Out of all cancers, glioblastoma is one of the worst. It’s the most frequent and aggressive of all brain tumours and there is no cure. Patients often have to undergo surgery, chemotherapy and radiotherapy for a less than 10 % chance of making it 5 years post-diagnosis.
Researchers working to discover a long sought-after treatment have been hitting a wall both conceptually and literally. As Paolo Decuzzi, senior researcher and professor at the Italian Institute of Technology, explains: “The main issue with glioblastoma is that it is ‘protected’ by the most impermeable biological barrier – the blood brain barrier. Potent chemotherapeutic agents, oligonucleotides for targeted therapy, antibodies for immunotherapies and conventional nanomedicines have a hard time crossing this barrier. Even in the rare cases when they succeed, the therapeutic molecules do not bio-distribute evenly within the tumour cells and leave residual malignant cells in the brain that reactivate within a few months after surgery.”
Decuzzi believes the solution may lie in a new generation of implantable drug delivery systems. Under the EU-funded POTENT project that was supported by the European Research Council (ERC), he developed mMESH, a delivery system that can be compartmentalised to welcome different therapeutic agents such as small drug molecules, peptides, antibodies, RNAs and nanomedicines.
A smart delivery system
Unlike existing implantable wafers, which are too rigid to adapt to the tumour’s surface, mMESH is made of a microscopic grid (mesh) of polymeric strains that can readily conform to biological surfaces with complex geometries. This greatly facilitates interaction between the drug delivery system and surrounding malignant tissue, ensuring a uniform distribution of the therapeutic agents in the process.
“Our solution is better than injectable gels, too,” Decuzzi remarks. “These gels fill up the entire resected cavity and often bring excessive doses of drugs to the brain, leading to neurotoxic effects. By comparison, mMESH releases the right concentrations of drugs, limits itself to tumour margins and propels the drugs deeper into the malignant tissue.”
What’s really interesting about mMESH is the drug compartments operate in a well-defined sequence. The first compartment dissolves within several hours to a few days and releases the most potent chemotherapeutic agents. The second compartment follows with molecules that enhance chemotherapy released over several weeks or months. As Decuzzi notes: “The type of therapeutic agent and its release rate can be fine-tuned during the fabrication process and tailored to the specific needs of the patient. The use of complex combination therapies is particularly important in glioblastoma which is characterised by its biological heterogeneity in both space and time.”
mMESH is also made of small amounts of biodegradable polymers, which means that it will dissolve completely without inducing any significant neurotoxicity. Preclinical models already show massive survival rate improvements compared to current clinical standards.
The project was completed in 2020, but Decuzzi has been actively optimising and developing further applications for mMESH. “We are testing different therapeutic agents to deliver antibodies for immunotherapies and cocktails of RNA molecules to improve even further the selectivity and efficacy of the treatment. We are also conducting a number of mechanical characterisations. The idea is to improve the stability and ability of the mMESH to conform to complex surgical surfaces and deliver drugs even deeper into the diseased tissue. Finally, we are involved in different ‘biotechnology accelerators’ to help launch a company that could attract investors, private/public foundations and patients’ associations to further support the preclinical development and clinical integration of our drug delivery technology.” If all goes according to plan, clinical testing could start within 2 to 4 years.