RESUMO
Doxorubicin (DOX) plays an important role in cancer treatment; however, high cardiotoxicity and low penetration in solid tumors are the main limitations of its use. Liposomal formulations have been developed to attenuate the DOX toxicity, but the technological enhancement of the liposomal formulation as well as the addition of another agent with antitumor properties, like alpha-tocopheryl succinate (TS), a semi-synthetic analog of vitamin E, could certainly bring benefits. Thus, in this study, it was proposed the development of liposomes composed of DOX and TS (pHSL-TS-DOX). A new DOX encapsulation method, without using the classic ammonium sulfate gradient with high encapsulation percentage was developed. Analysis of Small Angle X-ray Scattering (SAXS) and release study proved the pH-sensitivity of the developed formulation. It was observed stabilization of tumor growth using pHSL-TS-DOX when compared to free DOX. The toxicity tests showed the safety of this formulation since it allowed body weight initial recovery after the treatment and harmless to heart and liver, main target organs of DOX toxicity. The developed formulation also avoided the occurrence of myelosuppression, a typical adverse effect of DOX. Therefore, pHSL-TS-DOX is a promising alternative for the treatment of breast cancer since it has adequate antitumor activity and a safe toxicity profile.
Assuntos
Neoplasias da Mama/tratamento farmacológico , Doxorrubicina/análogos & derivados , alfa-Tocoferol/farmacologia , Animais , Antioxidantes/farmacologia , Células Sanguíneas , Peso Corporal/efeitos dos fármacos , Neoplasias da Mama/sangue , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Doxorrubicina/efeitos adversos , Doxorrubicina/síntese química , Doxorrubicina/química , Feminino , Humanos , Lipossomos/síntese química , Camundongos , Camundongos Endogâmicos BALB C , Miocárdio/patologia , Polietilenoglicóis/efeitos adversos , Polietilenoglicóis/síntese química , Polietilenoglicóis/química , SuccinatosRESUMO
Cancer is an important public health problem, being one of the leading causes of death worldwide. Most antineoplastic agents cause severe toxic effects and some types of cancer do not respond or are resistant to the existing pharmacotherapy, necessitating the research and development of new therapeutic strategies. Cardenolides have shown significant antitumor activity due to their ability to inhibit the Na+K+ATPase enzyme, and the expression of this enzyme is increased in tumor cells. Glucoevatromonoside containing peracetylated glucose hydroxyl groups (GEVPG) is a cardenolide derivative that has low solubility in aqueous media, which constitutes a barrier to its potential biological applications. In this context, the use of liposomes represents a promising strategy to deliver GEVPG, thus allowing its intravenous administration. In this study, long-circulating and fusogenic liposomes containing GEVPG (SpHL-GEVPG) were developed, and their chemical and physicochemical properties were evaluated. SpHL-GEVPG presented adequate properties, including a mean diameter of 182.2 ± 2.7 nm, a polydispersity index equal to 0.36 ± 0.03, a zeta potential of -2.37 ± 0.31 mV, and a GEVPG entrapment of 0.38 ± 0.04 mg/mL. Moreover, this formulation showed a good stability after having been stored for 30 days at 4 °C. The cytotoxic studies against breast (MDA-MB-231, MCF-7, and SKBR-3) and lung (A549) cancer cell lines demonstrated that SpHL-GEVPG treatment significantly reduced the cell viability. In addition, the SpHL-GEVPG formulation presented a good selectivity toward these cancer cells. The evaluation of the therapeutic efficacy of the treatment with SpHL-GEVPG showed a potent anticancer effect in an A549 human lung cancer xenograft model. SpHL-GEVPG administered at doses of 1.0 and 2.0 mg/kg (i.v.) induced antitumor effect comparable to paclitaxel given at dose of 10 mg/kg (i.v.) to mice. Therefore, the results of the present work indicate the potential applicability of SpHL-GEVPG as a new anticancer formulation.
Assuntos
Antineoplásicos/farmacologia , Cardenolídeos/farmacologia , Lipossomos/química , Animais , Antineoplásicos/química , Cardenolídeos/química , Morte Celular , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Feminino , Humanos , Concentração Inibidora 50 , Camundongos Endogâmicos BALB C , Tamanho da Partícula , Carga Tumoral , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Versican is an extracellular matrix proteoglycan that has been identified as a modulator of adhesion loss, cell motility, and tumour progression. This motility results from the interaction between versican and cell surface receptors. Studies have also demonstrated the relationship between this molecule and invasion in canine mammary tumours. Given the evidence for the participation of proteoglycans in tumour progression, this study aimed to assess versican expression and its association with cell surface receptors; human epidermal growth factor receptors 1, 2, and 3 (EGFR, HER-2, and HER-3) and CD44 through an immunohistochemical analysis of benign mixed tumours (BMTs), carcinomas in mixed tumours (CMTs), and carcinosarcomas (CSs) of the canine mammary gland. Malignant tumours were divided into low and high groups with respect to versican stromal expression. The results indicated that the BMTs showed weak stromal versican expression and correlations between the expression of stromal versican and EGFR in the epithelial membrane in benign areas (p=0.013, r=0.571). A higher stromal versican expression was observed adjacent to invasive epithelial areas compared with in situ areas in CMTs and CSs, suggesting a direct relationship between versican expression and invasiveness. Furthermore, the CSs exhibited a higher expression of HER-2, cytoplasmic HER-3, and CD44 in epithelial invasive cells in cases of higher stromal versican expression. Therefore, the cell surface receptors (HER-2, HER-3, and CD44) are more evident in CSs that overexpress versican in stroma adjacent to the invasive areas. These findings suggest that the association between these molecules may be directly related to the biological behaviour and invasiveness of these canine mammary tumours.
Assuntos
Biomarcadores Tumorais/análise , Doenças do Cão/patologia , Neoplasias Mamárias Animais/patologia , Versicanas/biossíntese , Animais , Biomarcadores Tumorais/biossíntese , Doenças do Cão/metabolismo , Cães , Receptores ErbB/biossíntese , Feminino , Receptores de Hialuronatos/biossíntese , Imuno-Histoquímica , Neoplasias Mamárias Animais/metabolismo , Receptor ErbB-2/biossíntese , Receptor ErbB-3/biossínteseRESUMO
Pancreatic adenocarcinoma is important in oncology because of its high mortality rate. Deaths may be avoided if an early diagnosis could be achieved. Several types of tumors overexpress gastrin-releasing peptide receptors (GRPr), including pancreatic cancer cells. Thus, a radiolabeled peptide derivative of gastrin-releasing peptide (GRP) may be useful as a specific imaging probe. The purpose of the present study was to evaluate the feasibility of using (99m)Tc-HYNIC-ßAla-Bombesin(7-14)as an imaging probe for Capan-1 pancreatic adenocarcinoma. Xenographic pancreatic tumor was developed in nude mice and characterized by histopathological analysis. Biodistribution studies and scintigraphic images were carried out in tumor-bearing nude mice. The two methods showed higher uptake by pancreatic tumor when compared to muscle (used as control), and the tumor-to-muscle ratio indicated that (99m)Tc-HYNIC-ßAla-Bombesin (7-14)uptake was four-fold higher in tumor cells than in other tissues. Scintigraphic images also showed a clear signal at the tumor site. The present data indicate that (99m)Tc-HYNIC-ßAla-Bombesin (7-14) may be useful for the detection of pancreatic adenocarcinoma.
Assuntos
Adenocarcinoma/diagnóstico por imagem , Bombesina/análogos & derivados , Compostos de Organotecnécio/farmacocinética , Neoplasias Pancreáticas/diagnóstico por imagem , Adenocarcinoma/patologia , Animais , Bombesina/farmacocinética , Linhagem Celular Tumoral , Peptídeo Liberador de Gastrina/análogos & derivados , Xenoenxertos/diagnóstico por imagem , Xenoenxertos/patologia , Humanos , Masculino , Camundongos Nus , Músculos/diagnóstico por imagem , Neoplasias Pancreáticas/patologia , Fragmentos de Peptídeos/farmacocinética , CintilografiaRESUMO
Pancreatic adenocarcinoma is important in oncology because of its high mortality rate. Deaths may be avoided if an early diagnosis could be achieved. Several types of tumors overexpress gastrin-releasing peptide receptors (GRPr), including pancreatic cancer cells. Thus, a radiolabeled peptide derivative of gastrin-releasing peptide (GRP) may be useful as a specific imaging probe. The purpose of the present study was to evaluate the feasibility of using99mTc-HYNIC-βAla-Bombesin(7-14)as an imaging probe for Capan-1 pancreatic adenocarcinoma. Xenographic pancreatic tumor was developed in nude mice and characterized by histopathological analysis. Biodistribution studies and scintigraphic images were carried out in tumor-bearing nude mice. The two methods showed higher uptake by pancreatic tumor when compared to muscle (used as control), and the tumor-to-muscle ratio indicated that99mTc-HYNIC-βAla-Bombesin(7-14)uptake was four-fold higher in tumor cells than in other tissues. Scintigraphic images also showed a clear signal at the tumor site. The present data indicate that99mTc-HYNIC-βAla-Bombesin(7-14)may be useful for the detection of pancreatic adenocarcinoma.
Assuntos
Animais , Humanos , Masculino , Adenocarcinoma , Bombesina/análogos & derivados , Compostos de Organotecnécio/farmacocinética , Neoplasias Pancreáticas , Adenocarcinoma/patologia , Bombesina/farmacocinética , Linhagem Celular Tumoral , Peptídeo Liberador de Gastrina/análogos & derivados , Xenoenxertos/patologia , Xenoenxertos , Camundongos Nus , Músculos , Neoplasias Pancreáticas/patologia , Fragmentos de Peptídeos/farmacocinéticaRESUMO
Due to the inadequate use of stethoscopic eartips and the possibility of they being a source of infection of the ear, a microbiologic study has been carried out on 34 stethoscopes. The material from the eartips was cultured, one eartip being "contaminated", and the other disinfected previously with 70 per cent aqueous alcohol. Microorganisms developed in 100 per cent of the contaminated eartips and in 64.71 per cent of the clean ones. Howver ther was no statistically significant difference between the two groups, showing that 70 per cent aqueous alcohol is not an efficient disinfectant