Scientists from Nanyang Technological University, Singapore (NTU Singapore) have developed microscopic peptide droplets that deliver large amounts of gene-silencing molecules into cancer and immune cells, reducing the growth of hard-to-treat colorectal tumours by about 67 per cent in mice.
The patent-pending system uses small interfering RNA, or siRNA, to disrupt the production of two proteins that cancer cells exploit to evade attacks by the immune system.
In the animal study, the combined siRNA treatment suppressed tumour growth to a level comparable with a combination of anti-PD-1 and anti-PD-L1 antibody treatments used as a benchmark.
The researchers estimate that an siRNA-based approach could potentially cost five to 10 times less to produce than monoclonal antibody treatments if successfully developed and scaled up.
Published in the peer-reviewed scientific journal Biomaterials, the study was led by Professor Ali Miserez, from NTU's School of Materials Science and Engineering (MSE) and School of Biological Sciences (SBS), in collaboration with Assistant Professor Bertrand Czarny, who holds a joint position at MSE and the NTU Lee Kong Chian School of Medicine.
Stopping cancer cells from giving a false "handshake"
Their unique approach targets two proteins called PD-1 and PD-L1. PD-1 sits on the surface of T cells, which are immune cells that can recognise and kill abnormal cells. Whereas PD-L1 is displayed by tumour cells to trick T cells into a 'false handshake'.
When PD-1 and PD-L1 meet and bind, it sends a stop signal to the T cell, telling it to hold back its attack, thus allowing cancer cells to exploit this natural immune checkpoint to protect themselves.
Existing checkpoint immunotherapies use monoclonal antibodies to block this interaction from outside the cells.
The NTU approach goes one step further by reducing the amount of PD-1 and PD-L1 that the cells make in the first place, thus lowering their chances of interaction.
Cells typically make proteins by reading working genetic instructions carried by messenger RNA. The researchers used siRNA to recognise and destroy the specific instructions used to make PD-1 or PD-L1.
Prof Miserez, senior author of the study, explained: "Our approach works from inside both types of cells. The siRNA destroys the instructions they need to make these proteins. It is a little like throwing a spanner into a production line, except the disruption is targeted at the recipe for PD-1 or PD-L1.
"What is important about our microdroplets is that they can carry large amounts of siRNA into the cells where it needs to act. By targeting both sides of this handshake at the same time, we can help the immune cells attack the tumour more effectively."
Two droplets, each with a different target
The researchers used two separate peptide microdroplet formulations together as a combination therapy.
