Ispitivanje antitumorskog delovanja 6-[trifenilstanil]-1-heksanola vezanog za mezoporozni nanomaterijal SBA-15 u modelu mišjeg melanoma in vitro i in vivo
Evaluation of antitumor activity of 6-(triphenylstannyl)hexan-1-ol loaded in SBA-15 mesoporous nanostructured material in the mouse model of melanoma in vitro and in vivo
Doctoral thesis (Published version)
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Despite rapid development in immunotherapy and targeted therapies, the global incidence of melanoma continues to increase. Besides, conventional chemotherapy demonstrates only limited efficacy in the treatment of advanced melanoma. Clinical application of widely used chemotherapeutic drug cisplatin, is hampered by the intrinsic resistance of this type of tumor, indicating the urgent need for the development of more effective chemotherapies for melanoma. The rapid progress in medicinal organometallic chemistry in the past few years allows rational design of novel platinum compounds, as well as nonplatinum metal-based antitumor agents, including organotin compounds, whose activity is not based on unrepairable interaction with DNA. Poor solubility and toxicity of organotin compounds, however, restrains more complex studies and further development in the preclinical and subsequently clinical setting. Nanotechnology now becomes an important part of pharmaceutical research and development, for improving the solubility and selective toxicity of cancer therapeutics. Encapsulating hydrophobic antitumor agents in ordered mesoporous silica nanomaterials is an emerging strategy to enhance drug dissolution. Due to its high drug loading capacity, SBA-15 is the most interesting mesoporous silicate for targeted drug delivery. Antitumor potential of organotin(IV) compound [Ph3Sn(CH2)6OH] grafted on nanostructured material SBA-15 (SBA-15pSn) in vitro and in vivo in the mouse model of melanoma, was tested for the first time in this study. Considering the enormous heterogeneity of this type of tumor, it was of interest to test these experimental therapeutics in a highly invasive human A375 melanoma cell line. Given the fact that SBA-15pSn nanoparticles are relatively large, the mechanism of cellular uptake was defined. At the molecular level, main intracellular events triggered by the treatment, as well as the expression of key signaling pathways mediating tumor cell response, were analyzed...
Keywords:Melanoma; Chemotherapy; Targeted drug delivery; Mesoporous silica; Organotin compounds; Differentiation; Cellular senescence
Source:University of Belgrade, Faculty of Biology, 2015, 1-122
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