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Immunomodulatory effect of tumor targeted polymer drugs
Mervartová, Ivana ; Šírová, Milada (advisor) ; Palich Fučíková, Jitka (referee)
5 Abstract Myeloid-derived suppressor cells (MDSC) are a very heterogeneous population of immature, activated myeloid progenitors of neutrophils, monocytes/macrophages and dendritic cells that have not differentiated into mature forms. A common feature of these cells is the ability to suppress immune responses of T cells, NK cells, and dendritic cells. It is known that MDSC accumulate under various pathological conditions, such as chronic inflammation or cancer. In breast cancer patients, the highest MDSC counts correlate with the occurrence of metastatic foci in lung tissue. The suppressive effects of MDSCs are associated with resistance to chemotherapy, reduced effectiveness of immunotherapy and overall poor prognosis of the disease. Therefore, many studies focus on MDSC. One possibility is the differentiation of MDSC into mature populations that lose their suppressive phenotype. In this work, we focused on modulation of MDSC activity by all-trans retinoic acid (ATRA), bound to a polymer conjugate based on N-(2-hydroxypropyl)methacrylamide (HPMA). ATRA is used in clinical practice for the treatment of acute promyelocytic leukemia, where the mechanism of action is the differentiation of pathological cells into more mature forms and thus the cessation of their proliferation. The binding of ATRA to the...
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Possible applications of polymeric nitric oxide donors in treatment of murine experimental tumors
Horková, Veronika ; Šírová, Milada (advisor) ; Krulová, Magdaléna (referee)
Polymer-based drug delivery systems represent one of the promising strategies for successful tumor treatment. Conjugation of a low-molecular-weight drug to a syn- thetic polymer carrier enables targeted drug delivery to tumor tissue/cells and limited systemic toxicity of the drug. The conjugates show extended circulation time, and preferentially accumulate in tumor tissue due to the Enhanced Permeability and Re- tention (EPR) effect. The EPR effect depends on a structural anomaly in tumor neovasculature, and vasodilators were shown to enhance the EPR effect via an in- crease of blood supply in the tumor. Polymer drug carriers based on water-soluble N-(2-hydroxypropyl)methacrylamide (HPMA) benefit from variable architecture, drug loading and controlled release. HPMA-based conjugates with cancerostatics have al- ready proved high anti-tumor activity, inducing complete tumor regression followed by resistance to a second tumor challenge in experimental murine models. Three HPMA-based conjugates with organic nitrates (labeled 1, 2, and 3) were pre- pared as polymer donors of nitric oxide (NO) with the aim to intensify the EPR effect, thereby enhancing accumulation of co-administered macromolecular cancerostatics in the tumor. In this study, the conjugates were non-toxic to cancer cells and did not potentiate...
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Possible applications of polymeric nitric oxide donors in treatment of murine experimental tumors
Horková, Veronika ; Šírová, Milada (advisor) ; Krulová, Magdaléna (referee)
Polymer-based drug delivery systems represent one of the promising strategies for successful tumor treatment. Conjugation of a low-molecular-weight drug to a syn- thetic polymer carrier enables targeted drug delivery to tumor tissue/cells and limited systemic toxicity of the drug. The conjugates show extended circulation time, and preferentially accumulate in tumor tissue due to the Enhanced Permeability and Re- tention (EPR) effect. The EPR effect depends on a structural anomaly in tumor neovasculature, and vasodilators were shown to enhance the EPR effect via an in- crease of blood supply in the tumor. Polymer drug carriers based on water-soluble N-(2-hydroxypropyl)methacrylamide (HPMA) benefit from variable architecture, drug loading and controlled release. HPMA-based conjugates with cancerostatics have al- ready proved high anti-tumor activity, inducing complete tumor regression followed by resistance to a second tumor challenge in experimental murine models. Three HPMA-based conjugates with organic nitrates (labeled 1, 2, and 3) were pre- pared as polymer donors of nitric oxide (NO) with the aim to intensify the EPR effect, thereby enhancing accumulation of co-administered macromolecular cancerostatics in the tumor. In this study, the conjugates were non-toxic to cancer cells and did not potentiate...
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