|
|
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...
|
|
|
Biological characteristics of polysccharide based contrast agents for cancer diagnostics
Křivánková, Markéta
Despite all the progress made in the treatment of cancer in recent years, it is still necessary to continue with the research of more effective and specific drugs. In recent years, there has been a growing interest in personalized medicine and its application through drug delivery systems, which could help increase the specificity of cancer treatment and subsequently its effectiveness. Drug delivery systems can use different platforms for their design, whether they are liposomes, micelles, nano crystals or others. A very interesting platform for the construction of drug delivery systems are polysaccharides, which were, as carriers of contrast agents in order to effectively display tumours, characterized in this doctoral thesis. But polysaccharides are interesting for more reasons. Both by its availability, and by its biocompatibility and non-toxic character. In this doctoral thesis we deal with two types of polysaccharides conjugates with linked contrast agents for magnetic resonance and fluorescent imaging. The first type of polysaccharide is glycogen, the second is mannan. Both constructs - glycogen and mannan based, were synthesized in a version with and without polymethyloxazolin, which should prolong their circulation in the organism. Both types of polysaccharide conjugates used passive...
|
|
|
Biological characteristics of polysccharide based contrast agents for cancer diagnostics
Křivánková, Markéta ; Jirák, Daniel (advisor) ; Shapoval, Oleksandr (referee) ; Vannucci, Luca Ernesto (referee)
Despite all the progress made in the treatment of cancer in recent years, it is still necessary to continue with the research of more effective and specific drugs. In recent years, there has been a growing interest in personalized medicine and its application through drug delivery systems, which could help increase the specificity of cancer treatment and subsequently its effectiveness. Drug delivery systems can use different platforms for their design, whether they are liposomes, micelles, nano crystals or others. A very interesting platform for the construction of drug delivery systems are polysaccharides, which were, as carriers of contrast agents in order to effectively display tumours, characterized in this doctoral thesis. But polysaccharides are interesting for more reasons. Both by its availability, and by its biocompatibility and non-toxic character. In this doctoral thesis we deal with two types of polysaccharides conjugates with linked contrast agents for magnetic resonance and fluorescent imaging. The first type of polysaccharide is glycogen, the second is mannan. Both constructs - glycogen and mannan based, were synthesized in a version with and without polymethyloxazolin, which should prolong their circulation in the organism. Both types of polysaccharide conjugates used passive...
|
|
|
The preparation and characterization of polymeric, enzymatically cleavable carriers for cancerostatic drugs
Zelený, Jan ; Etrych, Tomáš (advisor) ; Ječmen, Tomáš (referee)
As the development of cancerostatic drugs progresses it is becoming necessary to contemplate the question of how to deliver these drugs, which themselves tend to exhibit carcinogenic properties, effectively and accurately to the affected tissues and thus to circumvent their destructive effects upon the healthy parts of the organism. One approach to delivering drugs selectively to cancerous tissues is to make use of some of the specific properties which these tissues tend to possess, one of which being the so-called enhanced permeability and retention effect (EPR effect). This effect, which will be further discussed within this thesis, allows for macromolecules that are too massive to pass from the bloodstream into healthy tissue, to exit the blood vessels of cancerous tissue and to accumulate there. Therefore, a drug molecule can specifically enter cancerous tissue along with a suitable macromolecule, to which it is conveniently attached. If, moreover, the given drug is connected to the carrier molecule via an enzymatically cleavable spacer, it is possible to make use of lysosomal proteases (such as cathepsin B, which is overexpressed in some cancer cells) in order to attain its detachment from the carrier molecule and its subsequent activation. This bachelor thesis focuses on describing the...
|
|
|
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...
|
|
|
Enzyme-triggered polymer probes for fluorescence-guided surgery of solid tumors
Horáková, Lenka ; Etrych, Tomáš (advisor) ; Kaňa, Martin (referee)
This work is focused on the synthesis of macromolecular hydrophilic polymer conjugates with fluorophores for visualization of solid tumors. These polymer probes were designed for their utilization within the image-guided endoscopic surgery, where the boundaries of the tumor tissue would be fluorescently marked after i.v. administration. Polymer carriers should provide prolonged circulation of the probe in the body and the transport of the fluorescent dye into the desired place. Polymer probes based on N-(2-hydroxypropyl)methacrylamide (HPMA) copolymers prepared by radical copolymerization containing fluorescent dye cyanine7-NH2 (Cy7- NH2) were synthetized and evaluated. The dye was conjugated to the carrier via an enzymatically cleavable peptide linker, specifically Gly-Phe-Leu-Gly and Val-Cit-4-aminobenzylalcohol. The enzymatic hydrolysis of these polymer conjugates was studied using a model lysosomal enzyme cathepsin B. In vitro study was carried out using hypopharyngeal cancer cell line FaDu, in which the internalization of the probes into cells and accumulation in cell compartments was evaluated by the fluorescent confocal microscopy. Key words: nanomaterials, polymer probes, fluorescence, EPR effect [IN CZECH]
|
|
|
The preparation and characterization of polymeric, enzymatically cleavable carriers for cancerostatic drugs
Zelený, Jan ; Etrych, Tomáš (advisor) ; Ječmen, Tomáš (referee)
As the development of cancerostatic drugs progresses it is becoming necessary to contemplate the question of how to deliver these drugs, which themselves tend to exhibit carcinogenic properties, effectively and accurately to the affected tissues and thus to circumvent their destructive effects upon the healthy parts of the organism. One approach to delivering drugs selectively to cancerous tissues is to make use of some of the specific properties which these tissues tend to possess, one of which being the so-called enhanced permeability and retention effect (EPR effect). This effect, which will be further discussed within this thesis, allows for macromolecules that are too massive to pass from the bloodstream into healthy tissue, to exit the blood vessels of cancerous tissue and to accumulate there. Therefore, a drug molecule can specifically enter cancerous tissue along with a suitable macromolecule, to which it is conveniently attached. If, moreover, the given drug is connected to the carrier molecule via an enzymatically cleavable spacer, it is possible to make use of lysosomal proteases (such as cathepsin B, which is overexpressed in some cancer cells) in order to attain its detachment from the carrier molecule and its subsequent activation. This bachelor thesis focuses on describing the...
|
|
|
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...
|
|
|
Star polymeric carriers of drugs for targeting and pH-dependent release of drugs
Bittner, Matyáš ; Stiborová, Marie (advisor) ; Liberda, Jiří (referee)
This diploma thesis brings new data about design, synthesis, physico-chemical characterisation and biological efficacy of the novel star-like HPMA-based conjugates intended for treatment of solid tumors. Recently, many different water-soluble drug delivery systems based on N-(2- hydroxypropyl)methacrylamide (HPMA) copolymers have been described. Here, we report synthesis and physico-chemical characterisation of high molecular weight star-like HPMA- based polymer carriers with low polydispersity prepared by controlled grafting of HPMA copolymers onto PAMAM dendrimer core. With the aim to keep the polydispersity of drug delivery system as low as possible, reversible Addition-Fragmentation Chain Transfer (RAFT) polymerisation was used for HPMA-based polymer precursor preparation. The end groups of the polymer presursors was afterwards used for grafting using carbodidimide condensation reaction or copper free click chemistry on polyamidoamine (PAMAM) dendrimers resulting in a formation of star-like high-molecular-weight (HMW) drug carriers. Described synthetic procedure provided preparation of star-like HMW drug carriers with Mw between 1.105 - 3.105 g/mol and narrow distribution of Mw. The model drug, doxorubicin (Dox), was attached to the hydrazide group containing polymer cariers by pH- sensitive...
|
guest ::
