Preclinical validation of an original Ru(III)-based nanosystem in human models of breast cancer

(1)

SIB2019

PRECLINICAL VALIDATION OF AN ORIGINAL RU(III)-BASED

NANOSYSTEM IN HUMAN MODELS OF BREAST CANCER

MARIALUISA PICCOLO*

1

_{, GABRIELLA MISSO}

2

_{, FRANCESCO MAIONE}

1

_{, MARIA}

GRAZIA FERRARO

1

_{, CHIARA TAMMARO}

1

_{, CLAUDIA RICCARDI}

3

_{, MARCO}

TRIFUOGGI

3

_{, MICHELE CARAGLIA}

2

_{, LUIGI PADUANO}

3

_{, DANIELA}

MONTESARCHIO

3

, RITA SANTAMARIA

1

and CARLO IRACE

1

1DEPARTMENT OF PHARMACY, SCHOOL OF MEDICINE, UNIVERSITY OF NAPLES “FEDERICO II”, VIA

D. MONTESANO 49, 80131-NAPLES, ITALY.

2

_{DEPARTMENT OF PRECISION MEDICINE, UNIVERSITY OF CAMPANIA “LUIGI VANVITELLI”, NAPLES,}

ITALY.

3

_{DEPARTMENT OF CHEMICAL SCIENCES, UNIVERSITY OF NAPLES “FEDERICO II”, VIA CINTIA 421,}

80126-NAPLES, ITALY.

*

_{CORRESPONDING AUTHOR: marialuisa.piccolo@unina.it}

Abstract

Breast cancer is the second most common cancer worldwide and the leading cause of death in women. Despite progress in biomedical field, its incidence is increasing so that the search for novel chemotherapeutic options is nowadays an essential requirement to fight mammary neoplasm clinical subtypes. By exploring new effective metal-based chemotherapeutics, many ruthenium complexes have been recently proposed as anticancer drug candidates, showing ability to impact on diverse cellular and extra-cellular targets, as well as to trigger the activation of different cell death pathways. In addition, many nanomaterial Ru complexes have been designed and developed into anticancer drugs with interesting beneficial properties. In this context, we have demonstrated the efficacy of a ruthenium (III)-complex (AziRu) incorporated into a cationic nanosystem (HoThyRu/DOTAP), proved to be hitherto one of the most effective within the suite of nucleolipidic formulations we have developed for the in vivo transport of anticancer ruthenium (III)-based drugs1,2_{. Based on very motivating results on human breast cancer cells}

(BCC), in order to evaluate the animal biological response to systemic administration of HoThyRu/DOTAP nanosystem, along with its effects on the progression of breast cancer in vivo, we performed an antitumour study in vivo using athymic nude mice bearing human BCC xenografts. In depth analysis of tumour growth shows that HoThyRu/DOTAP significantly inhibits breast cancer cell proliferation in mice, without any sign of toxicity in treated animal group3_{. In addition, molecular biology experiments are}

currently ongoing ex vivo to deepen the cellular responses and/or resistance to treatments, as well as to support in vivo the activation of specific cell death pathways, i.e. apoptosis and autophagy. Overall, we have validated the efficacy and the safety in vivo of our ruthenium-based candidate drugs in the perspective of new therapeutic options for breast cancer treatment.

1_{Riccardi et al., EurJOC. 7: 1099-1119, 2017.} 2_{Irace et al., SREP. 7:45236, 2017.}