Modular Nanotransporters for Nuclear-Targeted Delivery of Auger Electron Emitters

This review describes artificial modular nanotransporters (MNTs) delivering their cargos into target cells and then into the nuclei – the most vulnerable cell compartment for most anticancer agents and especially for radionuclides emitting short-range particles. The MNT strategy uses natural subcellular transport processes inherent in practically all cells including cancer cells. The MNTs use these processes just as a passenger who purchased tickets for a multiple-transfer trip making use of different kinds of public transport to reach the desired destination. The MNTs are fusion polypeptides consisting of several parts, replaceable modules, accomplishing binding to a specific receptor on the cell and subsequent internalization, endosomal escape and transport into the cell nucleus. Radionuclides emitting short-range particles, like Auger electron emitters, acquire cell specificity and significantly higher cytotoxicity both in vitro and in vivo when delivered by the MNTs into the nuclei of cancer cells. MNT modules are interchangeable, allowing replacement of receptor recognition modules, which permits their use for different types of cancer cells and, as a cocktail of several MNTs, for targeting several tumor-specific molecules for personalized medicine

Modification of fluid lipid and mobile protein fractions of reticulocyte plasma membranes affects agonist-stimulated adenylate cyclase. Application of the percolation theory

AbstractThe technique of fluorescence recovery after photobleaching was used to measure the lateral mobility of membrane integral proteins in reticulocyte plasma membranes which were treated to modify the ‘fluid’ lipid or immobilized protein fractions, hence increasing the relative prevalence of obstacles to protein lateral motion. This was achieved by either: (1) treating the plasma membranes with phospholipase A2 followed by extraction of the hydrolysis products using fatty-acid-free bovine serum albumin, resulting in a decrease in the membrane ‘fluid’ lipid portion; or (2) preincubating the plasma membranes with polylysines, resulting in plasma membrane protein aggregation and immobilization. As the prevalence of obstacles to lateral motion increased in plasma membranes through the treatments described above, the mobility of the membrane integral proteins diminished. Experimental results for the dependence of protein mobility on the prevalence of obstacles to lateral motion were compared to theoretical data in order to verify the applicability of the percolation theory to reticulocyte plasma membranes. The influence of a decrease in the ‘fluid’ lipid and an increase in the immobilized membrane protein fractions upon the hormone-stimulated adenylate cyclase activity has been studied as well. As the ‘solid’ lipid and immobilized membrane protein fractions decreased, both the hormone-stimulated adenylate cyclase activity and the fraction of β-adrenergic receptors with high affinity to hormone diminished. It was shown that this correlation can be caused by a decrease in membrane fraction accessible to the movement of the interacting proteins of the adenylate cyclase complex. Hormonal stimulation of adenylate cyclase is discussed in terms of the percolation theory

Modular nanotransporters: a multipurpose in vivo working platform for targeted drug delivery

Tatiana A Slastnikova1,2, Andrey A Rosenkranz1,2, Pavel V Gulak1, Raymond M Schiffelers3, Tatiana N Lupanova1,4, Yuri V Khramtsov1, Michael R Zalutsky5, Alexander S Sobolev1,21Laboratory of Molecular Genetics of Intracellular Transport, Institute of Gene Biology, Moscow, Russia; 2Department of Biophysics, Biological Faculty, Moscow State University, Vorobyevy Gory, Moscow, Russia; 3Laboratory for Clinical Chemistry and Haematology, University Medical Center Utrecht, Utrecht, the Netherlands; 4Department of Bioengineering, Biological Faculty, Moscow State University, Vorobyevy Gory, Moscow, Russia; 5Department of Radiology, Duke University Medical Center, Durham, NC, USABackground: Modular nanotransporters (MNT) are recombinant multifunctional polypeptides created to exploit a cascade of cellular processes, initiated with membrane receptor recognition to deliver selective short-range and highly cytotoxic therapeutics to the cell nucleus. This research was designed for in vivo concept testing for this drug delivery platform using two modular nanotransporters, one targeted to the α-melanocyte-stimulating hormone (αMSH) receptor overexpressed on melanoma cells and the other to the epidermal growth factor (EGF) receptor overexpressed on several cancers, including glioblastoma, and head-and-neck and breast carcinoma cells.Methods: In vivo targeting of the modular nanotransporter was determined by immunofluorescence confocal laser scanning microscopy and by accumulation of 125I-labeled modular nanotransporters. The in vivo therapeutic effects of the modular nanotransporters were assessed by photodynamic therapy studies, given that the cytotoxicity of photosensitizers is critically dependent on their delivery to the cell nucleus.Results: Immunohistochemical analyses of tumor and neighboring normal tissues of mice injected with multifunctional nanotransporters demonstrated preferential uptake in tumor tissue, particularly in cell nuclei. With 125I-labeled MNT{αMSH}, optimal tumor:muscle and tumor:skin ratios of 8:1 and 9.8:1, respectively, were observed 3 hours after injection in B16-F1 melanoma-bearing mice. Treatment with bacteriochlorin p-MNT{αMSH} yielded 89%–98% tumor growth inhibition and a two-fold increase in survival for mice with B16-F1 and Cloudman S91 melanomas. Likewise, treatment of A431 human epidermoid carcinoma-bearing mice with chlorin e6- MNT{EGF} resulted in 94% tumor growth inhibition compared with free chlorin e6, with 75% of animals surviving at 3 months compared with 0% and 20% for untreated and free chlorin e6-treated groups, respectively.Conclusion: The multifunctional nanotransporter approach provides a new in vivo functional platform for drug development that could, in principle, be applicable to any combination of cell surface receptor and agent (photosensitizers, oligonucleotides, radionuclides) requiring nuclear delivery to achieve maximum effectiveness.Keywords: drug delivery, nanobiotechnology, nanomedicine, cancer therapy, photosensitizers, multifunctional nanotransporte

Detection of Coherent Terahertz Radiation from a High-Temperature Superconductor Josephson Junction by a Semiconductor Quantum-Dot Detector

We examine the application of Josephson radiation emitters to spectral calibration of single-photon-resolving detectors. Josephson junctions are patterned in a YBCO film on a bicrystal sapphire substrate and are voltage controlled to generate radiation in the frequency range of 0.05-1 THz. The detector used in this work consists of a gate-defined quantum-dot photon-to-charge transducer coupled to a single-electron transistor. Both the emitter and the detector are equipped with a matching on-chip wide-band antenna. The combination of a tuneable emitter and detector allows us to determine the efficacy of the YBCO emitter and also to analyze the elementary processes involved in the detection

Antitumor Activity of Auger Electron Emitter 111In Delivered by Modular Nanotransporter for Treatment of Bladder Cancer With EGFR Overexpression

Gamma-ray emitting 111In, which is extensively used for imaging, is also a source of short-range Auger electrons (AE). While exhibiting negligible effect outside cells, these AE become highly toxic near DNA within the cell nucleus. Therefore, these radionuclides can be used as a therapeutic anticancer agent if delivered precisely into the nuclei of tumor target cells. Modular nanotransporters (MNTs) designed to provide receptor-targeted delivery of short-range therapeutic cargoes into the nuclei of target cells are perspective candidates for specific intracellular delivery of AE emitters. The objective of this study was to evaluate the in vitro and in vivo efficacy of 111In attached MNTs to kill human bladder cancer cells overexpressing epidermal growth factor receptor (EGFR). The cytotoxicity of 111In delivered by the EGFR-targeted MNT (111In-MNT) was greatly enhanced on EJ-, HT-1376-, and 5637-expressing EGFR bladder cancer cell lines compared with 111In non-targeted control. In vivo microSPECT/CT imaging and antitumor efficacy studies revealed prolonged intratumoral retention of 111In-MNT with t½ = 4.1 ± 0.5 days as well as significant dose-dependent tumor growth delay (up to 90% growth inhibition) after local infusion of 111In-MNT in EJ xenograft-bearing mice

Cantor and band spectra for periodic quantum graphs with magnetic fields

We provide an exhaustive spectral analysis of the two-dimensional periodic square graph lattice with a magnetic field. We show that the spectrum consists of the Dirichlet eigenvalues of the edges and of the preimage of the spectrum of a certain discrete operator under the discriminant (Lyapunov function) of a suitable Kronig-Penney Hamiltonian. In particular, between any two Dirichlet eigenvalues the spectrum is a Cantor set for an irrational flux, and is absolutely continuous and has a band structure for a rational flux. The Dirichlet eigenvalues can be isolated or embedded, subject to the choice of parameters. Conditions for both possibilities are given. We show that generically there are infinitely many gaps in the spectrum, and the Bethe-Sommerfeld conjecture fails in this case.Comment: Misprints correcte

Landscape science: a Russian geographical tradition

The Russian geographical tradition of landscape science (landshaftovedenie) is analyzed with particular reference to its initiator, Lev Semenovich Berg (1876-1950). The differences between prevailing Russian and Western concepts of landscape in geography are discussed, and their common origins in German geographical thought in the late nineteenth and early twentieth centuries are delineated. It is argued that the principal differences are accounted for by a number of factors, of which Russia's own distinctive tradition in environmental science deriving from the work of V. V. Dokuchaev (1846-1903), the activities of certain key individuals (such as Berg and C. O. Sauer), and the very different social and political circumstances in different parts of the world appear to be the most significant. At the same time it is noted that neither in Russia nor in the West have geographers succeeded in specifying an agreed and unproblematic understanding of landscape, or more broadly in promoting a common geographical conception of human-environment relationships. In light of such uncertainties, the latter part of the article argues for closer international links between the variant landscape traditions in geography as an important contribution to the quest for sustainability

Molecular excitation in the Interstellar Medium: recent advances in collisional, radiative and chemical processes

We review the different excitation processes in the interstellar mediumComment: Accepted in Chem. Re