Drug Delivery Nanosystems for the Localized Treatment of Glioblastoma Multiforme.

Glioblastoma multiforme is one of the most prevalent and malignant forms of central nervous system tumors. The treatment of glioblastoma remains a great challenge due to its location in the intracranial space and the presence of the blood⁻brain tumor barrier. There is an urgent need to develop novel therapy approaches for this tumor, to improve the clinical outcomes, and to reduce the rate of recurrence and adverse effects associated with present options. The formulation of therapeutic agents in nanostructures is one of the most promising approaches to treat glioblastoma due to the increased availability at the target site, and the possibility to co-deliver a range of drugs and diagnostic agents. Moreover, the local administration of nanostructures presents significant additional advantages, since it overcomes blood⁻brain barrier penetration issues to reach higher concentrations of therapeutic agents in the tumor area with minimal side effects. In this paper, we aim to review the attempts to develop nanostructures as local drug delivery systems able to deliver multiple agents for both therapeutic and diagnostic functions for the management of glioblastoma.

Nanoparticles: pharmacological and toxicological significance.

Nanoparticles are tiny materials (<1000 nm in size) that have specific physicochemical properties different to bulk materials of the same composition and such properties make them very attractive for commercial and medical development. However, nanoparticles can act on living cells at the nanolevel resulting not only in biologically desirable, but also in undesirable effects. In contrast to many efforts aimed at exploiting desirable properties of nanoparticles for medicine, there are limited attempts to evaluate potentially undesirable effects of these particles when administered intentionally for medical purposes. Therefore, there is a pressing need for careful consideration of benefits and side effects of the use of nanoparticles in medicine. This review article aims at providing a balanced update of these exciting pharmacological and potentially toxicological developments. The classes of nanoparticles, the current status of nanoparticle use in pharmacology and therapeutics, the demonstrated and potential toxicity of nanoparticles will be discussed.

Generation of platelet angiostatin mediated by urokinase plasminogen activator: effects on angiogenesis.

BACKGROUND: Angiogenesis, the growth of new capillaries from pre-existing blood vessels, is regulated by a balance between its promoters and inhibitors. Platelets are an important circulating store of angiogenesis regulators. We have previously identified the angiogenesis inhibitor angiostatin in human platelets. AIM: To identify the mechanism of platelet angiostatin generation and its pharmacological regulation. METHODS: Platelet aggregometry, flow cytometry, Western blot, zymography, immunofluorescence microscopy, matrigel-induced angiogenesis of human umbilical vein endothelial cells (HUVECs), and a panel of selective proteinase inhibitors were used to study the mechanism of angiostatin generation by platelets, its pharmacological regulation, and effects on angiogenesis. Release of pro-MMP-2 by HUVECs was also used to quantify angiogenesis. RESULTS: Platelet membranes were identified as the site of angiostatin generation from plasminogen. Generation of angiostatin by platelet membranes was not affected by a matrix metalloproteinase (MMP) inhibitor, phenanthroline, but was inhibited by serine proteinase inhibitors aprotinin, leupeptin, plasminogen activator inhibitor-1, and selective inhibitor of urokinase plasminogen activator (uPA), uPA-STOP(TM). Angiostatin generation by intact platelets was inhibited by aprotinin, and the resulting incubate promoted angiogenesis to a greater extent than incubate where angiostatin generation occurred. Furthermore, HUVECs incubated with reaction mixture, where angiostatin generation was inhibited, released more pro-MMP-2 than HUVECs incubated with supernatants, where angiostatin generation occurred. CONCLUSIONS: We conclude that; (i) platelets constitutively generate angiostatin on their membranes; (ii) this mechanism is dependent on uPA, but not, MMPs; and (iii) inhibition of platelet angiostatin generation can further promote angiogenesis.

[Lung cancer at a university hospital: epidemiological and histological characteristics of a recent and a historical series]. / Características del cáncer de pulmón en un hospital universitario. Cambios epidemiológicos e histológicos en relación con una serie histórica.

OBJECTIVE: To describe the clinical, histological, and epidemiological characteristics of patients diagnosed with lung cancer in our hospital over a period of 5 years and compare them with those of historical cases treated at the same hospital. PATIENTS AND METHODS: The cases of patients diagnosed with lung cancer from January 1998 through December 2002 were studied retrospectively and compared with data published for the period from 1978 through March 1981. RESULTS: A total of 678 patients (89% men, mean age 67 years) were studied. Fifty-six percent of the men and 38% of the women were smokers (P<.001). The most common histological types were squamous cell carcinoma (33%) and adenocarcinoma (30%): squamous carcinoma in men (36%) and adenocarcinoma in women (56%). Metastasis was present in 42% of the patients with non-small cell lung cancer and in 55% of those with small cell lung cancer. In patients with a history of neoplastic disease, laryngeal tumors were most common in patients with squamous carcinoma whereas bladder tumors were the most frequent in patients with adenocarcinoma. The ratio of men to women was lower in the recent series than in the historical one. The percentage of squamous carcinoma was lower and that of adenocarcinoma higher (P<.001). The percentage of patients diagnosed with regional involvement was greater in the recent series (P<.001). CONCLUSIONS: Squamous cell carcinoma continues to be the most frequent histological type. Male sex and smoking are associated with squamous carcinoma and female sex is associated with adenocarcinoma. Epidemiological and histological patterns have changed, possibly in relation to changes in smoking habits.

Elucidation of flow-mediated tumour cell-induced platelet aggregation using an ultrasound standing wave trap.

BACKGROUND AND PURPOSE: Tumour cells activate and aggregate platelets [tumour cell-induced platelet aggregation (TCIPA)] and this process plays an important role in the successful metastasis of cancer cells. To date, most studies on TCIPA have been conducted under no-flow conditions. In this study, we have investigated TCIPA in real time under flow conditions, using an ultrasound standing wave trap that allows formation and levitation of cancer cell clusters in suspension, thus mimicking the conditions generated by flowing blood. EXPERIMENTAL APPROACH: Using 59M adenocarcinoma and HT1080 fibrosarcoma cells and human platelets, cancer cell cluster-platelet aggregates were imaged in real time using epi-fluorescence microscopy (F-actin) and investigated in detail using confocal microscopy (matrix metalloproteinase-2-GPIIb/IIIa co-localization) and scanning electron and helium-ion microscopy (<1 nm resolution). The release of gelatinases from aggregates was studied using zymography. KEY RESULTS: We found that platelet activation and aggregation takes place on the surface of cancer cells (TCIPA), leading to time-dependent disruption of cancer cell clusters. Pharmacological modulation of TCIPA revealed that EDTA, prostacyclin, o-phenanthroline and apyrase significantly down-regulated TCIPA and, in turn, delayed cell cluster disruption, However, EGTA and aspirin were ineffective. Pharmacological inhibition of TCIPA correlated with the down-regulation of platelet activation as shown by flow-cytometry assay of platelet P-selectin. CONCLUSION AND IMPLICATIONS: Our results show for the first time, that during TCIPA, platelet activation disrupts cancer cell clusters and this can contribute to metastasis. Thus, selective targeting of platelet aggregate-cancer cell clusters may be an important strategy to control metastasis.

[Legionella pneumophila pneumonia community epidemic outbreak in Barcelona: "The Barceloneta outbreak". Effect on the early diagnosis and treatment]. / Brote epidémico de neumonía comunitaria por Legionella pneumophila en Barcelona: "el brote de la Barceloneta". Efecto del diagnóstico y tratamiento precoz.

OBJECTIVE: Clinical and microbiological descriptive analysis of the outbreak of community legionnaire's disease recorded in the Barcelona's Barcelonesa neighborhood in November 2000. PATIENTS AND METHODS: Retrospective review of the epidemiological and clinical manifestations, as well as the evolution of the cases of Legionella pneumophila pneumonia associated with the outbreak and cared of in the Hospital del Mar. RESULTS: The 48 patients evaluated, all of them with confirmed diagnoses, represent 89% of the cases communicated. Seventy-five percent of patients showed some underlying disease, 54% had some criterion for severity, and mortality was 4%. In 81% of cases the detection of the antigen of Legionella pneumophila in urine was the diagnostic method. CONCLUSIONS: The detection in urine of the Legionella pneumophila antigen makes possible the early diagnosis of legionnaire's disease, particularly in epidemic outbreaks, which that facilitates the fast establishment of the adequate treatment and contributes to the reduction in mortality even in patients of high risk.