The proposed project seeks to open a new research front within the field of drug delivery to the solid tumours. Unsatisfactory response of tumours to chemotherapy is mainly related to impaired diffusion of the anticancer drug because of decreased drug uptake due to poor vasculature. Moreover, the drug is not able to penetrate the most hypoxic sites. Cells from these ‘untreated’ sites are responsible for relapse and metastasis. However, these avascular regions attract macrophages that migrate even to areas far away from blood vessels. Therefore, they might constitute a unique delivery system of drug containing particles to these parts of the tumour mass. A promising example of such particles that could be used are ferritins, whose caged architecture allows for efficient drug encapsulation and whose uptake from macrophage cells has been well demonstrated. My recent ground breaking finding was that macrophages are also able to specifically and actively transfer these taken up ferritins (loaded with the compound of choice) to cancer cells. Thus, these preliminary results indicate the possibility to use macrophages to deliver ferritin encapsulated compounds directly to the tumour cells even in its hypoxic areas. Then, the use of hypoxia-activated prodrugs (HAP) which are selectively activated only in hypoxic regions will be exploited in order to make cancer therapy safer. However, the molecular mechanism of ferritin uptake by macrophages, their storage, and transport to the cancer cells represent key issues to be investigated and pave the way to the experimental design of the present project. In the present project, we will develop and characterize a completely new and modern approach to anticancer therapy and drug delivery. As such we expect to be able to precisely administer drugs to the tumour site (even to the hypoxic regions) where it is activated by tumour-specific conditions, avoiding side effects of anticancer therapy.

Macrophage therapy is promising for solid tumor treatment as these cells are continuously recruited into the tumor mass, even the most hypoxic regions. Our pioneering research demonstrated that macrophages are able to take up ferritins loaded with anti-cancer drugs, creating Macrophage-Drug Conjugates (MDCs), and transfer these to cancer cells and kill them, a phenomenon we named TRAIN. In my ongoing ERC Starting Grant PROJECT ‘McHAP’, we have proven that MDCs can be sucessfully used not only to treat solid tumors but also to induce subsequent resistance to the tumor re-challenge. Acquisition of resistance to tumor development after specific therapy is a 'Golden Grail' in oncology. Now we aim to turn the MDC technology into a commercial and social value proposition by confirming mechanisms of tumor-resistance in tumor-bearing mice and identify immune response. This is crucial to raise interest of and establish a co-development (or licensing) deal with big pharma’s to realize commercialization and clinical uptake of our IP-protected MDC technology. During the ERC PoC project, we will perform high-dimensional spectral flow cytometry, spatial transcriptomics and single-cell transcriptomics of the tumor before and after MDC treatment to identify mechanisms of tumor-resistance and optimize our business case. This project will thus provide proof of concept for the immune activation after the MDC treatment and thus establish the viability, feasibility, commercialization and overall direction for our innovative MDC technology. This project will substantially contribute to bring our MDC technology to the market and clinical practice.

New therapeutic approaches have led to significant improvements in cancer treatment, but none have been able to overcome the limited efficacy of solid tumor treatment due to poor tumor delivery and the presence of hypoxic tumor cells. Macrophages represent a promising vesicle to deliver cancer therapeutics to solid tumors as they are continuously recruited into the tumor mass, even the most hypoxic regions. Our pioneering research demonstrated that macrophages are able to take up ferritins loaded with anti-cancer drugs, creating Macrophage-Drug Conjugates (MDCs), and transfer these to cancer cells and kill them, a phenomenon we named TRAIN. In my ongoing ERC STARTING GRANT PROJECT ‘MCHAP’, we have proven that MDCs can be used as a ‘Trojan horse’ to efficiently deliver drugs directly to the cancer cells via TRAIN. Now we aim to turn the MDC technology into a COMMERCIAL and SOCIAL VALUE PROPOSITION by confirming our findings in a PDX model, which is crucial to raise interest of and establish a co-development (or licensing) deal with big pharma’s to realize commercialization and clinical uptake of our IP-protected MDC technology. During the ERC PoC project, we determine the optimal efficacy of MDC delivery, examine the concentration of the drug delivered to the tumor and other organs, validate the efficacy of MDC delivery in PDX mice after MDC treatment,and optimize our business case. This project will thus provide PROOF OF CONCEPT for the efficacy and pharmacokinetics of, and establish the viability, feasibility, commercialization and overall direction for our innovative MDC technology. This project will substantially contribute to bring our MDC technology to the market and in clinical practice, where our MDC technology has the promising potential to improve prognosis of cancer patients, improve the performance of anti-cancer drugs, and reduce healthcare costs. THE NEW, INNOVATIVE MDC TECHNOLOGY CAN THUS REALIZE SIGNIFICANT BENEFITS FOR OUR SOCIETY AND OUR ECONOMY.