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A Microscale mesh that wraps around brain tumours
A flexible mesh to deliver anticancer drugs to the brain after tumour excision.
Lewis Packwood
June 2022
"At the beginning, I was working on finding a solution to improve the therapy for cancer,” says Daniele Di Mascolo1, a researcher at the Italian Institute of Technology in Genoa. “I was working on glioblastoma [GBM], but it's a very aggressive type of cancer with no practical solution for patients.” This form of brain cancer has a very poor prognosis: the survival rate for people with GBM is 18% after two years, and just 5% after five years2.
Daniele Di Mascolo
Entering the fortress
Di Mascolo – together with Paolo Decuzzi, the founding director of the Laboratory of Nanotechnology for Precision Medicine, Anna Lisa Palange and their team – began thinking about ways to overcome the issue of the blood– brain barrier. One way would be to implant the drugs directly into the brain, and they realised that the initial resection of the brain tumour would be the perfect opportunity to do this. “It is an invasive procedure, but it’s already part of the clinical standards,” reasons Di Mascolo. And inserting powerful anticancer drugs directly into the cancerous lesion has other benefits. “To place something in the brain can be tremendously advantageous, because you don’t need too much drug,” he says. “So you are lowering the risk of systemic side effects. With chemotherapy, you are hoping that some of the drugs that you’re injecting can reach the tumour at effective concentrations, but in the meantime, it will affect the normal activity of all the other tissues.”
Different teams have tried to implant drugs directly into the brain before. In the mid-1990s, a thin wafer encrusted with the chemotherapy drug carmustine was developed3, and later put into clinical use. But this device has drawbacks. Its rigid structure can’t perfectly fit the contours of the cancerous lesion, reducing the deployment of the drug deep into the tissue. In addition, the drug is released very quickly, within just a few days, limiting its therapeutic efficacy over the longer term4.
Perfectly conformed
The team’s solution is a device they call μMESH5. This incredibly tiny net is made up of poly(lactic-co-glycolic acid) (PLGA) strands just 3 micrometres wide, forming a grid of 20 micrometre by 20 micrometre square holes. The mesh is supported by a poly(vinyl alcohol) (PVA) layer that quickly dissolves after application. “Being very thin, it can perfectly conform to the application site,” says Di Mascolo. “Other devices developed in the past, they don’t interact with the cells. But the μMESH can interact with the cells, and this interaction can improve the activity of the drug.” In fact, the team found that cells would grow right through the device. “I was kind of amazed when I saw that tumour cells were growing on top of the mesh, and while they were growing, they were pulling in the μMESH,” he says.
To destroy cancer cells, μMESH uses a two-pronged approach. Docetaxel-loaded nanoparticles in the PVA layer act directly on the cells, while diclofenac within the PLGA strands sensitizes the cells to chemotherapy. The drugs in the PVA layer are released quickly, says Di Mascolo, “trying to kill as many tumour cells as possible”, then the remaining drugs are released more slowly over a longer period to prevent the disease resurging. So far, studies of μMESH have been progressing well, with no signs of toxicity. “In some of our in vivo experiments, mice were implanted with the μMESH and monitored for almost one year, and they were just doing fine, without any kind of issues,” says Di Mascolo. Decuzzi details the group’s next steps: “The team is actively working on identifying a lead μMESH configuration, and aim to start a new company that could advance this technology to the clinic, with first-in-human studies expected within the next two to three years.”
“I was kind of amazed when I saw that tumour cells were growing on top of the mesh, and while they were growing, they were pulling in the μMESH.”
Multidisciplinary approach
Di Mascolo started as a biologist working on human genetics, with a focus on degenerative diseases, particularly Alzheimer’s disease. “But I realised that maybe we need something more to try to help people, and I understood that maybe biology alone was not sufficient,” he says, “so I started a PhD in biomedical engineering.” He began working on drug delivery systems, but then moved away from neurodegenerative disease to focus on cancer. He credits his varied scientific background with providing a strong basis for devising new medical applications. “I strongly believe that we need more of that, more combinations of different disciplines,” he says. “You lose a little bit of deep understanding – you cannot be an expert in cell biology, molecular biology, nanofabrication, pharmacology – but it can help you in collecting ideas and proposing new solutions.”
He thinks that having a broader picture of any field is useful when trying to solve a problem, since sometimes a step-by-step approach is not enough. And he reckons the first move for any would-be inventor should be talking with the people who are grappling with the problem on the ground. “Talking with a clinician, for instance, in the biomedical research field should be the first thing [you do] to understand the problems with current treatments,” he says. “And then maybe you can think of something that can be helpful with the things that you know how to do.”
- Interview with Daniele Di Mascolo, May 2022.
- Poon, M.T.C., Sudlow, C.L.M., Figueroa, J.D. et al. Longer-term (≥ 2 years) survival in patients with glioblastoma in population-based studies pre- and post-2005: a systematic review and meta-analysis. Scientific Reports 2020;10:11622.
- Brem, H. et al. Placebo-controlled trial of safety and efficacy of intraoperative controlled delivery by biodegradable polymers of chemotherapy for recurrent gliomas. The Lancet 1995;345:1008–1012.
- Bota, D. A., Desjardins, A., Quinn, J. A., Affronti, M. L. & Friedman, H. S. Interstitial chemotherapy with biodegradable BCNU (Gliadel) wafers in the treatment of malignant gliomas. Therapeutics and Clinical Risk Management 2007;3:707–715.
- Di Mascolo, D. et al. Conformable hierarchically engineered polymeric micromeshes enabling combinatorial therapies in brain tumours. Nature Nanotechnology 2021;16:820–829