Nanotechnology for CNS delivery of biological therapeutics

Published on May 4, 2015   52 min

Other Talks in the Series: Nanomedicine

0:00
Welcome to the seminar on "Nanotechnology for CNS Delivery of Biological Therapeutics." My name is Mansoor Amiji. I'm a Distinguished Professor and Chairman of the Department of Pharmaceutical Sciences in the School of Pharmacy at Northeastern University in Boston, Massachusetts. I'm also the director of the laboratory of Biomaterials and Advanced Nano-Delivery Systems here at Northeastern University.
0:24
The diseases of the central nervous system, or CNS, currently represent 11% of the global disease burden. This number will increase to 14% in the year 2020, largely due to the aging demographics, both here in the United States and around the world. CNS diseases are especially devastating, as they are predominant in older adults with other morbidities. In neurodegenerative disease, for example, such as Alzheimer's and Parkinson's disease, lack of early diagnosis and current treatment strategies that are purely symptomatic are also additional challenges. A piece published in 2010 in Science, showed that CNS drug development takes a long time for approval, has poor success rate, and costs more than any other diseases. As such, currently there are very few major pharmaceutical and biotechnology companies having a program in CNS drug development. Biological therapies based on peptides, proteins, nucleic acid, and even cells have shown tremendous benefit in the pre-clinical evaluation for a variety of CNS diseases, especially neurodegenerative diseases. Many of these agents have disease modifying effects, rather than just providing symptomatic treatment. However, delivery of therapeutic agents, especially biologicals that are highly hydrophilic, large molecular weight, sometimes charged, and labile molecules to the brain, especially upon administration through the bloodstream, is impossible.
1:59
Although the predominant barrier for drug transport in the brain is called the blood-brain barrier, which is a highly regulated physical and biological barrier to transport, there are also other systemic issues, such as dilution and rapid clearance, which become important factors that limit the bioavailability of the drug in the brain.
2:22
Current strategies to enhance drug availability in the CNS falls into two major categories. The first one is invasive administration, and the second one is non-invasive administration. The invasive approach includes surgical implantation of catheters to the brain directly at any specific site so that the drug could be administered using various types of mechanisms injected directly into the area that the drug is needed. Other strategies for invasive administration include disruption of the blood-brain barrier using hypertonic solutions of mannitol, which creates a transient opening of the blood-brain barrier to allow for molecules to go through the bloodstream into the brain or implantable devices, such as those that are put either in the scalp after surgical resection, or when there is a surgery in the brain, and then there is cavitation of the local area. And subsequently, the implant is placed in the area where there's resected tissue. All of these invasive administrations require some sort of surgical intervention, clinical personnel, and sophisticated resources in order to accomplish them. Unfortunately, they also suffer from a number of other complications, and especially potential for creating a lot of different kinds of side effects. So a practical application of invasive approaches is quite difficult to achieve. As such, a number of investigators, including our team here at Northeastern, has been investigating non-invasive drug administration in the brain. The non-invasive approaches that I will highlight today include nanotechnology-based delivery solutions, as well as administration of drugs from the nose into the brain. The nanotechnology-based solutions require a nano-sized lipid or polymeric particle that can encapsulate the payload and help that payload get shuttled across the blood-brain barrier from the bloodstream into the brain. Intranasal delivery is another approach where the drug is administered in the nose with the approach to have the drug go either through the olfactory or other pathway into the brain. Intranasal administration bypasses the blood-brain barrier.
4:41
For our first example, we are using oil-in-water nano-sized emulsions. These are made with edible oils which are safe and metabolized in the bloodstream, in the body. The edible oils are emulsified into very small droplets and then mixed with components to make it into an emulsion. In the lab, this work was done by Lipa Shah, who was a PhD student here at Northeastern. Lipa currently working at Novartis Biomedical Research Institute. Lipa used omega 3 polyunsaturated fatty acid enriched flax seed and fish oils to develop these nano-sized oil-in-water emulsions. We use both ultrasonicator, which can provide small volumes, up to 5 ml, and then a microfluidizer obtained from a company that is based here in Newton, Massachusetts, called Microfluidics, to form larger volumes of these emulsions. The coarse emulsion is first prepared by mixing the oil and the various surfactants with water in the ratio that is optimized in our laboratory. Unless the coarse emulsion is formed, then it is either ultrasonicated or passed through the microfluidizer in order to perform the nano-sized oil-in-water emulsions. Using a microfluidizer, we can get emulsions up to 100 nanometer in diameter or less. The surface charge of the emulsion is -43 in this example based on the emulsifiers that we have used. In our study, we work with phospholipids as the emulsifier, mostly we pass to dylcholine, which comes in the brand name of Lipoid 80, as well as other polyethylene glycol containing surfactants, such as Tween 80 and Pluronic F85. The example that I'll show you with the nanoemulsion used for delivery in the CNS uses Tween 80 as a surfactant and Lipoid 80 as another. So these are mixed together to form a core surfactant mixture.
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Nanotechnology for CNS delivery of biological therapeutics

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