A Sniff of Success for Small Particles

Both the pharma industry and the research community have been investigating enhanced drug delivery to the brain for many years, but despite the time, effort and costs invested in this field, getting drugs to the brain continues to be a significant challenge. Historically, drug delivery to the brain relied either on intracerebral injections or on temporary disruption of the tight junctions of the blood-brain barrier; for example, with high-osmolar solutions. These approaches, however, feature a number of limitations, including invasiveness, tissue damage, and uncontrolled distribution of the drug after delivery. Could these drawbacks be avoided by delivering drugs via the nose? After all, the simplest and shortest path for airborne nanoparticles to reach the central nervous system is through the olfactory tract; once drugs permeate the nasal epithelium, they travel directly to the brain along olfactory nerves.

My work focuses on nanoparticles and, among other areas, I’ve been looking at how nanoparticles can help deliver drugs to the brain. I became aware of the exceptional properties of nanoparticles, and their potential applications in multiple disciplines, quite early on in my career. At first, I was working with nanoparticles in the agricultural sector. Subsequently, however, I became interested in the medical applications of nanotechnology.  At Washington University, I focus on nanoparticles for cancer therapy, medical imaging, and targeted drug delivery. In particular, I recognized that safe and effective cerebral drug delivery is a significant challenge, mainly due to the blood-brain barrier. Available non-invasive methods, such as systemic injections or oral pills, aren’t as precise or immediate as doctors might wish, and direct physical delivery to the brain involves risky techniques. I decided that there must be other options. In particular, there was already a good body of information on what happens when we inhale non-engineered nanoscale particles, such as those found in vehicle emissions, for example. These studies show that particles below 10 nm are transported from the nasal epithelium straight to the brain. So I decided to develop a non-surgical method of effectively and rapidly delivering drug to the brain, based on aerosolized nanoparticles of less than 10 nm in diameter. Monodisperse, aerosolized nanoparticles are applied via the nostrils, and are deposited in the upper regions of the nasal cavity. They then travel first to the olfactory bulb and then to the olfactory cortex – so in just two relays, drug-loaded particles can reach the cortex. Thus, the nasal route is the shortest and possibly the easiest path to the brain. In fact, the same is true for invertebrate olfactory circuitry, exemplified by the locust antenna, which also has the benefit of being a relatively simple system. Our experiments with this system show that aerosolized gold nanoparticles applied to locust antenna reach the insect brain within one hour, and that nanoparticle accumulation in the brain increases linearly with duration of application (1). Notably, electrophysiological recordings from neurons in the insect brain several hours after nanoparticle uptake did not show any significant alterations in their spontaneous and odor-evoked spiking properties. In other words, our system does not seem to disrupt normal neural function. In the next phase, we will load gold nanoparticles with drugs and use ultrasound to target precise doses to specific areas of the brain. Ultimately, I hope the work could one day lead to new treatment options for brain tumors.

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