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Evolving Drug Delivery Strategies to Overcome the Blood Brain Barrier.

ABSTRACT: The blood-brain barrier (BBB) poses a unique challenge for drug delivery to the central nervous system (CNS). The BBB consists of a continuous layer of specialized endothelial cells linked together by tight junctions, pericytes, nonfenestrated basal lamina, and astrocytic foot processes. This complex barrier controls and limits the systemic delivery of therapeutics to the CNS. Several innovative strategies have been explored to enhance the transport of therapeutics across the BBB, each with individual advantages and disadvantages. Ongoing advances in delivery approaches that overcome the BBB are enabling more effective therapies for CNS diseases. In this review, we discuss: (1) the physiological properties of the BBB, (2) conventional strategies to enhance paracellular and transcellular transport through the BBB, (3) emerging concepts to overcome the BBB, and (4) alternative CNS drug delivery strategies that bypass the BBB entirely. Based on these exciting advances, we anticipate that in the near future, drug delivery research efforts will lead to more effective therapeutic interventions for diseases of the CNS.

SUBMITTER: Hersh DS

PROVIDER: S-EPMC4900538 | biostudies-literature | 2016

REPOSITORIES: biostudies-literature

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Evolving Drug Delivery Strategies to Overcome the Blood Brain Barrier

Project description:The blood-brain barrier (BBB) poses a unique challenge for drug delivery to the central nervous system (CNS). The BBB consists of a continuous layer of specialized endothelial cells linked together by tight junctions, pericytes, nonfenestrated basal lamina, and astrocytic foot processes. This complex barrier controls and limits the systemic delivery of therapeutics to the CNS. Several innovative strategies have been explored to enhance the transport of therapeutics across the BBB, each with individual advantages and disadvantages. Ongoing advances in delivery approaches that overcome the BBB are enabling more effective therapies for CNS diseases. In this review, we discuss: (1) the physiological properties of the BBB, (2) conventional strategies to enhance paracellular and transcellular transport through the BBB, (3) emerging concepts to overcome the BBB, and (4) alternative CNS drug delivery strategies that bypass the BBB entirely. Based on these exciting advances, we anticipate that in the near future, drug delivery research efforts will lead to more effective therapeutic interventions for diseases of the CNS.

| S-EPMC4997920 | biostudies-literature

Peptide Shuttles for Blood-Brain Barrier Drug Delivery.

Project description: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.

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Novel drug-delivery approaches to the blood-brain barrier.

Project description:The blood-brain barrier (BBB) maintains homeostasis by blocking toxic molecules from the circulation, but drugs are blocked at the same time. When the dose is increased to enhance the drug concentration in the central nervous system, there are side-effects on peripheral organs. In recent years, genetic therapeutic agents and small molecules have been used in various strategies to penetrate the BBB while minimizing the damage to systemic organs. In this review, we describe several representative methods to circumvent or cross the BBB, including chemical and physical strategies.

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Blood-Brain Barrier Disruption in Neuro-Oncology: Strategies, Failures, and Challenges to Overcome.

Project description:The blood-brain barrier (BBB) presents a formidable challenge in the development of effective therapeutics in neuro-oncology. This has fueled several decades of efforts to develop strategies for disrupting the BBB, but progress has not been satisfactory. As such, numerous drug- and device-based methods are currently being investigated in humans. Through a focused assessment of completed, active, and pending clinical trials, our first aim in this review is to outline the scientific foundation, successes, and limitations of the BBBD strategies developed to date. Among 35 registered trials relevant to BBBD in neuro-oncology in the ClinicalTrials.gov database, mannitol was the most common drug-based method, followed by RMP-7 and regadenoson. MR-guided focused ultrasound was the most common device-based method, followed by MR-guided laser ablation, ultrasound, and transcranial magnetic stimulation. While most early-phase studies focusing on safety and tolerability have met stated objectives, advanced-phase studies focusing on survival differences and objective tumor response have been limited by heterogeneous populations and tumors, along with a lack of control arms. Based on shared challenges among all methods, our second objective is to discuss strategies for confirmation of BBBD, choice of systemic agent and drug design, alignment of BBBD method with real-world clinical workflow, and consideration of inadvertent toxicity associated with disrupting an evolutionarily-refined barrier. Finally, we conclude with a strategic proposal to approach future studies assessing BBBD.

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Treatment of Alzheimer's Disease and Blood-Brain Barrier Drug Delivery.

Project description:Despite the enormity of the societal and health burdens caused by Alzheimer's disease (AD), there have been no FDA approvals for new therapeutics for AD since 2003. This profound lack of progress in treatment of AD is due to dual problems, both related to the blood-brain barrier (BBB). First, 98% of small molecule drugs do not cross the BBB, and ~100% of biologic drugs do not cross the BBB, so BBB drug delivery technology is needed in AD drug development. Second, the pharmaceutical industry has not developed BBB drug delivery technology, which would enable industry to invent new therapeutics for AD that actually penetrate into brain parenchyma from blood. In 2020, less than 1% of all AD drug development projects use a BBB drug delivery technology. The pathogenesis of AD involves chronic neuro-inflammation, the progressive deposition of insoluble amyloid-beta or tau aggregates, and neural degeneration. New drugs that both attack these multiple sites in AD, and that have been coupled with BBB drug delivery technology, can lead to new and effective treatments of this serious disorder.

| S-EPMC7697739 | biostudies-literature

Current Strategies to Enhance Delivery of Drugs across the Blood-Brain Barrier.

Project description:The blood-brain barrier (BBB) has shown to be a significant obstacle to brain medication delivery. The BBB in a healthy brain is a diffusion barrier that prevents most substances from passing from the blood to the brain; only tiny molecules can pass across the BBB. The BBB is disturbed in specific pathological illnesses such as stroke, diabetes, seizures, multiple sclerosis, Parkinson's disease, and Alzheimer's disease. The goal of this study is to offer a general overview of current brain medication delivery techniques and associated topics from the last five years. It is anticipated that this review will stimulate readers to look into new ways to deliver medications to the brain. Following an introduction of the construction and function of the BBB in both healthy and pathological conditions, this review revisits certain contested questions, such as whether nanoparticles may cross the BBB on their own and if medications are selectively delivered to the brain by deliberately targeted nanoparticles. Current non-nanoparticle options are also discussed, including drug delivery via the permeable BBB under pathological circumstances and the use of non-invasive approaches to improve brain medication absorption.

| S-EPMC9145636 | biostudies-literature

Maltodextrin modified liposomes for drug delivery through the blood-brain barrier.

Project description:Central nervous system acting drugs, when administered intravenously, cannot show their effect in the brain due to the difficulty in crossing the blood-brain barrier (BBB). Levodopa is one of those drugs that are used to treat Parkinson's disease. In this study, a new liposomal levodopa delivery system that is modified with maltodextrin was developed in order to target and enhance transport through the BBB. An antioxidant, glutathione, was co-loaded in liposomes as a supportive agent and its effect on liposome stability and delivery was investigated. Glutathione co-loading had a positive effect on the viabilities of 3T3 and SH-SY5Y cells. Maltodextrin targeted liposomes showed high in vitro levodopa passage in the parallel artificial membrane permeability assay and had superior binding to MDCK cells. Results suggest that maltodextrin modification of liposomes is an effective way of targeting the BBB and the developed liposomal formulation would improve brain delivery of central nervous system agents.

| S-EPMC6071985 | biostudies-literature

Anti-miR delivery strategies to bypass the blood-brain barrier in glioblastoma therapy.

Project description:Small non-coding RNAs called miRNAs are key regulators in various biological processes, including tumor initiation, propagation, and metastasis in glioblastoma as well as other cancers. Recent studies have shown the potential for oncogenic miRNAs as therapeutic targets in glioblastoma. However, the application of antisense oligomers, or anti-miRs, to the brain is limited due to the blood-brain barrier (BBB), when administered in the traditional systemic manner. To induce a therapeutic effect in glioblastoma, anti-miR therapy requires a robust and effective delivery system to overcome this obstacle. To bypass the BBB, different delivery administration methods for anti-miRs were evaluated. Stereotaxic surgery was performed to administer anti-Let-7 through intratumoral (ITu), intrathecal (ITh), and intraventricular (ICV) routes, and each method's efficacy was determined by changes in the expression of anti-Let-7 target genes as well as by immunohistochemical analysis. ITu administration of anti-miRs led to a high rate of anti-miR delivery to tumors in the brain by both bolus and continuous administration. In addition, ICV administration, compared with ITu administration, showed a greater distribution of the miR across entire brain tissues. This study suggests that local administration methods are a promising strategy for anti-miR treatment and may overcome current limitations in the treatment of glioblastoma in preclinical animal models.

| S-EPMC5045404 | biostudies-literature

Nanotherapeutics for Nose-to-Brain Drug Delivery: An Approach to Bypass the Blood Brain Barrier.

Project description:Treatment of neurodegenerative diseases or other central nervous system (CNS) disorders has always been a significant challenge. The nature of the blood-brain barrier (BBB) limits the penetration of therapeutic molecules to the brain after oral or parenteral administration, which, in combination with hepatic metabolism and drug elimination and inactivation during its journey in the systemic circulation, decreases the efficacy of the treatment, requires high drug doses and often induces adverse side effects. Nose-to-brain drug delivery allows the direct transport of therapeutic molecules by bypassing the BBB and increases drug concentration in the brain. The present review describes mechanisms of nose-to-brain drug delivery and discusses recent advances in this area with especial emphasis on nanotechnology-based approaches.

| S-EPMC8704573 | biostudies-literature

Intraosseous administration into the skull: Potential blood-brain barrier bypassing route for brain drug delivery.

Project description:Progress in treating central nervous system (CNS) disorders is retarded owing to a limited understanding of brain disease pathology. Additionally, the blood-brain barrier (BBB) limits molecular entry into the brain. Many approaches for brain drug delivery to overcome the BBB, such as BBB permeability enhancement, transient BBB disruption, and direct surgical administration have been explored with limited success. Recent research has shown that direct vascular channels exist between the skull bone marrow and the meninges, allowing myeloid and lymphoid cells to migrate. We hypothesized that these direct channels may also allow brain drug delivery from the skull bone marrow to the brain. In this study, for the first time we propose intraosseous administration of drugs into the skull (intracalvariosseous [ICO]) as a novel approach for brain drug delivery via BBB bypassing routes. We tested the feasibility of the approach by applying nine representative compounds over thinned mouse skulls to simulate ICO and measuring the compound entry level in the brain compared to that after systemic administration. Surprisingly, we found that the skull is not completely impermeable to drug penetration into the brain and the tested compounds reached the brain tissue several tens-to-hundred times higher by ICO than systemic application. These findings suggest a role for the BBB bypassing route from skull to brain, apart from the systemic route, in the drug entry into the brain after ICO. This approach should be applicable to other CNS drugs and even BBB impermeable drugs. Overall ICO provides an innovative and advantageous pathway for effective treatment of brain diseases.

| S-EPMC10013776 | biostudies-literature

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