration and enhanced uptake in tumor cells. STICK-NPs significantly inhibit tumor growth and prolong the survival time with limited toxicity in mice with aggressive and chemoresistant diffuse intrinsic pontine glioma. This formulation tackles multiple physiological barriers on-demand with a simple and smart STICK design. Therefore, these features allow STICK-NPs to unleash the potential of brain tumor therapeutics to improve their treatment efficacy.     

Preparation,characterization, in vivo biodistribution and pharmacokinetic studies of donepezil-loaded PLGA nanoparticles for brain targeting

Objective: Alzheimer’s disease (AD) is a progressive neurodegenerative disorder manifested by cognitive, memory deterioration and variety of neuropsychiatric symptoms. Donepezil is a reversible cholinesterase inhibitor used for the treatment of AD. The purpose of this work is to prepare a nanoparticulate drug delivery system of donepezil using poly(lactic-co-glycolic acid) (PLGA) for sustained release and efficient brain targeting.

Materials and methods: PLGA nanoparticles (NPs) were prepared by the solvent emulsification diffusion–evaporation technique and characterized for particle size, particle-size distribution, zeta potential, entrapment efficiency, drug loading and interaction studies and in vivo studies using gamma scintigraphy techniques.

Results and discussion: The size of drug-loaded NPs (drug polymer ratio 1:1) was found to be 89.67?±?6.43?nm. The TEM and SEM images of the formulation suggested that particle size was within 20–100?nm and spherical in shape, smooth morphology and coating of Tween-80 on the NPs was clearly observed. The release behavior of donepezil exhibited a biphasic pattern characterized by an initial burst release followed by a slower and continuous sustained release. The biodistribution studies of donepezil-loaded PLGA NPs and drug solution via intravenous route revealed higher percentage of radioactivity per gram in the brain for the nanoparticulate formulation as compared with the drug solution (p?Conclusion: The high concentrations of donepezil uptake in brain due to coated NPs may help in a significant improvement for treating AD. But further, more extensive clinical studies are needed to check and confirm the efficacy of the prepared drug delivery system.     

Overcoming the blood–brain barrier in neurodegenerative disorders and brain tumours

Drug delivery is one of the major challenges in the treatment of central nervous system disorders. The brain needs to be protected from harmful agents, which are done by the capillary network, the so‐called blood–brain barrier (BBB). This protective guard also prevents the delivery of therapeutic agents to the brain and limits the effectiveness of treatment. For this reason, various strategies have been explored by scientists for overcoming the BBB from disruption of the BBB to targeted delivery of nanoparticles (NPs) and cells and immunotherapy. In this review, different promising brain drug delivery strategies including disruption of tight junctions in the BBB, enhanced transcellular transport by peptide‐based delivery, local delivery strategies, NP delivery, and cell‐based delivery have been fully discussed.Inspec keywords: drugs, tumours, neurophysiology, blood, biochemistry, brain, drug delivery systems, nanoparticles, biomedical materials, molecular biophysics, cellular biophysics, nanomedicine, diseases, proteins, reviewsOther keywords: blood–brain barrier, neurodegenerative disorders, central nervous system disorders, BBB, therapeutic agents, targeted delivery, peptide‐based delivery, local delivery strategies, NP delivery, cell‐based delivery, brain drug delivery strategies, brain tumours, nanoparticles, immunotherapy, review     

Investigations on pharmacokinetics and biodistribution of polymeric and solid lipid nanoparticulate systems of atypical antipsychotic drug: effect of material used and surface modification

The present study focuses on the effect of material used for the preparation of nanoparticulate (NP) systems and surface modification on the pharmacokinetics and biodistribution of atypical antipsychotic, olanzapine (OLN). NP carriers of OLN were prepared from two different materials such as polymer (polycaprolactone) and solid lipid (Glyceryl monostearate). These systems were further surface modified with surfactant, Polysorbate 80 and studied for pharmacokinetics–biodistribution in Wistar rats using in-house developed bioanalytical methods. The pharmacokinetics and biodistribution studies resulted in a modified and varied distribution of NP systems with higher area under curve (AUC) values along with prolonged residence time of OLN in the rat blood circulation. The distribution of OLN to the brain was significantly enhanced with surfactant surface-modified NP systems, followed by nonsurface-modified NP formulations as compared with pure OLN solution. Biodistribution study demonstrated a low uptake of obtained NP systems by kidney and heart, thereby decreasing the nephrotoxicity and adverse cardiovascular effects. By coating the NP with surfactant, uptake of macrophage was found to be reduced. Thus, our studies confirmed that the biodistribution OLN could be modified effectively by incorporating in NP drug delivery systems prepared from different materials and surface modifications. A judicious selection of materials used for the preparation of delivery carriers and surface modifications would help to design a most efficient drug delivery system with better therapeutic efficacy.     

Doxorubicin loaded PVA coated iron oxide nanoparticles for targeted drug delivery

Magnetic drug targeting is a drug delivery system that can be used in locoregional cancer treatment. Coated magnetic particles, called carriers, are very useful for delivering chemotherapeutic drugs. Magnetic carriers were synthesized by coprecipitation of iron oxide followed by coating with polyvinyl alcohol (PVA). Characterization was carried out using X-ray diffraction, TEM, TGA, FTIR and VSM techniques. The magnetic core of the carriers was magnetite (Fe₃O₄), with average size of 10 nm. The room temperature VSM measurements showed that magnetic particles were superparamagnetic. The amount of PVA bound to the iron oxide nanoparticles were estimated by thermogravimetric analysis (TGA) and the attachment of PVA to the iron oxide nanoparticles was confirmed by FTIR analysis. Doxorubicin (DOX) drug loading and release profiles of PVA coated iron oxide nanoparticles showed that up to 45% of adsorbed drug was released in 80 h, the drug release followed the Fickian diffusion-controlled process. The binding of DOX to the PVA was confirmed by FTIR analysis. The present findings show that DOX loaded PVA coated iron oxide nanoparticles are promising for magnetically targeted drug delivery.     

Magnetically Responsive Nanoparticles for Drug Delivery Applications Using Low Magnetic Field Strengths

The purpose of this study is to investigate the potential of magnetic nanoparticles for enhancing drug delivery using a low oscillating magnetic field (OMF) strength. We investigated the ability of magnetic nanoparticles to cause disruption of a viscous biopolymer barrier to drug delivery and the potential to induce triggered release of drug conjugated to the surfaces of these particles. Various magnetic nanoparticles were screened for thermal response under a 295-kHz OMF with an amplitude of 3.1 kA/m. Based on thermal activity of particles screened, we selected the nanoparticles that displayed desired characteristics for evaluation in a simplified model of an extracellular barrier to drug delivery, using lambda DNA/HindIII. Results indicate that nanoparticles could be used to induce DNA breakage to enhance local diffusion of drugs, despite low temperatures of heating. Additional studies showed increased diffusion of quantum dots in this model by single-particle tracking methods. Bimane was conjugated to the surface of magnetic nanoparticles. Fluorescence and transmission electron microscope images of the conjugated nanoparticles indicated little change in the overall appearance of the nanoparticles. A release study showed greater drug release using OMF, while maintaining low bulk heating of the samples ($T = 30$  $^circ$C). This study indicates that lower magnetic field strengths may be successfully utilized for drug delivery applications as a method for drug delivery transport enhancement and drug release switches.      

Lipid Nanoparticles with a Solid Matrix (SLN®, NLC®, LDC®) for Oral Drug Delivery

Solid lipid nanoparticles (SLN®), nanostructured lipid carriers (NLC®), and lipid–drug conjugates (LDC®), commonly produced by high-pressure homogenization, are interesting vectors for oral delivery of lipophilic and, to a certain extent, hydrophilic substances. Their production can be done without the use of organic solvents. Techniques to make them a physically stable delivery system have been developed. Scaling up of the production process from lab-size to large-scale dimensions using high-pressure homogenization can be easily achieved by using a different type of homogenizer. The machines used for large-scale production often yield an even better product quality than the lab-scale types. This review article covers the methods of production, characterization, mechanisms of oral bioavailability enhancement, scale-up, final oral dosage forms, and regulatory aspects of lipid nanoparticles for oral drug delivery. It focuses mainly on high-pressure homogenization production methods.     

Mesoporous Silica Nanoparticles: Synthesis,Biocompatibility and Drug Delivery

In the past decade, mesoporous silica nanoparticles (MSNs) have attracted more and more attention for their potential biomedical applications. With their tailored mesoporous structure and high surface area, MSNs as drug delivery systems (DDSs) show significant advantages over traditional drug nanocarriers. In this review, we overview the recent progress in the synthesis of MSNs for drug delivery applications. First, we provide an overview of synthesis strategies for fabricating ordered MSNs and hollow/rattle‐type MSNs. Then, the in vitro and in vivo biocompatibility and biotranslocation of MSNs are discussed in relation to their chemophysical properties including particle size, surface properties, shape, and structure. The review also highlights the significant achievements in drug delivery using mesoporous silica nanoparticles and their multifunctional counterparts as drug carriers. In particular, the biological barriers for nano‐based targeted cancer therapy and MSN‐based targeting strategies are discussed. We conclude with our personal perspectives on the directions in which future work in this field might be focused.     

Shuttle‐Mediated Nanoparticle Delivery to the Blood–Brain Barrier

Many therapeutic drugs are excluded from entering the brain due to their lack of transport through the blood–brain barrier (BBB). The development of new strategies for enhancing drug delivery to the brain is of great importance in diagnostics and therapeutics of central nervous diseases. To overcome this problem, a viral fusion peptide (gH625) derived from the glycoprotein gH of Herpes simplex virus type 1 is developed, which possesses several advantages including high cell translocation potency, absence of toxicity of the peptide itself, and the feasibility as an efficient carrier for delivering therapeutics. Therefore, it is hypothesized that brain delivery of nanoparticles conjugated with gH625 should be efficiently enhanced. The surface of fluorescent aminated polystyrene nanoparticles (NPs) is functionalized with gH625 via a covalent binding procedure, and the NP uptake mechanism and permeation across in vitro BBB models are studied. At early incubation times, the uptake of NPs with gH625 by brain endothelial cells is greater than that of the NPs without the peptide, and their intracellular motion is mainly characterized by a random walk behavior. Most importantly, gH625 peptide decreases NP intracellular accumulation as large aggregates and enhances the NP BBB crossing. In summary, these results establish that surface functionalization with gH625 may change NP fate by providing a good strategy for the design of promising carriers to deliver drugs across the BBB for the treatment of brain diseases.     

Lipid nanoparticles with a solid matrix (SLN, NLC, LDC) for oral drug delivery

Solid lipid nanoparticles (SLN), nanostructured lipid carriers (NLC), and lipid-drug conjugates (LDC), commonly produced by high-pressure homogenization, are interesting vectors for oral delivery of lipophilic and, to a certain extent, hydrophilic substances. Their production can be done without the use of organic solvents. Techniques to make them a physically stable delivery system have been developed. Scaling up of the production process from lab-size to large-scale dimensions using high-pressure homogenization can be easily achieved by using a different type of homogenizer. The machines used for large-scale production often yield an even better product quality than the lab-scale types. This review article covers the methods of production, characterization, mechanisms of oral bioavailability enhancement, scale-up, final oral dosage forms, and regulatory aspects of lipid nanoparticles for oral drug delivery. It focuses mainly on high-pressure homogenization production methods.     

Has nanotechnology led to improved therapeutic outcomes?

Nanoparticulate drug delivery systems provide new opportunities for solving issues associated with problematic drugs or disease states and have, therefore, created great expectations in the field of drug delivery. This review focuses on the potential benefits of nanoparticles compared with other conventional delivery systems. Several nanoparticulate drug delivery systems have already been marketed or are currently under development and are presented in this review. Results from clinical trials demonstrate that nanoparticulate formulations generally enable superior therapeutic outcomes than compared with standard formulations. Therefore, the implementation of nanotechnology in drug delivery represents an important advance with substantial potential to improve therapeutic effectiveness and increase patient’s quality of life.     

Has nanotechnology led to improved therapeutic outcomes?

Nanoparticulate drug delivery systems provide new opportunities for solving issues associated with problematic drugs or disease states and have, therefore, created great expectations in the field of drug delivery. This review focuses on the potential benefits of nanoparticles compared with other conventional delivery systems. Several nanoparticulate drug delivery systems have already been marketed or are currently under development and are presented in this review. Results from clinical trials demonstrate that nanoparticulate formulations generally enable superior therapeutic outcomes than compared with standard formulations. Therefore, the implementation of nanotechnology in drug delivery represents an important advance with substantial potential to improve therapeutic effectiveness and increase patient's quality of life.     

Electrostatic ligand coatings of nanoparticles enable ligand-specific gene delivery to human primary cells

A general method of coating polymer/DNA nanoparticles was developed. Peptide coated nanoparticles were found to have favorable biophysical characteristics including small particle size, near-neutral zeta potential, and stability in serum. At appropriate formulation conditions including near-neutral charge ratio, the coated nanoparticles enabled effective ligand-specific gene delivery to human primary endothelial cells in serum-containing media. As this nanoparticulate drug delivery system has high efficacy, ligand-based specificity, biodegradability, and low cytotoxicity, it may be potentially useful in several clinical applications.     

Influence of the surface properties on nanoparticle-mediated transport of drugs to the brain

Poly(alkyl cyanoacrylate) nanoparticles enable the delivery of a number of drugs, including doxorubicin, loperamide, tubocurarine, the NMDA receptor antagonist MRZ 2/576, and the peptides dalargin and kytorphin across the blood-brain barrier (BBB) after coating with surfactants. However, only the surfactants polysorbate (Tween) 20, 40, 60 and 80, and some poloxamers (Pluronic F 68) can induce this uptake. The mechanism for the delivery across the BBB most likely is endocytosis via the LDL receptor by the endothelial cells lining the brain blood capillaries after injection of the nanoparticles into the blood stream. This endocytotic uptake seems to be mediated by the adsorption of apolipoprotein B and/or E adsorption from the blood. Thus, the nanoparticles could mimic lipoprotein particles and act as "Trojan Horses." The drug, then, may be released either within these cells followed by passive diffusion into the brain or be transported into the brain by transcytosis.