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Nasal delivery: a new way to treat brain cancer? Imagine if a nasal spray could deliver a chemotherapy drug directly to a brain tumour. It’s a novel idea that could avoid invasive surgery and traditional chemotherapy for the 1,150 New Zealanders diagnosed with brain tumours each year. Early results from a Neurological Foundation–funded study exploring this approach are showing promising signs. University of Auckland pharmaceutical scientist Dr Manisha Sharma and her research team have been testing a way of packaging a glioblastoma chemotherapy drug into a spray that can be delivered directly to the brain via the nose’s olfactory pathway. Originally planned as a two-year project, COVID disrupted the timeline and stalled momentum. Now, after years of careful, step-by-step testing, the team has published its findings. Manisha cautions that the work is still at a very early stage, but the findings show the drug can be successfully delivered to glioblastoma cell lines, and in mouse models of glioblastoma. The teamwere pleased to demonstrate that in the animal models, the drug accumulated in the tumour but not in other tissues. “My role is to take a drug that already shows promise and package it in a way that it can be delivered safely and effectively to where it’s needed,” Manisha explains. “The challenge with brain tumours is not always the drug itself, but getting enough of it into the brain. The blood– brain barrier blocks most medicines before they ever reach the tumour. “By delivering the drug through the nose, via the olfactory region, we can bypass the blood–brain barrier and take it directly to the brain.” Inside the science Manisha’s research team are part of a multidisciplinary collaboration spanning chemistry, biology and drug delivery. Central to the work is Dr Jiney Jose, a principal investigator and experienced medicinal chemist, and Dr Peter Choi, a drug discovery scientist. Based at the Auckland Cancer Society Research Centre, they both develop tumour-specific therapeutics designed to cross the blood–brain barrier. Working alongside them is Centre for Brain Research Professor Mike Dragunow, who specialises in growing and studying human brain cancer cells in the lab to test how potential treatments behave in real tissue, and Dr Thomas Park, whose team prepared the cell culture work. The first stage of the research focused on drug design and delivery, an area of expertise for Manisha. Her team began by binding an existing chemotherapy drug to a special dye, creating a compound called a drug-dye conjugate. The conjugate has two purposes. It is fluorescent, which helps to show if the drug reaches its target, and its properties help the chemotherapy drug ‘stick’ to tumour cells. Next, the researchers encapsulated this compound inside microscopic carrier particles called micelles. They are tiny – about 100 nanometres in size – making them small enough to travel through the olfactory pathway directly to the brain. “Drugs are released gradually from the micelle over time, rather than all at once, which can improve effectiveness and reduce side effects,” Manisha says. The micelles were then tested on real brain tumour cells, grown in the lab from tissue derived from patients who had undergone glioblastoma surgery. The researchers exposed these cells to the drug, both on its own and packaged inside the micelles. This was a critical step to confirm that delivering the drug encapsulated in micelles does not reduce its effectiveness. “There have been many failed clinical trials for brain tumours, not because the drug didn’t work, but because it couldn’t get to the tumour,” Manisha says. “What we’re trying to do is protect the drug, make it more stable, and ensure a higher concentration actually reaches the brain.” The next step was to test the approach in animal models to see how it behaves in a living system. The team used mice with brain tumours and delivered the formulation through the nose, mimicking how it might be used in people. Because the drug was linked to a fluorescent dye, they could track where it travelled in the body and whether it reached the tumour. They found that the micelle formulation helped concentrate the drug in the brain region, rather than dispersing widely, providing early evidence that the approach could improve targeted delivery. “Amolecule can be very potent, but if you can’t deliver it in the right way, you won’t achieve the effect you need,” says Manisha. “That’s where drug delivery becomes just as important as the drug itself.” While still in its early stages, the next phase will focus on refining the system and testing it further in animal models to better understand how it might translate to human treatment. If successful, the implications could extend well beyond brain cancer. A reliable way to deliver drugs directly to the brain could open new possibilities for treating a wide range of neurological conditions. Manisha says while advances in drug development to treat brain disease are vital, improving how those drugs get into the brain is an area that has received far less attention. “Sometimes we don’t need entirely new drugs, we need better ways of delivering the ones we already have,” Manisha says. “We need to think about howwe support the next steps,” she adds. “That means building the team and continuing this work at a larger scale.” Manisha says she is deeply appreciative of the support provided through the Neurological Foundation’s Small Project Grant, and acknowledges the exceptional efforts of her PhD, masters and summer students. “Their commitment to conducting the experimental work and generating the data used in this study was essential to this research.” “Sometimes we don’t need entirely new drugs, we need better ways of delivering the ones we already have.” Dr Manisha Sharma Dr Manisha Sharma is a pharmaceutical scientist at the University of Auckland. In the lab: Manisha working with Harpinder and Puja. The research team: (left to right) Dr Peter Choi, masters student Puja Timilsina, Manisha, PhD graduate Dr Harpinder Brar and Dr Jiney Jose. 16 Headlines 17 Headlines