RESUMEN
Rattlesnakes are easily recognized by a rattle on the tail. Despite the advances in molecular, morphological, and evolutionary studies about several aspects of rattles, there are no studies elucidating these nanoscale topographical features using high-resolution techniques. Here we propose a set of approaches to show these micro/nano surface features searching for patterns or hidden signatures. The results showed that the older rattle ring (segment 8) presented higher roughness values when compared to other segments. Cluster analysis allowed the observation of similarities/differences among some groups, which reinforced the strong discrepancy of the segment 8 when compared to the others and enable possible topographical transitions among each segment features, considering their linkages and Euclidean distances. Attractive forces and surface hardness were also significant increased on segment 8, while adhesion was significantly decreased on the segments 5, 6, and 7 compared to segment 1 (P < 0.05). Fourier transform infrared spectroscopy showed typical profiles of keratin spectra considering the amino acids present in this protein structure. Energy dispersive spectroscopy results indicated possible different molecular composition on each segment. These set of approaches applied on the present study represents an array of new possibilities towards the qualitative and quantitative analyses of this type of biomaterials enabling to address several structural, chemical and mechanical questions ongoing on scientific world.
Asunto(s)
Crotalus , Nanoestructuras , Animales , Materiales Biocompatibles , Espectroscopía Infrarroja por Transformada de Fourier , Propiedades de SuperficieRESUMEN
The development of therapeutic strategies to attenuate chemotherapy toxicity represents an area of great interest in cancer research, and among them is nutritional therapy based on antioxidants. As research on this topic is still controversial and scarce, we aim to investigate the effects of antioxidant supplementation with vitamin C, vitamin E or pequi oil, a carotenoid-rich oil extracted from pequi (Caryocar brasiliense), on doxorubicin (DX)-induced oxidative damage to normal cells in Ehrlich solid tumor-bearing mice. Tumor weight and volume, histopathology, morphometry and immunohistochemistry were used to assess the treatments' efficacy in containing tumor aggressiveness and regression, while possible toxicity of treatments was assessed by animals' weight, morphological analysis of the heart, liver and kidneys, hemogram, and serum levels of total bilirubin, direct bilirubin, indirect bilirubin, aspartate aminotransferase (AST), alanine aminotransferase (ALT), gamma glutamyl transferase (GGT), alkaline phosphatase, creatinine and urea. Although all the chemotherapeutic treatments increased internal necrosis area and reduced the positive Ki-67 cells compared to non-treated tumors, the treatments with pequi oil provided before tumor inoculation (PTDX) or in continuous and concurrent administration with doxorubicin (PTPDX) were more effective in containing tumor growth, besides increasing lymphocyte-dependent immunity and reducing the adverse side effects associated with DX-induced oxidative damage to normal cells, mainly the PTDX treatment. Vitamins C and E given before tumor inoculation and chemotherapy were not successful against doxorubicin-induced cardiotoxicity, besides increasing doxorubicin-induced nephrotoxicity, indicating that, at least for doxorubicin, pequi oil instead of vitamins C and E would be the best option to reduce its adverse effects.
Asunto(s)
Antibióticos Antineoplásicos/toxicidad , Carcinoma de Ehrlich/tratamiento farmacológico , Carotenoides/análisis , Doxorrubicina/toxicidad , Aceites de Plantas/química , Animales , Antibióticos Antineoplásicos/uso terapéutico , Ácido Ascórbico/análisis , Carcinoma de Ehrlich/metabolismo , Carcinoma de Ehrlich/patología , Doxorrubicina/uso terapéutico , Femenino , Ratones , Estrés Oxidativo/efectos de los fármacos , Aceites de Plantas/farmacología , Vitamina E/análisisRESUMEN
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.
Asunto(s)
Antineoplásicos/farmacología , Compuestos Férricos/química , Nanopartículas de Magnetita/química , Rodio/farmacología , Alanina Transaminasa/sangre , Animales , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/patología , Ciclo Celular/efectos de los fármacos , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Ácido Cítrico/química , Ácido Cítrico/farmacología , Creatinina/sangre , Fragmentación del ADN/efectos de los fármacos , Femenino , Compuestos Férricos/análisis , Humanos , Inmunohistoquímica , Hierro/sangre , Antígeno Ki-67/análisis , Riñón/efectos de los fármacos , Riñón/metabolismo , Hígado/efectos de los fármacos , Hígado/metabolismo , Ratones , Ratones Endogámicos BALB C , Molécula-1 de Adhesión Celular Endotelial de Plaqueta/análisis , Rodio/química , Rayos UltravioletaRESUMEN
BACKGROUND: Rhodium (II) citrate (Rh(2)(H(2)cit)(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 (Rh(2)(H(2)cit)(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 Rh(2)(H(2)cit)(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 (Rh(2)(H(2)cit)(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 Rh(2)(H(2)cit)(4) induced cytotoxicity that was dependent on dose, time, and cell line. The IC(50) 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 Rh(2)(H(2)cit)(4)-loaded maghemite nanoparticles (Mag(h)-Rh(2)(H(2)cit)(4)) and Rh(2)(H(2)cit)(4)-loaded magnetoliposomes (Lip-Magh-Rh(2)(H(2)cit)(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 Rh(2)(H(2)cit)(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 Rh(2)(H(2)cit)(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 Rh(2)(H(2)cit)(4) treatment. Thus, magnetic nanoparticles represent an attractive platform as carriers in Rh(2)(H(2)cit)(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.