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Overcoming Refractory Pancreatic Cancer Through Long-Term Starvation Therapy
~ Development of nanomachines enabling enzymes to function stably for extended periods within living organisms ~
A paper titled “Transparent cloaks independent of three-dimensional stability enable starvation therapy for intractable cancers using nanomedicines” was published in Nature Biomedical Engineering (IF 26.6) on November 1 (Japan Standard Time). This research, led by Dr. Junjie Li (formerly an iCONM researcher, now a Specially Appointed Associate Professor at Kyushu University), was conducted in collaboration with Kyushu University, Institute of Science Tokyo, and the University of Tokyo.
https://doi.org/10.1038/s41551-025-01534-1
After intravenous injection, pharmaceuticals travel through the bloodstream to the affected area where they exert their effects. However, a significant portion is eliminated via the kidneys into urine or via the liver into bile, or undergoes chemical structural changes through metabolism, resulting in a limited amount actually reaching the target site. Nanomedicine aims to improve the efficiency of conventional drug therapy by encapsulating drugs within carriers (nanomicelles /nanomachines) measuring tens of nanometers in size. This allows a greater quantity of the drug to be delivered and concentrated at the target site. However, these nanomachines are also recognized as foreign bodies by the body and can be attacked and destroyed by immune cells. Therefore, to keep nanomachines within the body for as long as possible, stealth technology is necessary to evade the body's strict immune surveillance system. For example, stealth coating (invisibility cloak) using polyethylene glycol (PEG) to cover the exterior is widely employed. However, to apply nanomedicine as a “starvation therapy” that depletes nutrients essential for cancer cell growth, it is necessary to develop nanomachines with longer in vivo half-lives. This paper reports on the stealth effect achieved in the block copolymer, a constituent unit of the nanomachine, via an ion-pair network composed of polycation and polyanion. We demonstrated that increasing crosslinking between constituent polyions beyond a specific threshold reduces protein adsorption and macrophage uptake, enabling in vivo circulation with a half-life exceeding 100 hours. Based on this, we attempted to deliver a nanomachine equipped with asparaginase, which degrades L-asparagine essential for cancer cell growth, to cancer tissue by stealthing it with a semi-permeable ion-pair network. The extended half-life in circulation induced sustained asparagine starvation, improving treatment outcomes for metastatic breast and pancreatic cancers. These findings are expected to open new avenues for improving the pharmacokinetics of nanomaterials for therapeutic drug delivery by meticulously designing stable intermolecular structures.
Furthermore, we discovered that the barrier in the tumor microenvironment — a common challenge in pancreatic cancer treatment — becomes structurally loosened by sustained asparagine starvation, enabling immune cell infiltration. This finding has paved the way for combination therapy with immune checkpoint inhibitors.
While the mechanism behind this loosening is currently under investigation, it represents a highly intriguing discovery.
A Behind the Paper feature detailing the story behind this research has been published on Nature's official blog.
From PEG to ion-pair network: the “magic crosslinking” behind a steric stabilization-independent stealth cloak | Research Communities by Springer Nature