Clinical Testing Helps Research Firms Break Through the Biologic Blood-Brain Barrier With Nanocarriers

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Although scientists have spent more than a century making vaccines for rabies, such as in this image, they are now harnessing its ability to cross the blood brain barrier to transport therapeutics. Image Source: Wikimedia Commons User Fæ

The blood-brain barrier (BBB) is filtering (both literally and figuratively) the progression of brain biochemical science. This decidedly selective membrane is notorious for halting the progression of many therapeutics before they have the opportunity to enter clinical trials, while at the same time many viruses, such as rabies, manage to navigate the BBB’s defenses with ease.

Recently, Drs. Pilkington and Hill presented their newest discovery at a conference: an innovative aspirin. Their novel formulation, IP1867B, is a truly soluble form of aspirin.1  Patients suffering from brain tumors or neurological disorders will benefit as this significantly increases the ability of drugs to cross the BBB. This technology is expected to be used as a novel way to deliver medication for a variety of mental and neurological disorders, which will be a breakthrough for many drug-resistant and otherwise untreatable illnesses.

Receptor Mediated Transit

Methods to get through the BBB have been sought after for years. Many of these methods relied on the hijacking of receptor-mediated transport (RMT) for better drug delivery. This method uses an endogenous RMT ligand, a peptide ligand mimic, or an anti-receptor antibody to adequately target the biologic to a receptor for conveyance. Well established RMT targets include the insulin, transferrin and low density lipoprotein receptors. In recent years, researchers have begun to investigate a number of new targets, occasionally by identifying pathogens or antibodies that are known to cross the BBB.

In terms of antibodies, FC5 is a single domain llama antibody that has been shown to accumulate in the brains of mice during in vivo experiments. Through further research, scientists discovered that it was TMEM-30A, transmembrane protein 30A, that was interacting with the antibody. Although this technology hasn’t yet reached its full potential, modern lab software is making it possible to create new FC5-drug conjugates to bring medication into the brain more effectively.

In a paradoxical stroke of genius, scientists investigating the method by which rabies enters the CNS and infects brain cells were able to develop a peptidyl-targeting vector based on the portion of the rabies virus glycoprotein (RVG) that binds to the neuronal nicotinic acetylcholine receptors. Recently, this peptide has been used in conjunction with exosomes and with siRNA to treat Alzheimer’s Disease in rodent models. Both FC5 and RVG have been quite successful in vivo and it is important to note that few toxic or adverse immunogenic effects have been observed.2  

Nanocarrier Transport Into the Central Nervous System

Nanocarriers are one of the ways to deliver therapeutics directly to brain tissue. Many methods used to cross the BBB cause tiny disruptions, and can compromise the structural integrity of the BBB. Fortunately, nanocarriers do not cause any such disruptions and many are actually used in conjunction with the aforementioned RMT technologies.

In the case of illnesses such as schizophrenia, a variety of different antipsychotics may be prescribed, but this medication has a host of undesirable side effects, such as tardive dyskinesia, which may potentially be caused by disruptions in the brain and the BBB. Through the use of nanocarriers to shuttle medication, researchers are presented with the opportunity to weed out a number of dose and technology-related side effects, including tardive dyskinesia.

There are a number of vesicle type transport systems that are being developed, which are showing promising results pre-clinically. Exosomes, for example, are small, naturally-occurring vesicles that can navigate their way into the brain. They have the potential to be used in the treatment of a variety of different disorders and, pending FDA approval, within the next few years the clinical trial landscape will be peppered with exosome neurological trials.

Meanwhile, liposomes are nano-sized vesicles with an aqueous core enrobed in lipid membrane, which are able to find their way across the tough terrain of the BBB. Unfortunately, the use of conventional liposomes has been limited due to macrophage clearance, poor stability and low therapeutic transport rate. Through the use of innovative lab software, different surface coatings are being identified that can prevent macrophage identification and clearance. Additionally, recent advances in biologics software is allowing researchers to better examine how the lipid composition affects both stability and therapeutic transport rate in vivo.

Through advancements in this field, nanocarriers are mechanistically vast; in fact, there are many varieties of nanoparticle methods alone. Inorganic nanoparticles are of stable size and form mono-disperse suspensions in body fluids. Although they have the capacity to be very effective, challenges arise when researchers look at delivery efficiency and at toxicity. As many of these inorganic compounds are non-degradable, they have the potential to build up in the brain and cause their own issues. Polymeric nanoparticles are natural or synthetic solid polymer carriers and range from 1 to 1000 nm in diameter. Due to the nature of polymers, these are highly customizable for varying levels of staying power.

Research firms with their eyes set on clinical testing will need modern lab software to help them assess toxicity, catabolites, degradation and the possibility for undesired immunological responses. Solid lipid nanoparticles (SLNs) are nano-sized biocompatible lipids that are stabilized using surfactants. SLNs show biocompatibility and they have the capacity to be optimized for specific brain targeting; however, their ease of clearance and degradability poses issues need to be tracked in order to ensure success as this technology moves towards clinical trials.

Researchers could benefit from ways to identify and develop surface modifications that assist with both targeting and evasion of elimination. Fortunately, BIOVIA Designed to Cure can give research a helping hand in the push towards clinical translation. The Designed to Cure industry solution experience delivers collaborative, knowledge-driven innovation and predictive analytics to address these challenges. Please contact us today to learn more about how our software options can support the efforts of your lab.

  1. “Breakthrough in Brain Tumour Research,” June 28, 2016, http://medicalxpress.com/news/2016-06-breakthrough-brain-tumour.html
  2. “Targeting Receptor-Mediated Transport for Delivery of Biologics Across the Blood-Brain Barrier,” January 2015, http://www.annualreviews.org/doi/full/10.1146/annurev-pharmtox-010814-124852