James Lee

An oral delivery device based on self-folding hydrogels.

A self-folding miniature device has been developed to provide enhanced mucoadhesion, drug protection, and targeted unidirectional delivery. The main part of the device is a finger like bilayered structure composed of two bonded layers. One is a pH-sensitive hydrogel based on crosslinked poly(methyacrylic acid) (PMAA) that swells significantly when in contact with body fluids, while the other is a non-swelling layer based on poly(hydroxyethyl methacrylate) (PHEMA). A mucoadhesive drug layer is attached on the bilayer. Thus, the self-folding device first attaches to the mucus and then curls into the mucus due to the different swelling of the bilayered structure, leading to enhanced mucoadhesion. The non-swelling PHEMA layer can also serve as a diffusion barrier, minimizing any drug leakage in the intestine. The resulting unidirectional release provides improved drug transport through the mucosal epithelium. The functionality of this device is successfully demonstrated in vitro using a porcine small intestine.

Delivery of calf thymus DNA to tumor by folate receptor targeted cationic liposomes

Calf thymus DNA (ctDNA) has been shown to stimulate macrophages to produce cytokines both in vitro and in vivo when complexed with cationic liposomes. In addition, direct cytotoxicity of ctDNA has been found in tissue culture and in mice. In this study, ctDNA and folate receptor targeted cationic liposome complexes (ctDNA-F-CLs) were prepared and evaluated in FR (+) tumors. In addition, the underlying mechanism for the anti-cancer activity of ctDNA-F-CLs was investigated. Selective uptake of ctDNA-F-CLs was observed in FR (+) KB and L1210JF cells using flow cytometry. In RAW264.7 cells and DBA/2 mice, ctDNA-F-CLs and ctDNA-N-CLs significantly induced TNF-α and IL-6 production compared to free ctDNA. However, no significant difference in cytokine production was observed between ctDNA-N-CLs and ctDNA-F-CLs. In tumor bearing DBA/2 mice, ctDNA-F-CLs significantly increased INF-γ and IL-6 production compared to ctDNA-N-CLs. Furthermore in L1210JF cells, ctDNA-F-CLs had significantly increased cytotoxicity compared to ctDNA-N-CLs. Tumor cell apoptosis was also found in co-culture of RAW264.7 cells and ctDNA-F-CLs treated L1210JF cells. In L1210JF tumor bearing mice, ctDNA-F-CLs were found to significantly inhibit tumor growth and prolong the median survival time (MeST). In contrast, ctDNA-N-CLs and free ctDNA showed similar activities for tumor inhibition and animal survival. Moreover, the anti-cancer effect of ctDNA-F-CL was further enhanced by combination with anti-cancer drug doxorubicin. These results suggest that ctDNA-F-CLs are a promising agent for treatment of FR-positive tumors.

Lifting and sorting of charged Au nanoparticles by electrostatic forces in atomic force microscopy.

Manipulation of nanoparticles and biomolecules is an upcoming fi eld with potential applications in electronic and optical devices [ 1,2 ] and a variety of biosensors. [ 3,4 ] Ever since the fi rst particle manipulation experiment done by Eigler and Schweizer using scanning tunnel microscope, [ 5 ] there has been tremendous effort around the world to slide, lift or deposit nanoparticles with a high degree of specifi city and positioning them on desired substrates. [ 6–9 ] The atomic force microscope (AFM) is by far the most promising tool to manipulate single nanoparticles or nanoparticle conjugates. Depending on the path of the moving nanoparticle, manipulation can be categorized as horizontal or vertical. In the case of horizontal nanomanipulation, fewer factors affect the manipulation process (e.g., gravitational force, particle-substrate detachment force, and particle-probe attachment force could be ignored). The sliding nature of horizontal movement makes the particle-substrate interactions and particle-probe interactions less demanding. In recent works, nanostructures of various materials, sizes [ 10–13 ] and shapes [ 14 ] have been horizontally manipulated at ambient atmospheric conditions or even in fl uid environments. [ 15 ] Both contact and non-contact modes [ 16 ] of AFM have been successfully used for such particle manipulations. Vertical manipulation on the other hand is strongly dependent on both the probe-particle interaction and the particle-substrate interaction forces. The vertical deposition and patterning of small organic molecules on inorganic substrates has been widely reported using direct-writing techniques like dip pen nanolithography (DPN). [ 17,18 ] Removal or patterning of larger molecules like proteins and DNA require additional factors like mechanical forces as in AFM based nanografting [ 19,20 ] or electric forces as in electrochemical DPN, [ 21 ] nanopipetting [ 22,23 ] and dielectrophoretic deposition of DNA. [ 24 ] Thus far vertical lifting or deposition

Stromal ETS2 Regulates Chemokine Production and Immune Cell Recruitment during Acinar-to-Ductal Metaplasia

Preclinical studies have suggested that the pancreatic tumor microenvironment both inhibits and promotes tumor development and growth. Here we establish the role of stromal fibroblasts during acinar-to-ductal metaplasia (ADM), an initiating event in pancreatic cancer formation. The transcription factor V-Ets avian erythroblastosis virus E26 oncogene homolog 2 (ETS2) was elevated in smooth muscle actin–positive fibroblasts in the stroma of pancreatic ductal adenocarcinoma (PDAC) patient tissue samples relative to normal pancreatic controls. LSL-KrasG12D/+; LSL-Trp53R172H/+; Pdx-1-Cre (KPC) mice showed that ETS2 expression initially increased in fibroblasts during ADM and remained elevated through progression to PDAC. Conditional ablation of Ets-2 in pancreatic fibroblasts in a KrasG12D-driven mouse ADM model decreased the amount of ADM events. ADMs from fibroblast Ets-2–deleted animals had reduced epithelial cell proliferation and increased apoptosis. Surprisingly, fibroblast Ets-2 deletion significantly altered immune cell infiltration into the stroma, with an increased CD8+ T-cell population, and decreased presence of regulatory T cells (Tregs), myeloid-derived suppressor cells, and mature macrophages. The mechanism involved ETS2-dependent chemokine ligand production in fibroblasts. ETS2 directly bound to regulatory sequences for Ccl3, Ccl4, Cxcl4, Cxcl5, and Cxcl10, a group of chemokines that act as potent mediators of immune cell recruitment. These results suggest an unappreciated role for ETS2 in fibroblasts in establishing an immune-suppressive microenvironment in response to oncogenic KrasG12D signaling during the initial stages of tumor development.

Nanoparticles Increase The Efficacy Of Cancer Chemopreventive Agents In Cells Exposed To Cigarette Smoke Condensate

Lung cancer is a leading cause of death in developed countries. Although smoking cessation is a primary strategy for preventing lung cancer, former smokers remain at high risk of cancer. Accordingly, there is a need to increase the efficacy of lung cancer prevention. Poor bioavailability is the main factor limiting the efficacy of chemopreventive agents. The aim of this study was to increase the efficacy of cancer chemopreventive agents by using lipid nanoparticles (NPs) as a carrier. This study evaluated the ability of lipid NPs to modify the pharmacodynamics of chemopreventive agents including N-acetyl-L-cysteine, phenethyl isothiocyanate and resveratrol (RES). The chemopreventive efficacy of these drugs was determined by evaluating their abilities to counteract cytotoxic damage (DNA fragmentation) induced by cigarette smoke condensate (CSC) and to activate protective apoptosis (annexin-V cytofluorimetric staining) in bronchial epithelial cells both in vitro and in ex vivo experiment in mice. NPs decreased the toxicity of RES and increased its ability to counteract CSC cytotoxicity. NPs significantly increased the ability of phenethyl isothiocyanate to attenuate CSC-induced DNA fragmentation at the highest tested dose. In contrast, this potentiating effect was observed at all tested doses of RES, NPs dramatically increasing RES-induced apoptosis in CSC-treated cells. These results provide evidence that NPs are highly effective at increasing the efficacy of lipophilic drugs (RES) but are not effective towards hydrophilic agents (N-acetyl-L-cysteine), which already possess remarkable bioavailability. Intermediate effects were observed for phenethyl isothiocyanate. These findings are relevant to the identification of cancer chemopreventive agents that would benefit from lipid NP delivery.

Electrical Detection of Biological Conjugation by AlGaN/GaN Heterostructure Field Effect Transistors

The article presents the electrical detection of streptavidin and monokin induced by interferon gamma proteins and hybridization process of single strand DNA by AlGaN/GaN HFETs. For protein conjugation detection, AlGaN gate surface was functionalized by oxidation, 3-aminopropyltriethoxysilane treatment, and biotinylation using NHS-sulfo-biotin. For streptavidin (STA) detection, at different ionic strengths, the effect of Debye length on detection sensitivity has been demonstrated. For DNA hybridization detection, 12-mer prime ssDNA with matched and mismatched sequences were used as probe and target molecules.