Cancer cells get a load of ZIF

A metal organic framework coated with a cancer cell membrane has proved effective at delivering and releasing a cancer immunotherapy drug

Original source: Materials Today

An international team of researchers has found that loading a cancer immunotherapy drug onto a metal organic framework can improve both its delivery and its sustained release for treating leukemia. Furthermore, coating the drug-loaded framework with a cancer cell membrane can improve targeted delivery to solid tumors. These findings, reported in a paper in Science Advances, could lead to safer and more reliable cancer immunotherapies.

“We believe our findings are quite significant because they show that the undesirable side effects of immunotherapy can be modulated by choosing the right delivery vehicle,” says team member Niveen Khashab, a chemist at King Abdullah University of Science and Technology (KAUST) in Saudi Arabia. “They also show that targeted delivery can be realistically established through proper surface functionalization.”

Cancer immunotherapy involves using drugs that modulate the immune system to make it more effective in attacking tumors. Nivolumab is one such drug, which counteracts a strategy that cancer cells employ to evade the immune system. This is based on expressing PD-L1 molecules that deactivate T cells by blocking the PD-1 molecules on their surfaces.

Yet nivolumab, like other ‘immune checkpoint inhibitors’, can cause immune-related adverse effects, where excessive T cell activation leads to an immune response against the recipient’s organs. Scientists are looking for ways to improve the delivery of antibodies like nivolumab so that their release is slow, sustained and targeted, with minimal adverse effects.

Khashab’s group worked with a metal organic framework called zeolitic imidazolate (ZIF-8), a crystalline solid formed of zinc ion subunits attached to organic methylimidazole.

“ZIF-8 nanoparticles have shown great potential in cancer drug delivery in the last few years,” says Somayah Qutub, a PhD student in Khashab’s group. “They are composed of zinc ions and imidazole, which are naturally found in the body.” This makes the biocompatible, biodegradable and highly porous nature of ZIF-8 ideal for the safe loading and delivery of drugs like nivolumab.

Khashab’s team loaded nivolumab onto ZIF-8 and tested its effects on leukemia cells. They found that the antibody was slowly released from the ZIF-8 framework when in proximity to a slightly acidic tumor microenvironment. Once released, the antibody prevents T cells from being deactivated by cancerous cells.

The team also tested the system for delivering the antibody to solid tumors both in Petri dish experiments and in mice. They encapsulated nivolumab-loaded ZIF-8 with the membrane of the cancer cells that were being targeted. This led to the accurate delivery of the antibodies to the tumor, followed by their slow and sustained release. Importantly, the mice showed negligible toxicity from the drug, which significantly inhibited tumor growth and prolonged survival.

“Our next step is to improve this system,” says Qutub. “We are combining immunotherapy drugs with other anti-cancer modalities to have a synergic effect. We are also working on optimizing our cancer cell membrane coating with other materials so that the system can be easily reproducible, scalable and compatible with biopharmaceutical industry standards.”