Refined Insights in the Photochromic <i>spiro</i>-Dihydroindolizine/Betaine System

We have revisited the photochromic <i>spiro</i>-dihydroindolizine/betaine system by comparing state-of-the-art density functional theory calculations with experimental data. Time-dependent density functional theory calculations are employed to examine the transformations occurring after photoexcitation. This study confirms that photoexcitation of the <i>spiro</i>-dihydroindolizine leads to the formation of the <i>cis</i>-betaine. However, isomerization to the <i>trans</i>-betaine follows through a complicated and formerly unknown potential energy landscape, which consists of a network of transition states and intermediates. The available pathways across this potential energy landscape will determine the kinetics of the forward reaction from the <i>cis-</i>betaine to the <i>trans-</i>betaine and then, even more importantly, the back-reaction. Virtually all practical applications of this optical switch rely on these reactions and, therefore, occur within this landscape. Predicting the network of transition states and intermediates for substituted <i>spiro</i>-dihydroindolizine/betaine systems will enable the <i>in-silico</i> design of optical switches with enhanced performance

A nanobiosensor for the detection of arginase activity

A nanobiosensor for arginase detection was designed and synthesized. It features a central dopamine-coated iron/iron oxide nanoparticle to which sulfonated cyanine 7.0 is tethered via a stable amide bond. Cyanine 5.5 is linked to the N-terminal of the peptide sequence GRRRRRRRG. Arginine (R) reacts to ornithine (O) in the presence of arginase. Based on calibration with commercially obtained arginase II, the limit of detection (LOD) is picomolar. It is noteworthy that the nanobiosensor for arginase detection does not show a fluorescence increase when incubated with the enzyme NO-reductase, which also uses arginase as substrate, but is indicative of an inflammatory response by the host to cancer and infections. Arginase activity was determined in a syngeneic mouse model for aggressive breast cancer (4 T1 tumors in BALB/c mice). It was found that the arginase activity is systemically enhanced, but especially pronounced in the active tumor regions. (C) 2016 Elsevier Inc. All rights reserved

Insights from Theory and Experiment on the Photochromic <i>spiro</i>-Dihydropyrrolo–Pyridazine/Betaine System

We elucidated the photochromic <i>spiro</i>-4a,5-dihydropyrrolo­[1,2-<i>b</i>]­pyridazine/betaine (DPP/betaine) system by comparing state-of-the-art density functional theory calculations with nanosecond/millisecond UV–vis absorption spectroscopy, as well as steady-state absorption and cyclization kinetics. Time-dependent density functional theory calculations are employed to examine the transformations occurring after photoexcitation. This study shows that the photochromic <i>spiro</i>-4a,5-dihydropyrrolo­[1,2-<i>b</i>]­pyridazine and <i>spiro</i>-1,8a-dihydroindolizine (DHI) systems react according to similar pathways. However, notable differences exist. Although photoexcitation of the <i>spiro</i>-DPP system also leads to <i>cis-</i>betaines, which then isomerize to <i>trans-</i>betaines, we found two distinct classes of cis isomers (<i>cis</i>-betaine rotamer-1 and <i>cis</i>-betaine rotamer-2), which do not exist in <i>spiro</i>-1,8a-dihydroindolizine. Similar to our previous study on the <i>spiro</i>-DHI/betaine system, a complicated potential-energy landscape between cis and trans isomers exists in the <i>spiro</i>-DPP system, consisting of a network of transition states and intermediates. Because the <i>spiro</i>-DPP/betaine is even more complicated than the <i>spiro</i>-DHI/betaine system, (substituted) photochromic systems featuring a 4a,5-dihydropyrrolo­[1,2-<i>b</i>]­pyridazine functional unit will require thorough in silico design to function properly as logical gates or in devices for information storage

Peptide nanosponges designed for rapid uptake by leukocytes and neural stem cells

The structure of novel binary nanosponges consisting of (cholesterol-(K/D)nDEVDGC)3-trimaleimide units possessing a trigonal maleimide linker, to which either lysine (K)20 or aspartic acid (D)20 are tethered, has been elucidated by means of TEM. A high degree of agreement between these findings and structure predictions through explicit solvent and then coarse-grained molecular dynamics (MD) simulations has been found. Based on the nanosponges' structure and dynamics, caspase-6 mediated release of the model drug 5(6)-carboxyfluorescein has been demonstrated. Furthermore, the binary (DK20) nanosponges have been found to be virtually non-toxic in cultures of neural progenitor cells. It is of a special importance for the future development of cell-based therapies that DK20 nanosponges were taken up efficiently by leucocytes (WBC) in peripheral blood within 3 h of exposure. The percentage of live cells among the WBC was not significantly decreased by the DK20 nanosponges. In contrast to stem cell or leucocyte cell cultures, which have to be matched to the patient, autologous cells are optimal for cell-mediated therapy. Therefore, the nanosponges hold great promise for effective cell-based tumor targeting

Early breast cancer screening using iron/iron oxide-based nanoplatforms with sub-femtomolar limits of detection

Proteases, including matrix metalloproteinases (MMPs), tissue serine proteases, and cathepsins (CTS) exhibit numerous functions in tumor biology. Solid tumors are characterized by changes in protease expression levels by tumor and surrounding tissue. Therefore, monitoring protease levels in tissue samples and liquid biopsies is a vital strategy for early cancer detection. Water-dispersable Fe/Fe3O4-core/shell based nanoplatforms for protease detection are capable of detecting protease activity down to sub-femtomolar limits of detection. They feature one dye (tetrakis(carboxyphenyl)porphyrin (TCPP)) that is tethered to the central nanoparticle by means of a protease-cleavable consensus sequence and a second dye (Cy 5.5) that is directly linked. Based on the protease activities of urokinase plasminogen activator (uPA), MMPs 1, 2, 3, 7, 9, and 13, as well as CTS B and L, human breast cancer can be detected at stage I by means of a simple serum test. By monitoring CTS B and L stage 0 detection may be achieved. This initial study, comprised of 46 breast cancer patients and 20 apparently healthy human subjects, demonstrates the feasibility of protease-activity-based liquid biopsies for early cancer diagnosis

Early breast cancer screening using iron/iron oxide-based nanoplatforms with sub-femtomolar limits of detection

Proteases, including matrix metalloproteinases (MMPs), tissue serine proteases, and cathepsins (CTS) exhibit numerous functions in tumor biology. Solid tumors are characterized by changes in protease expression levels by tumor and surrounding tissue. Therefore, monitoring protease levels in tissue samples and liquid biopsies is a vital strategy for early cancer detection. Water-dispersable Fe/Fe3O4-core/shell based nanoplatforms for protease detection are capable of detecting protease activity down to sub-femtomolar limits of detection. They feature one dye (tetrakis(carboxyphenyl)porphyrin (TCPP)) that is tethered to the central nanoparticle by means of a protease-cleavable consensus sequence and a second dye (Cy 5.5) that is directly linked. Based on the protease activities of urokinase plasminogen activator (uPA), MMPs 1, 2, 3, 7, 9, and 13, as well as CTS B and L, human breast cancer can be detected at stage I by means of a simple serum test. By monitoring CTS B and L stage 0 detection may be achieved. This initial study, comprised of 46 breast cancer patients and 20 apparently healthy human subjects, demonstrates the feasibility of protease-activity-based liquid biopsies for early cancer diagnosis