Piccolo, Marialuisa (2017) Preclinical development of anticancer Ru-based nanoaggregates in breast cancer models. [Tesi di dottorato]

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Tipologia del documento:	Tesi di dottorato
Lingua:	English
Titolo:	Preclinical development of anticancer Ru-based nanoaggregates in breast cancer models
Autori:	Autore Email Piccolo, Marialuisa marialuisa.piccolo@unina.it
Data:	7 Dicembre 2017
Numero di pagine:	138
Istituzione:	Università degli Studi di Napoli Federico II
Dipartimento:	dep05
Dottorato:	phd071
Ciclo di dottorato:	30
Coordinatore del Corso di dottorato:	nome email D'Auria, Maria Valeria madauria@unina.it
Tutor:	nome email Irace, Carlo [non definito]
Data:	7 Dicembre 2017
Numero di pagine:	138
Parole chiave:	Breast cancer ruthenium complexes anticancer therapy
Settori scientifico-disciplinari del MIUR:	Area 05 - Scienze biologiche > BIO/10 - Biochimica
Depositato il:	19 Dic 2017 12:48
Ultima modifica:	10 Apr 2019 10:42
URI:	http://www.fedoa.unina.it/id/eprint/12067

Abstract

Cancer, a growing health problem around the world, affects millions of people every year, so that innovative anticancer drugs with specific molecular mechanisms of action are essential in chemotherapeutic treatment to kill specific cancer types, and to overcome toxic side effects as well as chemoresistance. Impaired apoptosis and autophagy seem to play a central role in cancer development and constantly limit the efficacy of conventional cytotoxic therapies. Indeed, current research efforts are focused on a deeper understanding of the cellular response and/or resistance to anticancer treatments, including the role of cell death pathways activation by metallochemotherapeutics such as novel ruthenium-based drugs, proposed as safe and effective potential drugs. Moreover, in the last few years nanostructures have gained considerable interest for the safe delivery of therapeutic agents. In these fields, we have recently developed a novel approach for the in vivo delivery of novel Ru(III) complexes, preparing stable nucleolipidic-based formulations endowed with considerable antiproliferative activity. In particular, aiming at improving the suitability of Ru(III) complexes in biological environment - specifically of AziRu, a pyridine NAMI-A analog - as well as their advantages for biomedical applications, we have designed innovative nanoaggregates by means of high-functionalized nucleolipidic Ru(III) complexes, ad hoc mixed with zwitterionic or cationic lipids to provide stable and biocompatible liposome formulations for cancer therapy. Hence, in line with this project and by in vitro bioscreens in the frame of preclinical studies, we have focused on the ability of nucleolipidic ruthenium-containing liposomes to inhibit cancer proliferation in selected human breast cancer models in vitro, possibly by predisposing cells to programmed cell death. In the case, breast cancer is the second most common cancer worldwide after lung cancer, the fifth most common cause of cancer death, and the leading cause of cancer death in women. The global weight of breast cancer exceeds all other cancers and the incidence rates of breast cancer are increasing. Luckily, the total survival rates of most cancers have been prolonged due to the energies of both clinicians and scientists. Behind an in-depth microstructural characterization, we have herein demonstrated that the most efficient ruthenium-containing cationic nanoaggregates we have hitherto developed are able to elicit both extrinsic and intrinsic apoptosis, as well as autophagy. Using especially designed fluorescent formulations and confocal microscopy approaches for targeted studies of intracellular localization, in addition to subcellular fractionation and inductively coupled plasma-mass spectrometry (ICP-MS) to assess cellular accumulation, we have detected, unlike the naked AziRu, a wide both cytosolic and nuclear distribution of the active Ru(III) complex. This would allow the ruthenium to interact with both mitochondrial and nuclear molecular targets, accounting for its ability to inhibit breast cancer cell proliferation by the activation of multiple cell death pathways, possibly via mitochondrial perturbations involving Bcl-2 family members, and Ru(III) ions incorporation into double-stranded DNA. To limit chemoresistance and counteract uncontrolled proliferation, multiple cell death pathways activation is a promising strategy for targeted therapy development, especially in aggressive cancer diseases such as triple-negative breast cancer with limited treatment options. The heterogeneity of breast cancers makes them both a fascinating and difficult solid tumour to diagnose and treat. Triple-negative breast cancers in particular are difficult to define lacking Her2 expression, estrogen and progesterone receptor, and do not respond to hormonal therapies or Her2-targeted therapies; hence, new systemic therapies are desperately needed. The oncology community needs for a new dawn of innovative and creative means to overcome these challenges so we can witness further breakthroughs. Moreover, allowing for the importance of the tumour microenvironment as well as of the stromal components playing both critical role in the tumourigenic process, the function of cancer-associated immune cell system and their cellular secrets were also investigated, in order to achieve a deeper understanding of the typical molecular pathways involved in the cross-talk between tumour components and stromal cells; this would allow to properly act on tumour microenvironment in order to further improve the efficacy of chemotherapy. In this case, the EPO/ESA treatment – commonly used in therapy for anaemia – can induce tumour progression and growth, because of its impact on the anti-cancer immune response. So overall these outcomes discharge original knowledge in the field of anticancer therapy and on ruthenium-based candidate drugs, thus providing new insights for future optimized cancer treatment protocols.

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