Feb 15 2021
A cancer immunotherapy drug loaded onto a metal-organic framework exhibits improved delivery as well as a steady release for treating leukemia.
The team loaded nivolumab, a cancer immunotherapy drug, onto a ZIF metal-organic framework composed of zinc ion subunits attached to organic methylimidazole (MIM), and encapsulated it within a membrane of the target cancer cells. Image Credit: © 2021 KAUST; Heno Hwang.
When the drug-loaded framework is coated with a cancer cell membrane, the targeted delivery to solid tumors is enhanced. Such outcomes could result in more reliable and safer 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. They also show that targeted delivery can be realistically established through proper surface functionalization.
Niveen Khashab, Chemist, King Abdullah University of Science and Technology
In cancer immunotherapy, drugs that alter the immune system to make it more efficient in attacking tumors are used. Nivolumab is such a drug and counteracts a cancer immune evasion approach that includes the expression of PD-L1 molecules that deactivate T cells by inhibiting the PD-1 molecules on their surfaces.
But similar to other 'immune checkpoint inhibitors,' nivolumab can lead to immune-related detrimental impacts, where too much T cell activation causes an immune response against the organs of the recipient. Researchers are looking for methods to enhance the delivery of antibodies such as nivolumab so that their release is gradual, persistent and targeted, with the least adverse impacts.
Khashab’s team collaborated with a metal-organic framework known as zeolitic imidazolate (ZIF-8), which is a crystalline solid made of zinc ion subunits fixed to organic methylimidazole.
ZIF-8 nanoparticles have shown great potential in cancer drug delivery in the last few years. They are composed of zinc ions and imidazole, which are naturally found in the body.
Somayah Qutub, PhD Student in Khashab’s Group, King Abdullah University of Science and Technology
This renders the biodegradable, biocompatible, and highly porous nature of ZIF-8 perfect for the secure loading and delivery of drugs such as nivolumab.
Khashab and her team loaded nivolumab onto ZIF-8 and investigated its impacts on leukemia cells. They identified that the antibody was gradually released from the ZIF-8 framework when it was close to a slightly acidic tumor microenvironment.
This process helps avoid the T cells from being deactivated by cancerous cells so that they can attack the leukemia cells.
The team tested the system for providing the antibody to solid tumors both in mice and in Petri dish experiments. They encapsulated ZIF-8 loaded with nivolumab together with the membrane of the targeted cancer cells.
This resulted in the precise delivery of the system to the tumor, and then the gradual and persistent release of the drug. Most significantly, the mice exhibited negligible toxicity from the drug, which considerably suppressed the growth of tumors and extended survival.
Our next step is to improve this system. 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.
Somayah Qutub, PhD Student in Khashab’s Group, King Abdullah University of Science and Technology
Journal Reference:
Alsaiari, S. K., et al. (2021) Sustained and targeted delivery of checkpoint inhibitors by metal-organic frameworks for cancer immunotherapy. Science Advances. doi.org/10.1126/sciadv.abe7174.