Over 3 billion people are suffering from neurological diseases worldwide.1 The most common ones include stroke, dementia, migraine, meningitis (infection and inflammation of brain fluid), and epilepsy (recurrent seizures). Many drug candidates targeting brain diseases fail due to their inability to cross the blood–brain barrier (BBB), which separates the bloodstream from cerebral fluid.2 With the growing elderly population, there is an increasing demand for drugs targeting neurological diseases and, consequently, the brain. Therefore, nanoscale delivery systems are receiving considerable attention in research for their potential to overcome the BBB and deliver drugs effectively and safely to the brain.
Complexities of the Blood–Brain Barrier
The blood–brain barrier (BBB) is a highly selective, dynamic, and semi-permeable membrane composed of specialized cells and tight junctions, which separates the blood from the brain. Its primary functions are to protect the brain's microenvironment, regulate the release of certain molecules and ions, and selectively transport specific molecules into the central nervous system (CNS). Along with vascular endothelial cells and surrounding brain cells, such as glial cells and pericytes, the BBB constitutes a neurovascular unit that regulates cerebral blood flow and supports neuronal development.3
The BBB is made up of specialized cells, including endothelial cells, pericytes, and astrocytes, and junctional complexes, such as tight and adherens junctions.2 Endothelial cells at the BBB act as “fences” allowing certain molecules to cross the barrier while blocking others. Their negative surface charge prevents negatively charged compounds, such as DNA- or RNA-based drugs and certain proteins, from entering the brain. Their lack of transcellular pores, high mitochondrial density, and specialized transporters further control the free diffusion of molecules between the blood and the brain. Additionally, tight and adherens junctions “seal” endothelial cells together, creating a size-excluding mechanical barrier that prevents the passage of charged macromolecules to the brain. This instead allows small, lipophilic molecules with a molecular weight (MW) < 400Da to cross the barrier.4
Astrocytes, the most abundant cells in the brain, interact with endothelial cells to regulate oxygen transport into the brain. Pericytes, which line blood vessels and have contractile properties, release signals that influence the number of tight junctions, thus playing a collaborative role with astrocytes in maintaining structural integrity of the BBB.5
Despite its crucial role in brain physiology, the BBB poses a significant obstacle for effective drug delivery to the brain, particularly to target neurodegenerative diseases (ND). Consequently, 98% of small molecule drugs fail to cross the BBB and exhibit poor pharmacokinetic properties at the brain, which limits the efficacy of many current CNS therapeutics.6
Current Strategies to Cross the BBB
Considering the complexities of the BBB, there are two ways to deliver drugs to the brain: invasive or non-invasive methods. Most current methods are invasive, involving disruption of the BBB to deliver drugs directly into brain tissues.7 These methods include intracranial implantation, deep-brain ultrasound stimulation, microneedle therapies, and intrathecal drug administration. Due to their invasive nature, these methods carry the risk of causing potential brain injury, a big concern when treating patients with existing NDs.8 Consequently, researchers are exploring non-invasive strategies, including nanoscale drug delivery systems, which aim to bypass the BBB without directly damaging brain tissue.
Nanocarriers for Brain-Targeted Drug Delivery
Nanomedicine is the study, design, and use of structures at the nanoscale.9 One specific application of nanomedicine is the use of nanocarriers. These are tiny systems designed to deliver drugs directly to targeted sites with sustained and controlled release.
The primary advantage of nanocarriers is their small size, which enables them to cross endothelial cells at the BBB through a process known as transcytosis. During transcytosis, nanocarriers are engulfed by cells, travel through the cell in vesicles, and are released when vesicles fuse with the cell membrane. Particle size is an important factor for effective brain-targeted drug delivery: too small and the nanocarriers risk being cleared from the body; too large and they may not be able to cross the BBB. Additionally, the physicochemical properties of nanocarriers, such as particle size, shape, and surface charge, can be altered to improve drug delivery to the brain. Nanocarriers can also be “fine-tuned” by functionalizing their surfaces with specific ligands or molecules that are recognized by different receptors in the BBB and brain tissues.10
The most crucial factor in designing nanocarriers is ensuring their safety. This could involve evaluating their interactions with various cell types, stability in the bloodstream, half-life, and overall biocompatibility.6 Several safety and toxicity studies indicate that nanocarriers, due to their lipophilicity, neutral surface charge, and low toxicity, are less likely to be rapidly eliminated from the body. However, once inside the body, nanocarriers are recognized as foreign molecules and targeted by immune cells for degradation. Therefore, the key challenges now would be to explore ways to minimize their toxicity, extend their half-life in the body despite immune attacks, and ensure that enough nanocarriers remain over a long period of time to provide therapeutic benefits.
Several different types of nanocarriers have been developed and extensively studied for brain-targeted drug delivery, including micelles, liposomes, and nanoparticles.
Micelles
Micelles are spherical, single-layered molecules with both hydrophilic and hydrophobic properties, allowing them to encapsulate drugs within their inner core.5 Their amphiphilic nature enables them to cross the BBB and remain stable in various physiological environments, giving them enough time to reach their target sites in the brain. A range of drugs can be loaded into micelles, including hydrophobic compounds, peptides, chemotherapeutics, and small active molecules. However, research indicates that micelles generally have a lower drug-loading capacity compared with other nanocarriers and may exhibit poor cellular uptake.11 This could result in insufficient drug delivery and reduced therapeutic efficacy, as evidenced by several studies that reported low systemic potency. Additionally, further investigation is required into the safety of micelles to ensure that they do not elicit unwanted immune responses.
Research into polymeric micelles for treating NDs has yielded promising results. One study found that when rivastigmine, a cholinesterase inhibitor used for Alzheimer's disease, was encapsulated in polymeric micelles, it remained stable in plasma for 48 hours.9 Another study revealed that micelles encapsulating curcumin, a polyphenolic compound with significant therapeutic potential for NDs, exhibited a 40- to 60-fold increase in bioavailability when delivered to the brains of mice.12 These findings underscore the potential of polymeric micelles to enhance the efficacy of treatments for neurodegenerative diseases.
Liposomes
Liposomes are spherical, amphiphilic molecules with a central aqueous core. Unlike micelles, liposomes are larger and have a bilayer structure, which allows them to encapsulate a range of molecules, including nucleic acids, proteins, and vaccines. Over the past 50 years, liposomes have become the most extensively studied nanocarrier systems for targeted drug delivery. Traditionally, liposomes could not cross the BBB, but modifications to their surface now enable them to deliver their contents into the brain. Despite this, there are rising concerns about their safety. Several studies have shown that introducing liposomes into the body can lead to increased liver enzyme levels, indicating potential hepatotoxicity. Nonetheless, liposomes remain a popular method for brain drug delivery, as evidenced by the growing number of investigational new drug (IND) applications in recent years.13
Research is ongoing to explore applications of liposomes in delivering drugs to the brain. One interesting study explored the use of liposomes coated with monoclonal antibodies against alpha-synuclein to treat Parkinson’s disease in mouse models.14 The study found that these targeted liposomes could cross a human BBB model and be taken up by primary neurons, highlighting their potential for in vivo applications.
Nanoparticles
Nanoparticles (NPs) are extremely small particles ranging from 1 to 100 nanometers in size, offering a promising alternative to traditional drug delivery methods. Among all nanocarrier systems, NPs designed for brain drug delivery are particularly prominent, representing 32% of research in this area.15 By functionalizing the surface of NPs with various ligands, these particles can cross the BBB through different transport mechanisms. However, some inorganic and polymeric NPs contain complex chemical components that may pose risks of neuronal damage, often necessitating rigorous safety and toxicology studies before clinical approval.
Gold NPs, known for their excellent biocompatibility and low toxicity, have shown potential in reducing tau hyperphosphorylation, decreasing pro-inflammatory cytokine levels, and promoting neuron growth factors in Alzheimer's disease models. Solid lipid NPs, which are organic and offer strong stability and high biocompatibility, have been shown to penetrate brain capillaries, cross the BBB, and enhance drug solubility.16 These NPs are also capable of providing controlled drug release over several months, demonstrating significant therapeutic efficacy.
Despite the promising results from numerous in vitro and in vivo studies, translating this technology into large-scale manufacturing remains challenging. While there are FDA-approved nanomedicines for systemic disorders, there are currently few approved for brain diseases. Additionally, research into the GMP manufacturing of NPs remains limited, with fewer than 10 relevant entries found in a recent PubMed search (August 2024).15 Altogether, addressing these manufacturing challenges is essential for advancing brain-targeted NPs from the lab to clinic and meeting unmet needs in brain disease treatment.
Conclusion
The global burden of neurological diseases highlights a pressing need for effective therapeutic interventions. The BBB, while crucial for protecting the brain, poses significant challenges for drug delivery. Traditional methods, often invasive and risky, have limited efficacy in treating complex neurodegenerative diseases due to their inability to cross the BBB. However, nanoscale drug delivery systems including micelles, liposomes, and nanoparticles offer a promising alternative by potentially overcoming the BBB's restrictions. To move from promising experimental results to commercial use, future research must focus on improving the safety profiles of nanocarriers, refining their design for better brain penetration, and overcoming manufacturing hurdles.
References
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