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Entrapment of Hypoxic Cancer by Macrophages Loaded with HAP

Periodic Reporting for period 2 - McHAP (Entrapment of Hypoxic Cancer by Macrophages Loaded with HAP)

Reporting period: 2018-07-01 to 2019-12-31

The project aim is two-fold: 1) to develop innovative cell-based drug delivery system to solid tumors and in particular to their hypoxic sites and 2) to identify molecular basis of a newly discovered phenomenon of iron binding-protein transfer from macrophage to cancer cells.

According to the statistics every second person will be diagnosed with cancer during their lifetime. One out of every four will die because of this disease. Despite enormous knowledge improvement, the prognosis in cases with advanced tumours is still unsatisfactory. Firstly, only 1-2% of the administered drug is delivered to the solid tumour, while the rest goes to other tissues causing side effects. These 1-2% reaches predominantly well vascularized regions and therefore, solid tumours initially often respond well to conventional anti-cancer therapy decreasing the tumour mass. However, subsequent regrowth or metastasis after radio- or chemotherapy remains a serious problem in clinical oncology due to difficulties in penetration of the anticancer drug to the most hypoxic areas where cancer cells may remain. Moreover, chemotherapy or radiotherapy may cause additional formation of large hypoxic areas, making the treatment of tumour regrowth even more difficult. The fact that the efficacy of anticancer therapy is limited by the presence of hypoxic tumour cells has led to the introduction of a variety of therapeutic approaches aimed at elimination of these hypoxic areas. Therefore, improving drug delivery to hypoxic regions might be a ground breaking strategy in oncology. A key consequence of hypoxia is an increase in infiltration of macrophages, which undergo polarization toward tumour associated macrophages (TAMs) with M2 phenotype and paradoxically actively facilitate tumour development and spread to distant sites. Because macrophages are continuously recruited into the tumour mass and actively migrate to avascular and hypoxic regions, they represent attractive vehicles to deliver genes or other particles into the tumour.

The general objective of the project is to investigate novel macrophages-based delivery system of anticancer drugs encapsulated in ferritin cages into the hypoxic tumor areas and to investigate the underlying molecular mechanisms. Macrophages are physiologically attracted by the tumour, then they have ability to migrate from blood vessels and infiltrate avascular and hypoxic areas. Therefore they might constitute a unique delivery system of drug containing particles to the hypoxic parts of the tumour. Caged architecture of ferritin allows for efficient drug encapsulation. Macrophages are able to specifically and actively transfer ferritins (loaded with component of choice) to cancer cells. 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. The final effect will be the novel and effective macrophage-based delivery system of ferritin encapsulated HAP that will constitute a starting point to development of a novel treatment strategy.
From the beginning of the project we have focused on the Task 1 (1.1) Task 2 (2.1 and 2.2) Task 3 (3.1 and 3.2) with the good results because these Tasks have been almost completed or the significant improvement has been achieved. We have identified mechanisms by which macrophages take up ferritins and we are close to identification of the mechanism of ferritin transfer from macrophage to cancer cell. This transfer is sufficient enough to kill cancer cells by the drug loaded inside ferritin cavity.

We have showed that macrophages actively migrate to the tumor lung metastases and reach tumor that are unreachable for other tumor options. We have also showed that the macrophage-ferritin therapy is safe for the animal.
Results of this project is to identify molecular basis of the newly discovered phenomenon (TRAIN) that has not been described before. Therefore these results constitute novel and original input into the basic science in the field of cancer immunology and immunotherapy.

Results of this project are important for development of innovative cell-based drug delivery system to solid tumours and especially their hypoxic sites located far away from blood vessels. This therapy may constitute a ground-breaking approach for targeting solid tumours.

Goals of the project are reached in accordance to the envisioned time-frames.