By Camila Aragón Alfaro
Photo Credit: John M Lund Photography Inc/Getty Images, Genetic Engineering
& Biotechnology News
Introduction
In October of last year, the World Federation of Neurology reported that neurological disorders had become the second leading cause of death and the leading cause of disability worldwide. The presented study, performed by the Global Burden of Disease (GBD), determined that 40% of the global population currently suffer from neurological disorders, a number that is projected to double by 2050 (World Federation of Neurology). It is no surprise then, that scientists are developing new methods to study and treat these damaging conditions.
The emerging field of nanotechnology offers one of the most promising possible treatments: nanoparticles. Nanoparticles (NPs) are materials that are between 1 and 100 nanometers in size—more than a thousand times smaller than the diameter of a single human hair. Nanoscale materials have already been used to tackle the toughest medical problems; the COVID-19 vaccine for example, contained them (Omberg). Because of their small size, nanoparticles can be extremely effective for therapeutic applications, like vaccines, as they can easily cross both bacterial and human cell membranes. Nanoparticles, however, face difficulties with reaching the brain, due to the extremely restrictive nature of the blood-brain barrier.
While there have been significant advances made regarding the possible ways of transporting nanoparticles into the barrier, as well as ongoing research on the potential of different nanoparticles, there are still many challenges that need to be addressed before determining their therapeutic potential. Devising effective methods to cross the blood-brain barrier is one of the biggest challenges in nanoparticle research—as it could open the possibility of employing new drug-delivery methods that could directly treat even the most complicated neurological disorders.
The Blood-Brain Barrier
It’s no secret that the brain is one of the most fragile organs in our body. Significant protections for our brains have evolved over time, most notably with our skull, in combination with the cushioning effect of cerebrospinal fluid (CSF), and the barrier of the meninges membrane, shielding it from physical injury. But some of the biggest threats to our brain are not physical—multiple disease-causing organisms, or pathogens, can reach the brain through the bloodstream. In cases like these, the best line of defense is none other than the blood-brain barrier.
The blood-brain barrier (BBB) is a selective semi-permeable membrane (Dotiwala et al.)—which allows for the passage of only certain substances between the brain’s small blood vessels, or capillaries, and the different components that make up brain tissue (Götz). The BBB is composed of a capillary basement membrane and three cellular elements: endothelial cells (ECs), which form a cell layer, the endothelium, that coats the interior wall of the blood vessels, pericytes (PCs), present along the walls of the capillaries and crucial for the maintenance of the BBB, and the end-feet of astrocytes, a subtype of glial cells, or non-neuronal cells in the nervous system that don't conduct electricity, and are shaped like stars (Wu et al., 2).
What makes the BBB a near-impenetrable barrier are the endothelial tight junctions (TJs). The endothelial cells in the capillaries that form the BBB are so tightly packed that they only allow tiny molecules, fat-soluble molecules (due to cell membranes being lipid-based), and certain gasses. Larger or water-based molecules rely on transport proteins to traverse the barrier (Cleveland Clinic), allowing for the BBB to protect the brain from harmful pathogens and toxins, while still maintaining access and regulation of the hormonal, nutrient, and water levels in the organ.
The Challenge
While the blood-brain barrier is great at obstructing the entrance of potentially malignant organisms, its restrictive nature also makes it the biggest impediment to any neurological therapeutic approach. It is estimated that the BBB prevents more than 98% of all small-molecule drugs and nearly 100% of large-molecule neurotherapeutics from entering the brain (Pardridge, 3). Furthermore, the BBB’s endothelial cells contain ATP-binding cassette transporters, also known as ABC transporters. ABC transporters use the chemical energy present in adenosine triphosphate (ATP), the source of energy in cells’ phosphate bonds, which is released after ATP reacts with water to break down said bonds—a process known as hydrolysis. This allows for the transport of various substances across the membrane—but the expulsion of compounds that might cross the BBB back into the bloodstream, which further restricts the number of molecules that can be effectively transported into the brain (Ceña & Játiva, 1513).
Various strategies have been devised to effectively penetrate the blood-brain barrier over the century since its discovery. These strategies can be classified into invasive techniques, such as opening or disrupting the BBB or injecting therapeutic proteins directly into the CSF, and non-invasive methods such as intranasal drug delivery or gene therapy (Bellettato & Scarpa, 3). All of these techniques however have several limitations. The temporary parting of the BBB’s tight junctions, be it by using osmotic pressure, microbubbles, or ultrasound, can damage the integrity of the barrier and cause an uncontrolled influx of unwanted molecules into the central nervous system (CNS) when the junctions open, potentially harming patients (Zhou et al., 291). Directly injecting enzymes—proteins that speed up chemical reactions—into the cerebrospinal fluid, while effective in both mice and dog models, is considered challenging to use in a clinical setting due to the short half-life of the enzymes. On the other hand, intranasal drug delivery is severely hampered by the limited concentration that can be achieved in the brain and spinal cord, the reduction of drug delivery efficiency as the drug’s molecular weight increases, and the variabilities in nasal absorption caused by irritation or nasal pathology (ie. the common cold). Finally, while effective in mice, gene therapy has encountered challenges with the human immune response, and difficulties from translating therapeutic approaches from small animal models to larger ones. (Bellettato & Scarpa, 6).
The Potential of Nanoparticles
Nanoparticle drug delivery methods offer several advantages over other strategies due to their reduced size, biocompatibility, prolonged blood-circulation, and non-toxicity (Teleanu et al., 5). Furthermore, nanoparticles offer other benefits such as minimal invasiveness, affordability, biodegradability, long-term stability, precise targeting ability, and excellent loading and releasing control through the BBB (Zhou et al., 291).
While nanotechnology-based medications, such as Abraxane, Daunoxome, and Doxil have already been approved for cancer treatment by the FDA (Sahu et al., 5), there is still a long way to go in the development of brain-focused nanoparticle technology. Current nanotechnology-mediated drug delivery systems under investigation include both specific and non-specific mechanisms for targeting brain sites (Teleanu et al., 5). Viable nanoparticles must maintain stability and remain in the bloodstream for long periods of time, avoid clumping and uptake by the immune system, and have minimal impact on the drug molecules they will carry (Zhang et al., 220).
The Development of Nanocarriers
The nano-carriers currently in development can be divided into two types: those made out of organic nanomaterials, and those made out of inorganic ones. Organic nanomaterials, primarily carbon based, are what constitute polymeric nanoparticles, liposomes, dendrimers, and micelles. Inorganic nanomaterials constitute gold and silica nanoparticles, and carbon nanotubes. Polymeric nanoparticles, which are composed of very large molecules, or macromolecules, have shown potential for treating CNS diseases due to their attractive drug delivery properties—including controlled drug release, customizable structures, cellular targeting and uptake, and its ability to avoid being ingested and eliminated by the immune system (Wu et al., 13). Modification of polymeric nanoparticles with specific ions or molecules known as ligands allows for the targeting of the receptors on the ECs, while their polymeric matrix can be triggered for drug release, resulting in prolonged, protected, and particularized drug delivery. Recent studies using polyalkyl cyanoacrylates nanoparticles (PACA NPs) loaded with doxorubicin (a chemotherapy drug) have been tested in patients with refractory solid tumors (Vauthier, 3), while the same particles loaded with mitoxantrone (a cancer medicine) have been tested in patients with liver cancer (Wang et al., 97). On the other hand, PACA NPs can be potentially used for the treatment of Alzheimer’s Disease (AD). AD is linked to the abundance of the amyloid-β peptide, so having antibodies that can detect this peptide is important for AD recovery. In some studies, PACA NPs were decorated with anti-amyloid-β1-42 antibodies, leading to memory recovery in AD mouse models (Carradori et al., 610). However, further investigation on the applications of PACA NPs for CNS disorders is still needed.
Liposomes are the best candidate to carry potential hydrophilic and hydrophobic molecules due to their lipid bilayer arrangement. These spherical vesicles are made of a double layer of lipid molecules, with the lipid’s hydrophobic (water repellent) tails facing the inside and the hydrophilic (water soluble) tails facing the outside, giving it amphiphilic properties and allowing it to transport many kinds of molecules. They have been shown to enhance drug solubility and controlled distribution, and their surface can be easily modified for targeted, prolonged, and sustained drug release. Currently, various liposomal drug delivery systems have been clinically approved for treatment of cancer, fungal, and viral infections (Nsairat et al., 9–10), and they have also been used in gene therapy. Multiple studies have reported the use of liposomal formulations for anti-cancer drugs, such as methotrexate, 5-fluorouracil, paclitaxel, doxorubicin, and erlotinib (Teleanu et al., 7).
Dendrimers are a type of nano-sized, radially symmetric synthetic macromolecules, with a structure consisting of tree-like arms or branches. Their globular structure comprises a core, with multiple branching layers extending from the central core and active functional groups in the outermost layer. The advantages they provide have made them the newest class of macromolecular nano-scale delivery systems after their discovery in 1978 (Wang et al., 1), and it is emerging as a possible therapeutic agent for anticancer therapies and diagnostic imaging (Abbasi et al., 5). Dendrimers have been applied in treating brain cancer, neurodegenerative diseases, stroke, neuroinflammation and circulatory arrest; polyamidoamine dendrimers have become the most commonly studied dendrimers for treating brain disease (Teleanu et al., 8).
Micelles are amphiphilic molecules - that is, a molecule that has both hydrophobic (nonpolar) and hydrophilic (polar) regions (Illustrated Glossary of Organic Chemistry). Their size ranges from 5 to 100 nanometers. Micelles can be used for the delivery of hydrophobic molecules, and can provide controlled and sustained release, chemical and physical drug stability, and improve drug bioavailability (Joseph et al., 145). There are several of nanomicelle-based drug delivery systems that allow it to gain edge over classical drug delivery methods: they can entrap hydrophobic drugs and increase their solubility, their ability to target specific portions of the CNS can lead to maximum efficiency in delivery and minimal side effects, they can release drugs when triggered by stimuli, such as pH or temperature, they have the capability to ensure a continuous supply of therapeutic agents, and their small size is well-suited for intravenous injection without risk of arterial blockage (Bose et al., 1–3). Recent studies have focused on curcumin delivery for targeting glioma, a common type of brain tumor, and Alzheimer’s disease through using micelles as nanocarriers; micelles with contrast agents are also being investigated for potential applications in magnetic resonance imaging of neuroinflammation and stroke injuries caused by clots in the brain (Teleanu et al., 9).
Inorganic nanoparticles, while not very biodegradable, have been widely used in biomedical applications. Gold nanoparticles (AuNPs) could be potentially used for therapeutic applications for neurodegenerative disorders due to their anti-inflammatory and antioxidant properties (de Bem Silveira et al., 2425). These properties are theorized to contribute to their neuroprotective effects and ability to reduce oxidative stress—a critical factor in the pathogenesis of neurodegenerative disease. Because of these effects, AuNPs would be able to prevent further neuronal damage caused by excessive inflammation or lack of oxidation, reduce neuroinflammation-associated neurotoxicity, and to maintain stable conditions within cells through homeostasis. Additionally, AuNPs can enhance the secretion of neurotrophic factors— biomolecules that support neuron survival (Krieglstein, 843)—, which helps to maintain neuronal health and plasticity, and enhance connectivity between them. Most importantly, AuNPs may be able to reduce the clustering of misfolded proteins—a significant occurrence in many neurodegenerative disorders (Chiang et al., 2–3).
Recent studies have shown AuNPs’ potential for treating Alzheimer’s, as it can protect neurons against toxicity induced by amyloid-β clustering, has high levels of inhibition efficency (Hou et al., 2), and assist in relieving memory impairment and neural damage (Sanati et al., 2305). AuNPs can also improve cognitive and antioxidant function, and reduce the hyperphosphorylation of the tau protein—a key feature of Alzheimer’s—, in which the biomolecule becomes tangled and misfolded (dos Santos Tramontin et al., 932). Additionally, research in mice using AuNPs to treat Parkinson’s disease (PD) has demonstrated outcomes such as reduction of oxidative stress, improvement of motor symptoms, and partial improvement of neurotrophic factors (da Silva Córneo et al., 8).
Silica nanoparticles (SiNPs) are composed of silicon dioxide (silica), the most abundant element on earth. SiNPs can be easily hybridized with other inorganic nanoparticles and they possess uniform pore and controllable particle sizes, large surface areas, capacity to maintain stability, adaptable surfaces, and biocompatibility (Huang et al., 1), making them potential nano-vehicles for the delivery of drugs and imaging probes through the BBB. While their performance in clinical trials has been promising, there are still several hurdles to overcome before SiNPs’ can be implemented, including ensuring safety with prolonged exposure, determining long-term toxicity profiles from various administration methods, and exploring scale-up techniques, particularly in producing reliable batches of the macroparticle. Moreover, only solid SiNPs without pores or with small pores have been tested, which has a lower cargo-loading capacity compared to dendritic, virus-like, large-pore and mesoporous (that is, with pores with diameters from 2 to 50 nanometers) SiNPs, which have the capability to load multiple drugs and biologics (Janjua et al., 1072).
Finally, carbon nanotubes (CNTs) are hollow graphite sheet tubes with a diameter in the nanometer range that present great promise in biomedical applications due to their ability to continue operating while containing chemical compounds that can alter their physical and biological properties. Carbon nanodots coated with polymers and chemically-altered carbon nanotubes with multiple walls have been used to transport drugs during brain cancer therapy, which has been found to have successfully penetrated the blood-brain barrier, enhancing the drugs’ uptake in tumors (Kafa et al., 228, Wang et al., 38). Another study that compared the absorption of the Alzheimer’s drug berberine in a control group where it was administered normally, to an experimental group where multi-walled CNTs had transported it, found the experimental groups had shown greater levels of brain absorption of the drug, and has a potential in reducing amyloid-β levels (Lohan et al., 277). Nevertheless, the possible toxicity of CNTs due to their nanostructure and biopersistence is of major concern, and further inquiry is needed on their impacts (Zhang et al., 7).
The Transport Strategies
There are four main possible mechanisms for nanoparticle transport across the blood-brain barrier, which can be divided into two categories: passive and active. Passive methods are energy independent, as they do not require ATP hydrolysis, and consist of simple molecules diffusion through endothelial cells (Zhou et al., 292). Nonetheless, it is difficult to get most biomolecules through using this process, with only the most lightweight lipid-soluble ones being able to do so effectively (Grabrucker et al., 2). Therefore, most research has focused on active transport mechanisms, such as carrier-mediated transport, receptor-mediated transcytosis, and adsorption-mediated transcytosis.
Carrier-mediated transport (CMT) uses carrier systems for transportation, and it is best known for being the most common technique for small molecules that cannot passively diffuse through the brain due to their polarity, such as glucose. While efforts have been made to use CMT systems, only small peptides have been shown to be shipped through the brain effectively. Yet, CMT can best operate only in specific molecular configurations, which can be easily disrupted by small changes to the molecule, making CMT unideal in most cases (Lopes van den Broek, Shalgunov & Herth, 3).
Receptor-mediated transcytosis (RMT) is currently the most studied mechanism for BBB nanomedicine transport, and the main pathway for macromolecules across this barrier. In RMT, nanoparticles are transported into the brain by binding to specific receptors on one side, then absorbed into small cellular containers called endosomes through a process called endocytosis, before being released to the other side through exocytosis. During RMT, substances get exposed to different environments—within the endosomes, the pH range changes from 7.0 to 7.4 outside the cell to 4.5 to 6.5 inside the cell—, meaning that nanoparticles would have to withstand rapid changes in conditions. Still, RMT has the potential to transport higher amounts of nanomedicines compared to CMT, and it has been proved to be more versatile, being used for liposomes, polymers, nanoparticles, and proteins, (Lopes van den Broek, Shalgunov & Herth, 4).
Finally, in adsorption-mediated transcytosis (AMT) nanomolecules are transported across cellular barriers via electrostatic interactions between ligands in the bloodstream and the cell membrane, leading to their internalization (Xiao & Gan, 2). Nanomedicines, which tend to be positively charged, can easily interact with the negatively charged cell membrane. However, this method of crossing the BBB only seems to work in one direction—from blood to brain—and analysis over its effectiveness continues (Grabucker et al., 3).
Moving Forward
While nanoparticles are certainly a promising method for drug delivery across the brain—especially in recent studies—there is still a lot of research yet to be done. Despite advancements in nanoparticle engineering, targeting methodologies, and drug formulations, numerous challenges remain, including limited penetration, potential toxicity, and immune response activation. Continued interdisciplinary research efforts are paramount to advancing our understanding of blood-brain barrier biology and refining nanoparticle delivery systems. Integrating innovative approaches, such as being able to chemically attach ligands to the surface of nanoparticles, making nanoparticles responsive to environmental cues, and making them mimic natural biological systems, holds immense potential for enhancing the specificity, efficacy, and safety of nanoparticle-based therapies for even the most challenging of neurological diseases.
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Excelente revision