Yersinia enterocolitica associated myopericarditis: case report and review of the literature.

We report a case of myopericarditis associated with Yersinia enterocolitica infection in an otherwise well 50-year-old man. We discuss the clinical features, microbiology and treatment of this rare cause of myopericarditis.

Falcine meningioma masquerading as biliary colic - Case report and literature review.

Right upper quadrant (RUQ) abdominal pain and discomfort is a common presenting complaint often associated with abdominal pathology. We report a rare presentation of structural intracranial pathology in a patient initially presenting with RUQ abdominal discomfort. While initial investigations concentrating on abdominal causes revealed no likely culprit, progression of symptoms to involve right lower limb weakness eventually prompted the patient's re-presentation and eventual definitive diagnosis. This case depicts a hitherto unreported cause for abdominally-manifested seizures.

Anxiolytic effects of acute and maintenance ketamine, as assessed by the Fear Questionnaire subscales and the Spielberger State Anxiety Rating Scale.

BACKGROUND: Ketamine has rapid anxiolytic effects in treatment-resistant obsessive compulsive, post-traumatic stress, generalised anxiety and social anxiety disorders. OBJECTIVES: This study aimed to assess changes following acute and maintenance ketamine therapy on the Fear Questionnaire (FQ) subscales and the Spielberger State Anxiety Inventory (SSAI). METHODS: This secondary analysis used data from a mixed open-label and double-blinded placebo-controlled study. A total of 24 patients received short-term ascending subcutaneous doses of ketamine and were then eligible to enter a 3-month maintenance phase of 1 mg/kg ketamine dosed once or twice weekly. FQ and SSAI data were analysed using mixed models to identify between-dose differences and to describe trends during maintenance. RESULTS: Acute ketamine dosing showed a rapid dose-related reduction in all three FQ subscales (agoraphobia, social phobia and blood-injury phobia) and in the SSAI. A progressive decrease in pre-dose rating-scale scores was evident during the 3 months of maintenance therapy. CONCLUSIONS: Ketamine demonstrated dose-related improvements in all FQ subscales and in the SSAI. Both scales appear to be suitable tools to assess the anxiolytic effects of ketamine in patients with treatment-resistant anxiety. Furthermore, ketamine appears to have broad, dose-related anti-phobic effects. These findings raise the possibility that ketamine may have therapeutic potential in the treatment of other phobic states, such as specific phobia.

Raloxifene nano-micelles effect on triple-negative breast cancer is mediated through estrogen receptor-ß and epidermal growth factor receptor.

Triple-negative breast cancer (TNBC) is an aggressive subtype of breast cancer that differs in progression, recurrence, and prognosis from other forms of breast cancer. The heterogeneity of TNBC has remained a challenge as no targeted therapy is currently available. Previously, we and others have demonstrated that raloxifene, a selective oestrogen receptor modulator, was also acting independently of the oestrogen receptor-α. However, raloxifene is characterised by a low bioavailability in vivo. Thus, we encapsulated raloxifene into a styrene-maleic acid (SMA) micelle to improve its pharmacokinetics. The micellar raloxifene had higher cytotoxicity when compared to the free formulation, promoted a higher cellular uptake and affected critical signalling pathways. Furthermore, SMA-raloxifene reduced TNBC tumour growth more efficiently than free raloxifene. Finally, we showed that this effect was partially mediated through oestrogen receptor-ß. In conclusion, we have provided new insight into the role of raloxifene nanoformulation in improving the management of TNBC.

Micellar formulations of Crizotinib and Dasatinib in the management of glioblastoma multiforme.

Glioblastoma multiforme (GBM) defies the currently practiced management of radiotherapy, chemotherapy and surgery and hence, it is associated with a high fatality rate with a median survival of 14.6 months. In our previous work investigating different tyrosine kinase inhibitors (TKIs), we established that a combination of Crizotinib and Dasatinib exerted the most potent effect on different GBM cell lines. In this work, to improve targeted therapy at the site of the tumour and avoid systemic toxicity, we exploited the enhanced permeability and retention effect by designing micellar formulations of these two TKIs. Crizotinib and Dasatinib were successfully encapsulated in poly(styrene-co-maleic acid) (SMA) micelles which were then evaluated for their physicochemical characteristics, anti-proliferative effect, mode of cell death, efficacy in spheroid models, effect on cell signalling, antiangiogenic potential and in vivo anticancer activity. Our results showed that this combination had induced a potent anti-proliferative effect in four GBM cell lines grown as a monolayer and as a spheroid. The combination was also efficacious in in vitro models of angiogenesis and vascular mimicry. In vivo data showed the enhanced activity of the micellar TKIs compared to free drugs. In conclusion, we proved that micellar formulations of Crizotinib and Dasatinib carry promising in vitro and in vivo efficacy that warrant further investigation.

ALK and IGF-1R as independent targets in crizotinib resistant lung cancer.

ALK positive non-small cell lung cancer is highly responsive to ALK inhibitors such as crizotinib, but drug resistance typically develops within a year of treatment. In this study we investigated whether IGF-1R is an independent druggable target in ALK-positive lung cancer cells. We confirmed that combination ALK and IGF-1R inhibitor treatment is synergistically cytotoxic to ALK-positive lung cancer cells and that this remains the case for at least 12 days after initial exposure to crizotinib. ALK-positive cells with acquired resistance to crizotinib did not acquire cross-resistance to IGF-1R inhibition, though combination treatment in the resistant cells gave additive rather than synergistic cytotoxicity. We concluded that IGF-1R is an independent druggable target in ALK-positive lung cancer and support the trial of combination treatment.

Styrene maleic acid-encapsulated paclitaxel micelles: antitumor activity and toxicity studies following oral administration in a murine orthotopic colon cancer model.

Oral administration of paclitaxel (PTX), a broad spectrum anticancer agent, is challenged by its low uptake due to its poor bioavailability, efflux through P-glycoprotein, and gastrointestinal toxicity. We synthesized PTX nanomicelles using poly(styrene-co-maleic acid) (SMA). Oral administration of SMA-PTX micelles doubled the maximum tolerated dose (60 mg/kg vs 30 mg/kg) compared to the commercially available PTX formulation (PTX [Ebewe]). In a murine orthotopic colon cancer model, oral administration of SMA-PTX micelles at doses 30 mg/kg and 60 mg/kg reduced tumor weight by 54% and 69%, respectively, as compared to the control group, while no significant reduction in tumor weight was observed with 30 mg/kg of PTX (Ebewe). In addition, toxicity of PTX was largely reduced by its encapsulation into SMA. Furthermore, examination of the tumors demonstrated a decrease in the number of blood vessels. Thus, oral delivery of SMA-PTX micelles may provide a safe and effective strategy for the treatment of colon cancer.

Prospects of Nanocarriers for Oral Delivery of Bioactives Using Targeting Strategies.

The oral route is the preferred mode of administration, however the poor intestinal absorption of many bioactive compounds limit their efficacy. Several strategies have been developed to overcome the low oral bioavailability of bioactive compounds. Nanocarriers present a unique opportunity to overcome this limitation due to their diverse bioactive carriage potential, surface functionality and design flexibility. Despite these favorable characteristics, the oral delivery of nanocarriers faces several challenges which are discussed in this review. The review addresses the different mechanisms of transport across the intestinal epithelium. In addition, we will comment on the various methods and models for evaluating the intestinal permeability, with a critical discussion of the uniformity of these models in investigating the oral bioavailability of nanocarrier systems. Finally, we will discuss some of the recently developed nanocarriers for oral delivery of bioactives that show promising results.

A combination of sorafenib and nilotinib reduces the growth of castrate-resistant prostate cancer.

Castrate-resistant prostate cancer (CRPC) remains incurable due to the lack of effective therapies. Several tyrosine kinases have been implicated in the development and growth of CRPC, as such targeting these kinases may offer an alternative therapeutic strategy. We established the combination of two tyrosine kinase inhibitors (TKIs), sorafenib and nilotinib, as the most cytotoxic. In addtion, to improve their bioavailability and reduce their metabolism, we encapsulated sorafenib and nilotinib into styrene-co-maleic acid micelles. The micelles' charge, size, and release rate were characterized. We assessed the effect of the combination on the cytotoxicity, cell cycle, apoptosis, protein expression, tumor spheroid integrity, migration, and invasion. The micelles exhibited a mean diameter of 100 nm, a neutral charge, and appeared highly stable. The micellar TKIs promoted greater cytotoxicity, decreased cell proliferation, and increased apoptosis relative to the free TKIs. In addition, the combination reduced the expression and activity of several tyrosine kinases and reduced tumor spheroid integrity and metastatic potential of CRPC cell lines more efficiently than the single treatments. The combination increased the therapeutic potential and demonstrated the relevance of a targeted combination therapy for the treatment of CRPC. In addition, the efficacy of the encapsulated drugs provides the basis for an in vivo preclinical testing.

A combination of tyrosine kinase inhibitors, crizotinib and dasatinib for the treatment of glioblastoma multiforme.

Glioblastoma multiforme (GBM) is the most common and aggressive primary brain tumor. Despite the advances in surgery, radiotherapy and chemotherapy, patient survival averages only 14.6 months. In most GBM tumors, tyrosine kinases show increased activity and/or expression and actively contribute to the development, recurrence and onset of treatment resistance; making their inhibition an appealing therapeutic strategy. We compared the cytotoxicity of 12 tyrosine kinase inhibitors in vitro. A combination of crizotinib and dasatinib emerged as the most cytotoxic across established and primary human GBM cell lines. The combination treatment induced apoptotic cell death and polyploidy. Furthermore, the combination treatment led to the altered expression and localization of several tyrosine kinase receptors such as Met and EGFR and downstream effectors as such as SRC. Furthermore, the combination treatment reduced the migration and invasion of GBM cells and prevented endothelial cell tube formation in vitro. Overall, our study demonstrated the broad specificity of a combination of crizotinib and dasatinib across multiple GBM cell lines. These findings provide insight into the development of alternative therapy for the treatment of GBM.

The Use of Styrene Maleic Acid Nanomicelles Encapsulating the Synthetic Cannabinoid Analog WIN55,212-2 for the Treatment of Cancer.

UNLABELLED: Synthetic cannabinoid WIN55,212-2 (WIN) has shown a promise as an anticancer agent but causes psychoactive side-effects. In the present study, nano-micelles of styrene maleic acid (SMA)-conjugated WIN were synthesized to reduce side-effects and increase drug efficacy. SMA-WIN micelles were characterised and their in vitro cytotoxic effect was compared to that of free WIN against triple-negative breast cancer (MDA-MB-231), hormone receptor-positive breast cancer (MCF-7) and castration-resistant prostate cancer (PC3) cell lines. SMA-WIN micelles were synthesised with a ~15% loading, 132.7 nm average diameter, -0.0388 mV charge, and pH-dependent release rate. A dose-dependent inhibition of cell growth was observed in all three cell lines treated with both free and micellar WIN, with both formulations demonstrating equal cytotoxicity. CONCLUSION: SMA-WIN demonstrated characteristics theorized to improve in vivo drug biodistribution. Potent cytotoxicity was found against breast and prostate cancer cells in vitro, showing promise as a novel treatment against breast and prostate cancer.

Styrene maleic acid micelles as a nanocarrier system for oral anticancer drug delivery - dual uptake through enterocytes and M-cells.

Drug delivery systems could potentially overcome low bioavailability and gastrointestinal toxicity, which are the major challenges for the development of oral anticancer drugs. Herein, we demonstrate the ability of styrene maleic acid (SMA) nanomicelles encapsulating epirubicin to traverse in vitro and ex vivo models of the intestinal epithelium without affecting the tissue integrity. Further, SMA micelles encapsulating a fluorescent dye dioctadecyl-3,3,3',3'-tetramethylindocarbocyanine perchlorate (DiI) showed twofold higher accumulation in the liver and spleen, 15-fold higher accumulation in the tumor, and sixfold higher accumulation in the lung as compared with the free DiI, following oral administration in a mice xenograft breast cancer model. Additionally, SMA micelles showed colocalization with microfold (M)-cells and accumulation in Peyer's patches, which together confirms the M-cell mediated uptake and transport of SMA micelles. Our results indicate that SMA micelles, showing dual uptake by enterocytes and M-cells, are a potential tool for safe oral anticancer drug delivery.

Effect of styrene maleic acid WIN55,212-2 micelles on neuropathic pain in a rat model.

Cannabinoid receptor agonists are moderately effective at reducing neuropathic pain but are limited by psychoactivity. We developed a styrene maleic acid (SMA) based on the cannabinoid WIN 55,212-2 (WIN) and tested in a rat model of neuropathic pain and in the rotarod test. We hypothesized that miceller preparation can ensure prolonged plasma half-life being above the renal threshold of excretion. Furthermore, SMA-WIN could potentially reduce the central nervous system effects of encapsulated WIN by limiting its transport across the blood-brain barrier. Using the chronic constriction injury model of sciatic neuropathy, the SMA-WIN micelles were efficacious in the treatment of neuropathic pain for a prolonged period compared to control (base WIN). Attenuation of chronic constriction injury-induced mechanical allodynia occurred for up to 8 h at a dose of 11.5 mg/kg of SMA-WIN micelles. To evaluate central effects on motor function, the rotarod assessment was utilized. Results showed initial impairment caused by SMA-WIN micelles to be identical to WIN control for up to 1.5 h. Despite this, the SMA-WIN micelle formulation was able to produce prolonged analgesia over a time when there was decreased impairment in the rotarod test compared with base WIN.

Nanomedicine for drug targeting: strategies beyond the enhanced permeability and retention effect.

The growing research interest in nanomedicine for the treatment of cancer and inflammatory-related pathologies is yielding encouraging results. Unfortunately, enthusiasm is tempered by the limited specificity of the enhanced permeability and retention effect. Factors such as lack of cellular specificity, low vascular density, and early release of active agents prior to reaching their target contribute to the limitations of the enhanced permeability and retention effect. However, improved nanomedicine designs are creating opportunities to overcome these problems. In this review, we present examples of the advances made in this field and endeavor to highlight the potential of these emerging technologies to improve targeting of nanomedicine to specific pathological cells and tissues.

A novel role for raloxifene nanomicelles in management of castrate resistant prostate cancer.

Of patients with castrate resistant prostate cancer (CRPC), less than 25-33% survive more than five years. Recent studies have implicated estrogen, acting either alone or synergistically with androgens in the development of castrate resistant prostate cancer. Several in vitro and in vivo studies, as well as a limited number of clinical trials, have highlighted the potential of selective estrogen receptor modulators, such as raloxifene (Ral) for the treatment of castrate resistant prostate cancer. However, the poor oral bioavailability and metabolism of selective estrogen receptor modulators limit their efficiency in clinical application. To overcome these limitations, we have used styrene co-maleic acid (SMA) micelle to encapsulate raloxifene. Compared to free drug, SMA-Ral micelles had 132 and 140% higher cytotoxicity against PC3 and DU 145 prostate cell lines, respectively. SMA-Ral effectively inhibits cell cycle progression, increases apoptosis, and alters the integrity of tumor spheroid models. In addition, the micellar system induced changes in expression and localization of estrogen receptors, epidermal growth factor receptor (EGFR), and downstream effectors associated with cell proliferation and survival. Finally, SMA-Ral treatment decreased migration and invasion of castrate resistant prostate cancer cell lines. In conclusion, SMA-Ral micelles can potentially benefit new strategies for clinical management of castrate resistant prostate cancer.

Curcumin-derivative nanomicelles for the treatment of triple negative breast cancer.

BACKGROUND: Triple negative breast cancer (TNBC) is a subtype of breast cancer characterized by its poor outcome and a lack of targeted therapies. Recently, our laboratory has developed a second generation curcumin derivative, 3,5-bis(3,4,5-trimethoxybenzylidene)-1-methylpiperidine-4-one (RL71) that shows potent in vitro cytotoxicity. RL71 is hydrophobic with poor bioavailability which limits its clinical development. PURPOSE: We have designed styrene-co-maleic acid (SMA) micelles encapsulating 5, 10 or 15% RL71 by weight/weight ratio to improve its solubility and pharmacokinetic profile. METHODS: The micelles charge, size and release rate were characterized. We evaluated their cytotoxicity against TNBC cell lines. The internalization of the drug inside the cells was measured by HPLC and the efficiency of the micelles was tested using a tumor spheroid model. RESULTS: The micelles exhibited mean diameters of 125-185 nm and had a neutral charge. SMA-RL71 micelles have a cytotoxicity profile comparable to the free drug against several TNBC cell lines. Moreover, the 15% loaded micelles increased the stability of RL71 and demonstrated higher activity in a tumor spheroid model. CONCLUSION: The current study demonstrates the efficiency of SMA for drug delivery, the influence of physicochemical characteristics on cytotoxicity, and provides the basis for preclinical testing in vivo.

Anticancer nanomedicine and tumor vascular permeability; Where is the missing link?

Anticancer nanomedicine was coined to describe anticancer delivery systems such as polymer conjugates, liposomes, micelles, and metal nanoparticles. These anticancer delivery platforms have been developed with the enhanced permeability and retention (EPR) effect as a central mechanism for tumor targeting. EPR based nanomedicine has demonstrated, beyond doubt, to selectively target tumor tissues in animal models. However, over the last two decades, only nine anticancer agents utilizing this targeting strategy have been approved for clinical use. In this review, we systematically analyze various aspects that explain the limited clinical progress yet achieved. The influence of nanomedicine physicochemical characteristics, animal tumor models, and variations in tumor biology, on EPR based tumor targeting is closely examined. Furthermore, we reviewed results from over one hundred publications to construct patterns of factors that can influence the transition of EPR based anticancer nanomedicine to the clinic.