Neurodegenerative diseases are extraordinarily difficult to treat due to the unique physiology of the brain. One key obstacle is the blood-brain barrier (BBB), a natural selective semipermeable border that restricts the passage of toxins and pathogens present in the main bloodstream. This barrier also prevents the entry of drugs or other therapeutics to the brain, hindering the treatment of diseases by conventional methods of drug delivery. Thus, the focus of much ongoing research has been on novel drug delivery methods to cross the BBB and engage with the target.
At present, various approaches are under investigation, such as invasive intracerebroventricular infusions, convection-magnified delivery, osmotic shock, and ultrasound, to permit delivery via antibodies, peptides, or colloidal carriers through specific receptors. This article discusses some recent advances toward delivering therapeutics across the BBB.
Nose-to-brain patch for the treatment of multiple sclerosis:
The N2B-patch project, which is funded by the European Union’s Horizon 2020 program, started in 2017 with the intent to deliver biologics through a medical device from the nose to the brain. This project aims to treat multiple sclerosis (MS), which currently has no cure and affects around 2.5 million patients worldwide.
The project envisions three basic outputs:
- An ensemble composed of biomaterial-based drug particles and active pharmaceutical ingredients (biomolecules) for MS treatment
- The hydrogel formulation as a carrier
- The applicator device
These components will combine together to bypass the BBB by opening a direct transport route from the nasal cavity to the brain. This promising technology will not only support demyelinating disorders such as MS but also pave a path for the treatment of other neurological and neurodegenerative indications.
On-demand opening of the BBB to facilitate the delivery of current therapeutics:
DOMEUS is another project developing a medical device that is being conducted by CarThera, a clinical-stage company founded in 2010. This project aims to treat severe brain disorders such as glioblastoma, brain metastasis, and Alzheimer’s disease using the SonoCloud device. This implant has the potential to temporarily open the BBB on demand by emitting low-intensity pulsed ultrasound waves. This device will allow the delivery of therapeutics into the brain at levels up to 7 times higher than what is possible today. Therefore, chemotherapy treatment for tumors will also be more efficient, with fewer side effects on the body.
In January 2020, CarThera published a report of ultrasound-mediated paclitaxel drug delivery across the BBB to treat glioma in a mouse model. In August 2020, CarThera initiated a phase 1/2 clinical trial in collaboration with Northwestern University and Bristol-Myers Squibb for patients with recurrent glioblastoma. The company is expecting product launch to the international market by 2023.
Next-generation CDNF-derived peptides to treat Parkinson’s disease:
In September 2019, a project was initiated to treat Parkinson’s disease with cerebral dopamine neurotrophic factor (CDNF). CDNF can successfully reverse neurodegeneration caused by Parkinson’s disease but cannot penetrate the BBB. Therefore, the current project aims to develop CDNF-derived peptides that can pass through the BBB. The key steps for successful penetration into the BBB are as follows:
- The length of CDNF will be minimized
- The CDNF fragment will be mutated to improve its stability in the blood and tissues
- The CDNF fragment will be adjoined with nanoparticles to enhance stability and ability
This project was funded under the European Union Horizon 2020 scheme and is expected to end in May 2022.
PEGylated-PLA nanoparticles crossing the BBB to deposit in blood vessels:
In September 2020, researchers from the Institut National de la Recherche Scientifique (INRS) in Canada published a report that polylactic acid (PLA)-based nanoparticles encapsulated in polyethylene glycol (PEG) could cross the BBB. Both in-vivo (cultured cells) and in-vitro (zebrafish) models were successfully tested.
One major disadvantage of nanoparticles is that they could accumulate in the brain and cause neurodegeneration. However, these novel polymeric nanoparticles are nontoxic, as PLA is a biocompatible material and can be easily removed from the body via normal physiological processes. Similarly, PEG is already used for encapsulation or preservation of many food items and living organisms. The optimization study concluded that the size of particles heavily influences the rate of nanoparticle absorption through the BBB.
The team is further planning to elaborate the work in other active ingredients and animal models.
The nanoparticles injected (intravenous injection) traveled through blood and deposited around brain vessels.
Source: Institut national de la recherche Scientifique
Nanoparticle platform for delivery of siRNA across the BBB to treat traumatic brain injury:
An article published in January 2021 by researchers from MIT and Harvard Medical School reported on siRNA delivery across the BBB for possible treatment during traumatic brain injury (TBI). The study was designed in three main stages:
- Fabrication of siRNA to inhibit the expression of the tau protein, which has a significant role in neurodegeneration
- Engineering of the nanoparticle by poly (lactic-co-glycolic acid), or PLGA, an FDA-approved biodegradable and biocompatible polymer
- Tuning the entry of nanoparticles across the BBB through tight junctions by modulation of surface chemistry and coating density
The researchers leveraged the knowledge of previously identified genes for this unique challenge. The mode of engineered nanoparticles was through injection within or outside the window of breached BBB in mice with TBI, and the results show that the accumulation of nanoparticles in the TBI mouse model was three times higher in comparison to the traditional method. The data presented is very promising as a drug delivery approach for the treatment of TBI. Looking forward, the authors mentioned that this technology needs application enhancement in terms of both targets and other neurodegenerative diseases.
Neurotransmitter-derived lipidoids for enhanced brain delivery through intravenous injection:
In August 2020, a research group from Tufts University constructed nanoparticles tagged with neurotransmitter molecules to traverse the BBB. They selected the three natural active transporter neurotransmitters tryptamine, phenethylamine, and phenylethanolamine. These neurotransmitters were conjugated with lipid molecules, embedded in nanoparticles, and tagged with a fluorescent dye. When this composite was injected into the liver of the mouse model, only the tryptamine molecule was successfully traced in the brain.
Further, a successful attempt to carry amphotericin B (an antifungal drug) and tau antisense oligonucleotides with tryptamine-conjugated nanoparticles across the BBB was accomplished. This work has potential, but it is just the tip of the iceberg and the technology is still a ways from the clinical phase, according to lead author Qiaobing Xu.
In vivo delivery of a gene-editing protein (Cre-recombinase) into the mouse brain, visualized as red fluorescence (scale bar 100 μm). Inset: transmission electron microscopy image of lipid nanoparticles containing Cre-recombinase (scale bar 0.1 μm).
Image courtesy of Qiaobing Xu, Tufts University
Ongoing research paves the path of future discoveries and success:
Although drugs are available to treat certain neurodegenerative diseases, very few of them can reach the desired target due to the BBB. Efforts at the industry and university levels are rapidly accelerating progress in this area. However, the work remains in the early stages, with minimal proof of safety and efficacy in clinical models, especially for novel approaches such as ultrasound waves and nanoparticle carriers.
More research is needed to optimize and develop new drug delivery techniques to improve the survival of patients. As highlighted in this article, several radically different strategies are being pursued to tackle this problem. One or more of these approaches may prove to be the key that ultimately unlocks the BBB for effective delivery of therapeutics to the brain.
If you have any questions or would like to know if we can help your business with its innovation challenges, please leave your info here or contact Jeremy Schmerer, Healthcare & Life Sciences Lead, directly at email@example.com or Linda Cohen, Strategic Accounts Manager at firstname.lastname@example.org.