Multifunctional mesoporous silica nanoparticles for combined therapeutic, diagnostic and targeted action in cancer treatment

The main objective in the development of nanomedicine is to obtain delivery platforms for targeted delivery of drugs or imaging agents for improved therapeutic efficacy, reduced side effects and increased diagnostic sensitivity. A (nano)material class that has been recognized for its controllable properties on many levels is ordered mesoporous inorganic materials, typically in the form of amorphous silica (SiO 2). Characteristics for this class of materials include mesoscopic order, tunable pore dimensions in the (macro)molecular size range, a high pore volume and surface area, the possibility for selective surface functionality as well as morphology control. The robust but biodegradable ceramic matrix moreover provides shelter for incorporated agents (drugs, proteins, imaging agents, photosensitizers) leaving the outer particle surface free for further modification. The unique features make these materials particularly amenable to modular design, whereby functional moieties and features may be interchanged or combined to produce multifunctional nanodelivery systems combining targeting, diagnostic, and therapeutic actions. This review covers the latest developments related to the use of mesoporous silica nanoparticles (MSNs) as nanocarriers in biomedical applications, with special focus on cancer therapy and diagnostics. © 2011 Bentham Science Publishers Ltd

MDA-MB-231 breast cancer cells and their CSC population migrate towards low oxygen in a microfluidic gradient device

\u3cp\u3eMost cancer deaths are caused by secondary tumors formed through metastasis, yet due to our limited understanding of this process, prevention remains a major challenge. Recently, cancer stem cells (CSCs) have been proposed as the source of metastases, but only little is known about their migratory behavior. Oxygen gradients in the tumor have been linked to directional migration of breast cancer cells. Here, we present a method to study the effect of oxygen gradients on the migratory behavior of breast CSCs using a microfluidic device. Our chip contains a chamber in which an oxygen gradient can be generated between hypoxic (<1%) and ambient (21%) conditions. We tracked the migration of CSCs obtained from MDA-MB-231 breast cancer cells, and found that their migration patterns do not differ from the average MDA-MB-231 population. Surprisingly, we found that the cells migrate towards low oxygen levels, in contrast with an earlier study. We hypothesize that in our device, migration is exclusively due to the pure oxygen gradient, whereas the effects of oxygen in earlier work were obscured by additional cues from the tumor microenvironment (e.g., nutrients and metabolites). These results open new research directions into the role of oxygen in directing cancer and CSC migration.\u3c/p\u3

A novel breast-cancer model of early stage invasion

The majority of breast cancer deaths are not caused by the primary tumor, but by metastasis to other organs. However, the mechanisms that underlie the first stage of metastasis, the invasion of cancer cells into surrounding tissue remain elusive, due to the complexity of the cellular, biochemical, and biophysical interactions in cancer tissue. \u3cbr/\u3e\u3cbr/\u3eIn this work, we propose a novel in vitro breast cancer model that focuses on dissecting the influence of the biophysical properties of the extracellular matrix (ECM) on the onset of cancer invasion. Based on microfluidic technology, it will provide us with the necessary tools to independently vary different material and cell properties, while it provides the cells with a physiologically relevant environment.\u3cbr/\u3

A novel breast cancer model of early stage invasion:using microfluidic methods to mimic a heterogeneous physical tumor microenvironment

The majority of breast cancer deaths are not caused by the primary tumor, but by metastasis to other organs. In this work, we propose a novel in vitro breast cancer model that focuses on dissecting the influence of the biophysical properties of the extracellular matrix (ECM) on the onset of cancer invasion. Based on microfluidic technology, it will provide us with the necessary tools to independently vary different material and cell properties, while it provides the cells with a physiologically relevant environment.\u3cbr/\u3

Decoding the PTM-switchboard of Notch

\u3cp\u3eThe developmentally indispensable Notch pathway exhibits a high grade of pleiotropism in its biological output. Emerging evidence supports the notion of post-translational modifications (PTMs) as a modus operandi controlling dynamic fine-tuning of Notch activity. Although, the intricacy of Notch post-translational regulation, as well as how these modifications lead to multiples of divergent Notch phenotypes is still largely unknown, numerous studies show a correlation between the site of modification and the output. These include glycosylation of the extracellular domain of Notch modulating ligand binding, and phosphorylation of the PEST domain controlling half-life of the intracellular domain of Notch. Furthermore, several reports show that multiple PTMs can act in concert, or compete for the same sites to drive opposite outputs. However, further investigation of the complex PTM crosstalk is required for a complete understanding of the PTM-mediated Notch switchboard. In this review, we aim to provide a consistent and up-to-date summary of the currently known PTMs acting on the Notch signaling pathway, their functions in different contexts, as well as explore their implications in physiology and disease. Furthermore, we give an overview of the present state of PTM research methodology, and allude to a future with PTM-targeted Notch therapeutics.\u3c/p\u3

Lateral induction limits the impact of cell connectivity on Notch signaling in arterial walls

\u3cp\u3eIt is well known that arteries grow and remodel in response to mechanical stimuli. Vascular smooth muscle cells are the main mediators of this process, as they can switch phenotype from contractile to synthetic, and vice-versa, based on the surrounding bio-chemo-mechanical stimuli. A correct regulation of this phenotypic switch is fundamental to obtain and maintain arterial homeostasis. Notch, a mechanosensitive signaling pathway, is one of the main regulators of the vascular smooth muscle cell phenotype. Therefore, understanding Notch dynamics is key to elucidate arterial growth, remodeling, and mechanobiology. We have recently developed a one-dimensional agent-based model to investigate Notch signaling in arteries. However, due to its one-dimensional formulation, the model cannot be adopted to study complex nonsymmetrical geometries and, importantly, it cannot capture the realistic “cell connectivity” in arteries, here defined as the number of cell neighbors. Notch functions via direct cell-cell contact; thus, the number of cell neighbors could be an essential feature of Notch dynamics. Here, we extended the agent-based model to a two-dimensional formulation, to investigate the effects of cell connectivity on Notch dynamics and cell phenotypes in arteries. The computational results, supported by a sensitivity analysis, indicate that cell connectivity has marginal effects when Notch dynamics is dominated by the process of lateral induction, which induces all cells to have a uniform phenotype. When lateral induction is weaker, cells exhibit a nonuniform phenotype distribution and the percentage of synthetic cells within an artery depends on the number of neighbors.\u3c/p\u3

Analyses in zebrafish embryos reveal that nanotoxicity profiles are dependent on surface-functionalization controlled penetrance of biological membranes

\u3cp\u3eMesoporous silica nanoparticles (MSNs) are extensively explored as drug delivery systems, but in depth understanding of design-toxicity relationships is still scarce. We used zebrafish (Danio rerio) embryos to study toxicity profiles of differently surface functionalized MSNs. Embryos with the chorion membrane intact, or dechoroniated embryos, were incubated or microinjected with amino (NH\u3csub\u3e2\u3c/sub\u3e-MSNs), polyethyleneimine (PEI-MSNs), succinic acid (SUCC-MSNs) or polyethyleneglycol (PEG-MSNs) functionalized MSNs. Toxicity was assessed by viability and cardiovascular function. NH\u3csub\u3e2\u3c/sub\u3e-MSNs, SUCC-MSNs and PEG-MSNs were well tolerated, 50 μg/ml PEI-MSNs induced 100% lethality 48 hours post fertilization (hpf). Dechoroniated embryos were more sensitive and 10 μg/ml PEI-MSNs reduced viability to 5% at 96hpf. Sensitivity to PEG-and SUCC-, but not NH\u3csub\u3e2\u3c/sub\u3e-MSNs, was also enhanced. Typically cardiovascular toxicity was evident prior to lethality. Confocal microscopy revealed that PEI-MSNs penetrated into the embryos whereas PEG-, NH2-and SUCC-MSNs remained aggregated on the skin surface. Direct exposure of inner organs by microinjecting NH\u3csub\u3e2\u3c/sub\u3e-MSNs and PEI-MSNs demonstrated that the particles displayed similar toxicity indicating that functionalization affects the toxicity profile by influencing penetrance through biological barriers. The data emphasize the need for careful analyses of toxicity mechanisms in relevant models and constitute an important knowledge step towards the development of safer and sustainable nanotherapies.\u3c/p\u3

The nervous system of Tricladida. I. Neuroanatomy of Procerodes littoralis (Maricola, Procerodidae) : an immunocytochemical study

The organization of the nervous system of Procerodes littoralis (Tricladida, Maricola, Procerodidae) was studied by immunocytochemistry, using antibodies to authentic flatworm neuropeptide F (NPF) (Moniezia expansa). Compared to earlier investigations of the neuroanatomy of tricladid flatworms, the pattern of NPF immunoreactivity in Procerodes littoralis reveals differences in the following respects: 1. Shape and structure of the brain. 2. Number and composition of longitudinal nerve cords. 3. Shape of branches of, and transverse connections between, main ventral nerve cords. 4. Composition of the pharyngeal nervous system. The rich innervation by NPF immunoreactive (IR) fibres and cells of the subepithelial muscle layer, the pharynx musculature and the musculature of the male copulatory apparatus indicates a neurotransmitter or neuromodulatory influence on muscular activity. © 1995 Sheffield Academic Press