Free Rhodium (II) citrate and rhodium (II) citrate magnetic carriers as potential strategies for breast cancer therapy

Abstract Background Rhodium (II) citrate (Rh2(H2cit)4) has significant antitumor, cytotoxic, and cytostatic activity on Ehrlich ascite tumor. Although toxic to normal cells, its lower toxicity when compared to carboxylate analogues of rhodium (II) indicates Rh2(H2cit)4 as a promising agent for chemotherapy. Nevertheless, few studies have been performed to explore this potential. Superparamagnetic particles of iron oxide (SPIOs) represent an attractive platform as carriers in drug delivery systems (DDS) because they can present greater specificity to tumor cells than normal cells. Thus, the association between Rh2(H2cit)4 and SPIOs can represent a strategy to enhance the former's therapeutic action. In this work, we report the cytotoxicity of free rhodium (II) citrate (Rh2(H2cit)4) and rhodium (II) citrate-loaded maghemite nanoparticles or magnetoliposomes, used as drug delivery systems, on both normal and carcinoma breast cell cultures. Results Treatment with free Rh2(H2cit)4 induced cytotoxicity that was dependent on dose, time, and cell line. The IC50 values showed that this effect was more intense on breast normal cells (MCF-10A) than on breast carcinoma cells (MCF-7 and 4T1). However, the treatment with 50 μM Rh2(H2cit)4-loaded maghemite nanoparticles (Magh-Rh2(H2cit)4) and Rh2(H2cit)4-loaded magnetoliposomes (Lip-Magh-Rh2(H2cit)4) induced a higher cytotoxicity on MCF-7 and 4T1 than on MCF-10A (p < 0.05). These treatments enhanced cytotoxicity up to 4.6 times. These cytotoxic effects, induced by free Rh2(H2cit)4, were evidenced by morphological alterations such as nuclear fragmentation, membrane blebbing and phosphatidylserine exposure, reduction of actin filaments, mitochondrial condensation and an increase in number of vacuoles, suggesting that Rh2(H2cit)4 induces cell death by apoptosis. Conclusions The treatment with rhodium (II) citrate-loaded maghemite nanoparticles and magnetoliposomes induced more specific cytotoxicity on breast carcinoma cells than on breast normal cells, which is the opposite of the results observed with free Rh2(H2cit)4 treatment. Thus, magnetic nanoparticles represent an attractive platform as carriers in Rh2(H2cit)4 delivery systems, since they can act preferentially in tumor cells. Therefore, these nanopaticulate systems may be explored as a potential tool for chemotherapy drug development.

This research was supported by the Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPQ), Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES), Fundação de Apoio a Pesquisa no Distrito Federal (FAPDF, Grant: 193.000.466/08) and Financiadora de Estudos e Projetos (Finep). The authors are grateful to Prof. Ricardo Bentes de Azevedo for his laboratory support and to Prof. Antônio Raimundo Lima Cruz Teixeira for supplying the flow cytometry equipment. We also thank Ms. Graziella Anselmo Joanitti for her important technical support on flow cytometry proceedings and Calliandra Maria de Souza Silva for her English revision.

This research was supported by the "Conselho Nacional de Desenvolvimento Científico e Tecnológico" (CNPQ), "Coordenação de Aperfeiçoamento de Pessoal de Nível Superior" (CAPES), "Fundação de Apoio a Pesquisa no Distrito Federal" (FAP-DF, Grant: 193.000.466/08) and "Financiadora de Estudos e Projetos" (Finep). The authors are grateful to Prof. Ricardo Bentes de Azevedo for his laboratory support and to Prof. Antônio Raimundo Lima Cruz Teixeira for supplying the flow cytometry equipment. We also thank Ms. Graziella Anselmo Joanitti for her important technical support on flow cytometry proceedings and Calliandra Maria de Souza Silva for her English revision.