RESUMEN
Most commercial anticancer nanomedicines are administered intravenously. This route is fast and precise as the drug enters directly into the systemic circulation, without undergoing absorption processes. When nanoparticles come into direct contact with the blood, however, they interact with physiological components that can induce colloidal destabilization and/or changes in their original biochemical identity, compromising their ability to selectively accumulate at target sites. In this way, these systems usually lack active targeting, offering limited therapeutic effectiveness. In the literature, there is a paucity of in-depth studies in complex environments to evaluate nanoparticle stability, protein corona formation, hemolytic activity, and targeting capabilities. To address this issue, fluorescent silica nanoparticles (SiO2NPs) are here functionalized with zwitterionic (kinetic stabilizer) and folate groups (targeting agent) to provide selective interaction with tumor cell lines in biological media. The stability of these dually functionalized SiO2NPs is preserved in unprocessed human plasma while yielding a decrease in the number of adsorbed proteins. Experiments in murine blood further proved that these nanoparticles are not hemolytic. Remarkably, the functionalized SiO2NPs are more internalized by tumor cells than their healthy counterparts. Investigations of this nature play a crucial role in garnering results with greater reliability, allowing the development of nanoparticle-based pharmaceutical drugs that exhibit heightened efficacy and reduced toxicity for medical purposes.
RESUMEN
Most nanomaterial-based medicines are intravenously applied since oral administration comprises challenging-related biological obstacles, such as interactions with distinct digestive fluids and their transport through the intestinal barrier. Moreover, there is a lack of nanoparticle-based studies that faithfully consider the above-cited obstacles and boost oral-administered nanomedicines' rational design. In this study, the physicochemical stability of fluorescent model silica nanoparticles (f-SiO2NPs) passing through all simulated gastrointestinal fluids (salivary, gastric, and intestinal) and their absorption and transport across a model human intestinal epithelium barrier are investigated. An aggregation/disaggregation f-SiO2NPs process is identified, although these particles remain chemically and physically stable after exposure to digestive fluids. Further, fine imaging of f-SiO2NPs through the absorption and transport across the human intestinal epithelium indicates that nanoparticle transport is time-dependent. The above-presented protocol shows tremendous potential for deciphering fundamental gastrointestinal nanoparticles' evolution and can contribute to rational oral administration-based nanomedicine design.
Asunto(s)
Líquidos Corporales , Nanopartículas , Humanos , Mucosa Intestinal , Tracto Gastrointestinal , Administración OralRESUMEN
The antiangiogenic therapy for prostate cancer with Nintedanib, a potent inhibitor of important growth factor receptors, has been proven to delay tumor progression and arrest tumor growth; thus, the aim herein is to evaluate Nintedanib effects on tumor cells, besides angiogenesis and apoptosis processes, metalloproteinases and hypoxia factor in an animal model. Nintedanib promoted growth inhibition and cell death in a dose-dependent manner, showing no tumor selectivity. Transgenic Adenocarcinoma of the Mouse Prostate (TRAMP) were treated with Nintedanib (10 mg/kg/day) in different stages of tumor development and the ventral prostate was examined for protein levels by means of immunohistochemistry and Western blotting and apoptosis evaluation. In vitro antiproliferative activity of Nintedanib was also assessed in nine human tumor cell lines. Early Nintedanib treatment has shown decreased levels of FGF-2, VEGFR-1, MMP-9 and HIF-1α and a significantly increased apoptosis of epithelial cells. Furthermore, late Nintedanib treatment decreased FGF-2, VEGFR-1 and FGFR-3 levels. Importantly, even after treatment discontinuation, treated animals displayed a significant decrease in VEGFR-1 as well as MMP-9. Although Nintedanib treatment in late stages of tumor growth has shown some good results, it is noteworthy that the drug presents the best tissue response when administered in the early stages of disease development. Nintedanib treatment has shown to be a promising approach for prostate cancer therapy, especially in the early stages of the disease, interfering in different carcinogenesis progression pathways.
Asunto(s)
Adenocarcinoma/tratamiento farmacológico , Inhibidores de la Angiogénesis/uso terapéutico , Apoptosis , Hipoxia/patología , Indoles/uso terapéutico , Próstata/patología , Neoplasias de la Próstata/irrigación sanguínea , Neoplasias de la Próstata/tratamiento farmacológico , Adenocarcinoma/irrigación sanguínea , Adenocarcinoma/patología , Inhibidores de la Angiogénesis/farmacología , Animales , Apoptosis/efectos de los fármacos , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Matriz Extracelular/efectos de los fármacos , Matriz Extracelular/metabolismo , Factores de Crecimiento de Fibroblastos/metabolismo , Humanos , Indoles/farmacología , Masculino , Metaloproteinasa 9 de la Matriz/metabolismo , Ratones , Ratones Endogámicos C57BL , Estadificación de Neoplasias , Neoplasias de la Próstata/patología , Receptor 1 de Factores de Crecimiento Endotelial Vascular/metabolismoRESUMEN
Prostate cancer is the most prevalent type of cancer in men around the world. Due to its high incidence, new therapies have been evaluated, including drugs capable of inhibiting the FGF/VEGF pathways, as Nintedanib. The aim herein was to evaluate the Nintedanib therapeutic effects on morphology and COX-2 and IL-17 levels in the prostate anterior lobe in different grades of the tumor progression in TRAMP mice. Animals were treated with Nintedanib at a dose of 10â¯mg/kg/day in initial and intermediate grades of tumor development. At the end of treatment, the prostate anterior lobe was collected and submitted to morphological, immunohistochemical and Western Blotting analyses. The results showed that Nintedanib delayed the prostate carcinogenesis progression, with over 20% of reduction in frequency of tissue injuries, particularly in the group treated from 12 to 16 weeks of age. Also, decreased COX-2 and IL-17 levels were observed in both groups treated with Nintedanib in the prostate anterior lobe. Thus, we concluded that Nintedanib was effective in delaying tumor progression and, despite not directly acting on inflammation, Nintedanib may adversely affect inflammatory pathways, favoring prostate cancer delay.
Asunto(s)
Ciclooxigenasa 2/genética , Indoles/administración & dosificación , Inflamación/tratamiento farmacológico , Interleucina-17/genética , Neoplasias de la Próstata/tratamiento farmacológico , Animales , Carcinogénesis/efectos de los fármacos , Progresión de la Enfermedad , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Humanos , Indoles/efectos adversos , Inflamación/inducido químicamente , Inflamación/genética , Inflamación/patología , Masculino , Ratones , Adenohipófisis/efectos de los fármacos , Adenohipófisis/patología , Próstata/efectos de los fármacos , Próstata/patología , Neoplasias de la Próstata/genética , Neoplasias de la Próstata/patología , Miembro 25 de Receptores de Factores de Necrosis Tumoral/genéticaRESUMEN
The acute promyelocytic leukemia (APL) is a rare disease, affecting 0.1/100,000 individuals globally. Despite significant advances in APL therapy, some patients still experience relapsed disease. Currently, arsenic trioxide (As2O3) was found to be effective in relapsed APL treatment and considered as standard treatment for these cases. However, it has been shown that exposure to As2O3 may exert adverse effects on the male reproductive system since this substance might also induce apoptosis of other important cell types including stem cells. Studies demonstrated that treatment with this metallic substance decreased plasma levels of testosterone and interfered with sperm parameters such as concentration, motility, and viability. In addition, As2O3 was found to produce significant damage to spermatocytes, which may be associated with testicular toxicity and consequent inhibition of spermatogenesis. The aim of this study was to determine sub-chronic treatment effects of As2O3 on sperm and testicular morphology, androgen receptor (AR) immunoreactivity in testes and epididymis, in addition to evaluation of fertility parameters in adult male mice. Thirty adult Swiss mice were divided into three experimental groups: control; received distilled water (vehicle) while treated received 0.3 or 3 mg/kg/day As2O3 subcutaneously, for 5 days per week, followed by 2 days of interruption, for 5 weeks. Results showed that As2O3 (1) decreased spermatozoa number, (2) produced seminiferous epithelium degeneration and exfoliation of germ cells tubule lumen (3) altered nucleus/cytoplasm proportion of Leydig cells and (4) reduced AR immunoreactivity in both Leydig and epithelial epididymal cells. Further, fetal viability tests demonstrated an increase in post-implantation loss in females that were mated with As2O3-treated males. Data indicate that As2O3 exposure altered the spermatogenic process and subsequently fetal viability.
Asunto(s)
Viabilidad Fetal/efectos de los fármacos , Óxidos/toxicidad , Testículo/efectos de los fármacos , Animales , Trióxido de Arsénico , Arsenicales/administración & dosificación , Modelos Animales de Enfermedad , Epidídimo/efectos de los fármacos , Epidídimo/metabolismo , Fertilidad/efectos de los fármacos , Leucemia Promielocítica Aguda/tratamiento farmacológico , Células Intersticiales del Testículo/efectos de los fármacos , Células Intersticiales del Testículo/metabolismo , Masculino , Ratones , Óxidos/administración & dosificación , Receptores Androgénicos/metabolismo , Reproducción/efectos de los fármacos , Epitelio Seminífero/efectos de los fármacos , Epitelio Seminífero/metabolismo , Espermatogénesis/efectos de los fármacos , Espermatozoides/efectos de los fármacos , Espermatozoides/metabolismo , Testículo/metabolismo , Pruebas de Toxicidad Subcrónica , Aumento de Peso/efectos de los fármacosRESUMEN
BACKGROUND: In recent times, anti-cancer treatments have focused on Fibroblast Growth Factor (FGF) and Vascular-Endothelial Growth Factor (VEGF) pathway inhibitors so as to target tumor angiogenesis and cellular proliferation. One such drug is Nintedanib; the present study evaluated the effectiveness of Nintedanib treatment against in vitro proliferation of human prostate cancer (PCa) cell lines, and growth and progression of different grades of PCa lesions in pre-clinical PCa transgenic adenocarcinoma for the mouse prostate (TRAMP) model. METHODS: Both androgen-independent (LNCaP) and androgen-dependent (PC3) PCa cell lines were treated with a range of Nintedanib doses for 72 h, and effect on cell growth and expression of angiogenesis associated VEGF receptors was analyzed. In pre-clinical efficacy evaluation, male TRAMP mice starting at 8 and 12 weeks of age were orally-fed with vehicle control (10% Tween 20) or Nintedanib (10 mg/Kg/day in vehicle control) for 4 weeks, and sacrificed immediately after 4 weeks of drug treatment or sacrificed 6-10 weeks after stopping drug treatments. At the end of treatment schedule, mice were sacrificed and ventral lobe of prostate was excised along with essential metabolic organ liver, and subjected to histopathological and extensive molecular evaluations. RESULTS: The total cell number decreased by 56-80% in LNCaP and 45-93% in PC3 cells after 72 h of Nintedanib treatment at 2.5-25 µM concentrations. In pre-clinical TRAMP studies, Nintedanib led to a delay in tumor progression in all treatment groups; the effect was more pronounced when treatment was given at the beginning of the glandular lesion development and continued till study end. A decreased microvessel density and VEGF immunolocalization was observed, besides decreased expression of Androgen Receptor (AR), VEGFR-1 and FGFR-3 in some of the treated groups. No changes were observed in the histological liver analysis. CONCLUSIONS: Nintedanib treatment was able to significantly decrease the growth of PCa cell lines and also delay growth and progression of PCa lesions to higher grades of malignancy (without inducing any hepatotoxic effects) in TRAMP mice. Furthermore, it was observed that Nintedanib intervention is more effective when administered during the early stages of neoplastic development, although the drug is capable of reducing cell proliferation even after treatment interruption.
Asunto(s)
Adenocarcinoma/prevención & control , Antineoplásicos/farmacología , Indoles/farmacología , Neoplasias de la Próstata/prevención & control , Animales , Animales Modificados Genéticamente , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Progresión de la Enfermedad , Humanos , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones EndogámicosRESUMEN
Cisplatin (CP) is used to treat a number of cancers, including testicular cancer. Studies indicate that CP-treatment can impair spermatogenesis in humans and rodents by germ cell DNA binding, through different modes of action. CP-paternal exposure resulted in adverse effects in F1 male offspring. In this study, F1 female offspring was assessed for reproductive development after CP-paternal exposure. Peri-pubertal male rats, treated with 1mg/Kg/day of CP or vehicle for 3 weeks, were mated with unexposed females. F1 female offspring of CP-treated fathers showed a decrease in fetal ovary germ cells, in estrous cycle length and FSH levels, and an increase in the percentage of antral follicles in adults. Based on our previous results and the findings of the present work we concluded that CP-paternal exposure leads to adverse effects on rat male and female reproductive development, raising concern, in humans, for children born to men exposed to CP.
Asunto(s)
Antineoplásicos/toxicidad , Cisplatino/toxicidad , Exposición Paterna , Efectos Tardíos de la Exposición Prenatal , Diferenciación Sexual/efectos de los fármacos , Animales , Ciclo Estral/efectos de los fármacos , Femenino , Fertilidad/efectos de los fármacos , Hormona Folículo Estimulante/sangre , Células Germinativas/efectos de los fármacos , Masculino , Ovario/efectos de los fármacos , Embarazo , Ratas Wistar , Conducta Sexual Animal/efectos de los fármacosRESUMEN
Arsenic trioxide (As2O3) has shown effectiveness in treatment of leukemia but is also associated with reproductive toxicity. Since remediation with N-acetylcysteine (NAC) may mitigate the adverse effects caused by exposure, we assessed the effects of As2O3 and its potential reversibility after exposure cessation or coadministration of NAC. Animals received 0.3 or 3.0 mg/Kg/day of As2O3 subcutaneously and 40 mM of NAC in tap water. As2O3 treatment impaired spermatogenesis and sperm motility and decreased seminal vesicle weight and testosterone serum levels; after suspension of treatment, these parameters remained altered. When NAC was administered, animals showed improvement in sperm parameters and seminal vesicle weight. In vitro epididymal contractility was increased in As2O3-treated animals. We concluded that As2O3 is toxic to the male mouse genital system by compromising sperm quality and quantity; these effects persisted even after suspension of the treatment. However, the coadministration of NAC ameliorates the harmful effects of the drug on the male genital system.