New Coating Helps Therapeutic Nanoparticles Penetrate Brain

New Coating Helps Therapeutic Nanoparticles Penetrate Brain

The brain is a notoriously difficult organ to treat, but Johns Hopkins researchers report they are one step closer to having a drug-delivery system flexible enough to overcome some key challenges posed by brain cancer and perhaps other maladies affecting that organ.

In a report published online on August 29 in Science Translational Medicine, the Johns Hopkins team says its bioengineers have designed nanoparticles that can safely and predictably infiltrate deep into the brain when tested in rodent and human tissue.

“We are pleased to have found a way to prevent drug-embedded particles from sticking to their surroundings so that they can spread once they are in the brain,” says Justin Hanes, Ph.D., Lewis J. Ort Professor of Ophthalmology, with secondary appointments in chemical and biomolecular engineering, biomedical engineering, oncology, neurological surgery and environmental health sciences, and director of the Johns Hopkins Center for Nanomedicine.

After surgery to remove a brain tumor, standard treatment protocols include the application of chemotherapy directly to the surgical site to kill any cells left behind that could not be surgically removed. To date, this method of preventing tumor recurrence is only moderately successful, in part, because it is hard to administer a dose of chemotherapy high enough to sufficiently penetrate the tissue to be effective and low enough to be safe for the patient and healthy tissue.

To overcome this dosage challenge, engineers designed nanoparticles – about one-thousandth the diameter of a human hair – that deliver the drug in small, steady quantities over a period of time. Conventional drug-delivery nanoparticles are made by entrapping drug molecules together with microscopic, string-like molecules in a tight ball, which slowly breaks down when it comes in contact with water. According to Charles Eberhart, M.D., a Johns Hopkins pathologist and contributor to this work, these nanoparticles historically have not worked very well because they stick to cells at the application site and tend to not migrate deeper into the tissue.

Elizabeth Nance, a graduate student in chemical and biomolecular engineering at Hopkins, and Hopkins neurosurgeon Graeme Woodworth, M.D., suspected that drug penetration might be improved if drug-delivery nanoparticles interacted minimally with their surroundings. Nance first coated nano-sized plastic beads of various sizes with a clinically tested molecule called PEG, or poly(ethylene glycol), that had been shown by others to protect nanoparticles from the body’s defense mechanisms. The team reasoned that a dense layer of PEG might also make the beads more slippery.

The team then injected the coated beads into slices of rodent and human brain tissue. They first labeled the beads with glowing tags that enabled them to see the beads as they moved through the tissue. Compared to non-PEG-coated beads, or beads with a less dense PEG coating, they found that a dense coating of PEG allowed larger beads to penetrate the tissue, even those beads that were nearly twice the size previously thought to be the maximum possible for penetration within the brain. They then tested these beads in live rodent brains and found the same results.

The researchers then took biodegradable nanoparticles carrying the chemotherapy drug paclitaxel and coated them with PEG. As expected, in rat brain tissue, nanoparticles without the PEG coating moved very little, while PEG-covered nanoparticles distributed themselves quite well.

“It’s really exciting that we now have particles that can carry five times more drug, release it for three times as long and penetrate farther into the brain than before,” says Nance. “The next step is to see if we can slow tumor growth or recurrence in rodents.” Woodworth added that the team “also wants to optimize the particles and pair them with drugs to treat other brain diseases, like multiple sclerosis, stroke, traumatic brain injury, Alzheimer’s and Parkinson’s.” Another goal for the team is to be able to administer their nanoparticles intravenously, which is research they have already begun.

Authors on the paper include Elizabeth Nance, Graeme Woodworth, Kurt Sailor, Ting-Yu Shih, Qingguo Xu, Ganesh Swaminathan, Dennis Xiang, Charles Eberhart and Justin Hanes, all from The Johns Hopkins University.

This work was supported by grants from the National Cancer Institute (R01CA164789 and U54CA151838).

Targeted drug delivery by ferrying nanoparticles is a major field of research, promising highly effective therapies for all kinds of diseases while limiting side effects. The brain has been particularly interesting for this research, as it’s an organ that’s evolved all kinds of defense strategies – from the scalp to the blood brain barrier – making it difficult to work on, directly.

The brain’s extracellular space (ECS) is a network of channels that form between cells within which an ionic fluid transports nutrients, signaling molecules, and other chemicals throughout the brain. The narrow channels of the ECS limit the size of the particles that can move through, a problem that has put serious brakes on the use of nano-therapies in the brain.

Johns Hopkins University scientists have good news though, having discovered that by coating nanoparticles with polyethylene glycol (PEG) they were able to pass ones through the ECS nearly twice as big as before. It seems that beside the narrowness of the channels, there’s also a mechanism that makes particles stick to the walls. A dense coating of PEG helps the particles glide through, which the team demonstrated in mouse brains by moving 114 nm particles through the ECS, a significant improvement over previously used 64nm particles.

More from the study abstract:

Using these minimally adhesive PEG-coated particles, we estimated that human brain tissue ECS has some pores larger than 200 nm and that more than one-quarter of all pores are ?100 nm. These findings were confirmed in vivo in mice, where 40- and 100-nm, but not 200-nm, nanoparticles spread rapidly within brain tissue, only if densely coated with PEG. Similar results were observed in rat brain tissue with paclitaxel-loaded biodegradable nanoparticles of similar size (85 nm) and surface properties. The ability to achieve brain penetration with larger nanoparticles is expected to allow more uniform, longer-lasting, and effective delivery of drugs within the brain, and may find use in the treatment of brain tumors, stroke, neuroinflammation, and other brain diseases where the blood-brain barrier is compromised or where local delivery strategies are feasible.

Prevailing opinion suggests that only substances up to 64 nm in diameter can move at appreciable rates through the brain extracellular space (ECS). This size range is large enough to allow diffusion of signaling molecules, nutrients, and metabolic waste products, but too small to allow efficient penetration of most particulate drug delivery systems and viruses carrying therapeutic genes, thereby limiting effectiveness of many potential therapies. We analyzed the movements of nanoparticles of various diameters and surface coatings within fresh human and rat brain tissue ex vivo and mouse brain in vivo. Nanoparticles as large as 114 nm in diameter diffused within the human and rat brain, but only if they were densely coated with poly(ethylene glycol) (PEG). Using these minimally adhesive PEG-coated particles, we estimated that human brain tissue ECS has some pores larger than 200 nm and that more than one-quarter of all pores are ?100 nm. These findings were confirmed in vivo in mice, where 40- and 100-nm, but not 200-nm, nanoparticles spread rapidly within brain tissue, only if densely coated with PEG. Similar results were observed in rat brain tissue with paclitaxel-loaded biodegradable nanoparticles of similar size (85 nm) and surface properties. The ability to achieve brain penetration with larger nanoparticles is expected to allow more uniform, longer-lasting, and effective delivery of drugs within the brain, and may find use in the treatment of brain tumors, stroke, neuroinflammation, and other brain diseases where the blood-brain barrier is compromised or where local delivery strategies are feasible.

Source : http://www.hopkinsmedicine.org/news/media/releases/improved_nanoparticles_deliver_drugs_into_brain

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