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

<p>Abstract</p> <p>Background</p> <p>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)₄as 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)₄and 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.</p> <p>Results</p> <p>Treatment with free Rh₂(H₂cit)₄induced cytotoxicity that was dependent on dose, time, and cell line. The IC₅₀values 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)₄induces cell death by apoptosis.</p> <p>Conclusions</p> <p>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)₄treatment. Thus, magnetic nanoparticles represent an attractive platform as carriers in Rh₂(H₂cit)₄delivery systems, since they can act preferentially in tumor cells. Therefore, these nanopaticulate systems may be explored as a potential tool for chemotherapy drug development.</p

Antitumor effect and toxicity of free rhodium (II) citrate and rhodium (II) citrate-loaded maghemite nanoparticles in mice bearing breast cancer

Background: Magnetic fluids containing superparamagnetic iron oxide nanoparticles represent an attractive platform as nanocarriers in chemotherapy. Recently, we developed a formulation of maghemite nanoparticles coated with rhodium (II) citrate, which resulted in in vitro cytotoxicity enhanced up to 4.6 times when compared to free rhodium (II) citrate formulation on breast carcinoma cells. In this work, we evaluate the antitumor activity and toxicity induced by these formulations in Balb/c mice bearing orthotopic 4T1 breast carcinoma. Methods: Mice were evaluated with regard to the treatments’ toxicity through analyses of hemogram, serum levels of alanine aminotransferase, iron, and creatinine; DNA fragmentation and cell cycle of bone marrow cells; and liver, kidney and lung histology. In addition, the antitumor activity of rhodium (II) citrate and maghemite nanoparticles coated with rhodium (II) citrate was verified by tumor volume reduction, histology and immunohistochemistry. Results: Regarding the treatments’ toxicity, no experimental groups had alterations in levels of serum ALT or creatinine, and this suggestion was corroborated by the histopathologic examination of liver and kidney of mice. Moreover, DNA fragmentation frequency of bone marrow cells was lower than 15% in all experimental groups. On the other hand, the complexes rhodium (II) citrate-functionalized maghemite and free rhodium (II) citrate led to a marked growth inhibition of tumor and decrease in CD31 and Ki-67 staining. Conclusions: In summary, we demonstrated that both rhodium (II) citrate and maghemite nanoparticles coated with rhodium (II) citrate formulations exhibited antitumor effects against 4T1 metastatic breast cancer cell line following intratumoral administration. This antitumor effect was followed by inhibition of both cell proliferation and microvascularization and by tumor tissue injury characterized as necrosis and fibrosis. Remarkably, this is the first published report demonstrating the therapeutic efficacy of maghemite nanoparticles coated with rhodium (II) citrate. This treatment prolonged the survival period of treated mice without inducing apparent systemic toxicity, which strengthens its use for future breast cancer therapeutic applications

Association between MUC1 gene polymorphism and expected progeny differences in Nelore cattle (Bos primigenius indicus)

MUC1 is a heavily glycosylated mammalian transmembrane protein expressed by mucosal secretory tissues for both protection against microbial infection and lubrication. An important characteristic of MUC1 is its variable number of tandem repeats (VNTR) containing several sites for O-glycosylation. VNTR length has been associated with many human diseases and with certain economically important traits in domestic ruminants. The aim of the present study was to correlate the length of MUC1 gene VNTR with expected progeny differences (EPDs) obtained for growth, fertility and carcass traits. Five alleles were identified, with alleles containing short VNTRs being more frequent than those with long, thereby demonstrating that Brazilian Nelore cattle are characterized by high frequencies in short MUC1 VNTRs. Statistical analyses revealed there to be no significant association between VNTR length and EPDs for weight at 120 days (W120 ), scrotal circumference at 365 (SC 365 ) and 450 (SC 450 ) days, age at first calving (AFC), and rib eye area (REA)

Strangeness Enhancement in Cu+Cu and Au+Au Collisions at \sqrt{s_{NN}} = 200 GeV

We report new STAR measurements of mid-rapidity yields for the $\Lambda$, $\bar{\Lambda}$, $K^{0}_{S}$, $\Xi^{-}$, $\bar{\Xi}^{+}$, $\Omega^{-}$, $\bar{\Omega}^{+}$ particles in Cu+Cu collisions at \sNN{200}, and mid-rapidity yields for the $\Lambda$, $\bar{\Lambda}$, $K^{0}_{S}$ particles in Au+Au at \sNN{200}. We show that at a given number of participating nucleons, the production of strange hadrons is higher in Cu+Cu collisions than in Au+Au collisions at the same center-of-mass energy. We find that aspects of the enhancement factors for all particles can be described by a parameterization based on the fraction of participants that undergo multiple collisions

Inclusive charged hadron elliptic flow in Au + Au collisions at sNN\sqrt{s_{NN}} = 7.7 - 39 GeV

A systematic study is presented for centrality, transverse momentum ($p_T$) and pseudorapidity ($\eta$) dependence of the inclusive charged hadron elliptic flow ($v_2$) at midrapidity($|\eta| < 1.0$) in Au+Au collisions at $\sqrt{s_{NN}}$ = 7.7, 11.5, 19.6, 27 and 39 GeV. The results obtained with different methods, including correlations with the event plane reconstructed in a region separated by a large pseudorapidity gap and 4-particle cumulants ($v_2{4}$), are presented in order to investigate non-flow correlations and $v_2$ fluctuations. We observe that the difference between $v_2{2}$ and $v_2{4}$ is smaller at the lower collision energies. Values of $v_2$, scaled by the initial coordinate space eccentricity, $v_{2}/\varepsilon$, as a function of $p_T$ are larger in more central collisions, suggesting stronger collective flow develops in more central collisions, similar to the results at higher collision energies. These results are compared to measurements at higher energies at the Relativistic Heavy Ion Collider ($\sqrt{s_{NN}}$ = 62.4 and 200 GeV) and at the Large Hadron Collider (Pb + Pb collisions at $\sqrt{s_{NN}}$ = 2.76 TeV). The $v_2(p_T)$ values for fixed $p_T$ rise with increasing collision energy within the $p_T$ range studied ($< 2 {\rm GeV}/c$). A comparison to viscous hydrodynamic simulations is made to potentially help understand the energy dependence of $v_{2}(p_{T})$. We also compare the $v_2$ results to UrQMD and AMPT transport model calculations, and physics implications on the dominance of partonic versus hadronic phases in the system created at Beam Energy Scan (BES) energies are discussed.Comment: 20 pages, 12 figures. Version accepted by PR