Johns Hopkins team uses improved nanoparticles to deliver drugs into brain
Next step is to see if they can slow tumour growth
The brain is a notoriously difficult organ to treat, but Johns Hopkins University researchers in the US report that they are a 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.
The scientists have designed nanoparticles that can safely and predictably infiltrate deep into the brain when tested in rodent and human tissue.
Their research is published online in Science Translational Medicine.
‘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, Lewis J Ort Professor of Ophthalmology, and director of the Johns Hopkins Center for Nanomedicine.
After surgery to remove a brain tumour, 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 tumour recurrence is only moderately successful, in part, because it is hard to administer a dose of chemotherapy high enough to penetrate the tissue sufficiently to be effective and low enough to be safe for the patient and healthy tissue.
To overcome this challenge, the Johns Hopkins team designed nanoparticles 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. Charles Eberhart, a Johns Hopkins pathologist and contributor to this work, says these nanoparticles historically have not worked very well because they stick to cells at the application site and do not migrate deeper into the tissue.
Elizabeth Nance, a graduate student in chemical and biomolecular engineering at Johns Hopkins, and Johns Hopkins neurosurgeon Graeme Woodworth, 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 PEG (poly(ethylene glycol) molecule that had been shown by others to protect nanoparticles from the body’s defence mechanisms. The team reasoned that a dense layer of PEG might also make the beads more slippery.
The researchers then injected the coated beads into slices of rodent and human brain tissue. They first labelled the beads with glowing tags that enabled them to be seen as they moved through the tissue. Compared with non-PEG-coated beads, or beads with a less dense coating, they found that a dense coating of PEG allowed larger beads to penetrate the tissue, even 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 later 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 tumour growth or recurrence in rodents.’
Woodworth added that the team also wants to optimise the particles and pair them with drugs to treat other brain diseases, such as multiple sclerosis, stroke, traumatic brain injury, Alzheimer’s and Parkinson’s. Another goal is to be able to administer their nanoparticles intravenously.