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FRIMEDBIO-Fri prosj.st. med.,helse,biol

From evading to embracing immune cells – Development of neutrophil-targeted anti-cancer nanomedicine

Alternative title: Utnytte immunceller - Utvikling av nøytrofil-rettet anti-kreft nanomedisin

Awarded: NOK 8.0 mill.

Project Number:

314984

Project Period:

2021 - 2024

Nanomedicines are nanoparticles containing drugs and these agents have extensively been studied for anti-cancer therapy during the last decades. The rationale for using nanomedicines to treat cancer is that the nanoparticles can deliver higher concentrations of the drug to tumors as compared to conventional drugs. Although this has been demonstrated to work in some cases, the immune system represents a major hurdle for nanoparticles on their way to tumors. The immune system has evolved to, amongst others, recognize and neutralize non-endogenous particles, such as viruses, bacteria, and nanoparticles. The development of strategies to reduce nanoparticle recognition by the immune system, and thereby increase the amount of administered particles reaching tumors, is one of the main activities in the field. Although successful to some extent, it is well established that immune cells still take up the majority of administered nanoparticles. Interestingly, enabled by increasing understanding of immune cell functions in cancer, immunotherapy has become an important tool in the clinic for cancer treatment. Since nanoparticles are extensively taken up by certain immune cells, nanoparticles are recognized as potentially useful tools to deliver immunotherapeutic drugs to these immune cells in cancer patients. In this project we aim to develop nanoparticles (liposomes, lipidic vesicles) that are taken up by specific types of immune cells (neutrophils) that play detrimental roles in cancer. We have now made liposomes that are taken up to a high extent by these immune cells. We have characterised an enzyme (Arginase 1) in our breast cancer mouse model that is known to contribute to cancer development. We found that it is expressed in high levels by immune cells that take up nanoparticles. We have made nanoparticles with Arginase 1 inhibitor and are testing these now for therapeutic effects. In addition to Arginase 1, we are also targeting so-called 'neutrophil extracellular traps' or NETs. NETs are pieces of DNA secreted by neutrophils. NETs contribute to tumor growth and metastasis and are thus important therapeutic targets related to neutrophils. NETs also cause thrombosis, which many breast cancer patients suffer from. We have found and tested several NET inhibitors in vitro, which we are now encapsulating in nanoparticles, which we also will test for therapeutic effects. During the coming year, we will find out whether our drug loaded nanoparticles improve therapeutic effects in our mouse model of breast cancer. If this is the case, this project will result in nanomedicine targeting specific immune cells that could improve cancer treatment.

In spite of astonishing preclinical cancer cures and the approval of multiple formulations, nanomedicine’s impact on cancer patient care remains limited in the light of the multi-billion global research and development effort in the field. A central problem is rapid nanoparticle recognition and clearance by phagocytic immune cells upon systemic administration. It is becoming increasingly evident that nanomedicine's unsatisfactory clinical exploitation may be tackled by utilizing these extensive interactions with the immune system. At the same time, neutrophils (phagocytic immune cells) are increasingly understood to be important immunomodulators in cancer, however no neutrophil targeted anti-cancer immunotherapeutics exist. Here we propose to utilize the extensive nanoparticle interactions with phagocytic neutrophils in the development of novel, neutrophil-targeted anti-cancer nanotherapies. We will optimize the neutrophil specificity of our liposomal drugs and assess their therapeutic effects in stand-alone fashion, as well as in combination with a mouse version of approved immunotherapy in immunocompetent mouse models of breast cancer. To gain a mechanistic understanding for potential therapeutic effects, we will assess liposome biodistribution and tumor and metastasis development using advanced in vivo imaging methodology in combination with highly complementary and state-of-the-art in vivo/ex vivo immune response and cell profiling methodology. If completed succesfully, this project will result in neutrophil-targeted nanomedicine able to enhance anti-cancer immune responses in immunotherapeutic regimens in mice. We have already developed liposomes with high neutrophil affinity, which may be sufficient to achieve certain therapeutic effects. However, to explore nanomedicine's potential in the development of neutrophil-targeted therapies in and beyond the scope of the current proposal, we also aim to increase neutrophil specificity.

Funding scheme:

FRIMEDBIO-Fri prosj.st. med.,helse,biol

Funding Sources