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

The Systematics of Olivine CaO + Cr-Spinel in High-Mg# Arc Volcanic Rocks: Evidence for in-Situ Mantle Wedge Depletion at the Arc Volcanic Front

We investigated the state of the arc background mantle (i.e. mantle wedge without slab component) by means of olivine CaO and its Cr-spinel inclusions in a series of high-Mg# volcanic rocks from the Quaternary Trans-Mexican Volcanic Belt. Olivine CaO was paired with the Cr# [molar Cr/(Cr + Al) *100] of Cr-spinel inclusions, and 337 olivine+Cr-spinel pairs were obtained from 33 calc-alkaline, high-K and OIB-type arc front volcanic rocks, and three monogenetic rear-arc basalts that lack subduction signatures. Olivine+Cr-spinels display coherent elemental and He–O isotopic systematics that contrast with the compositional diversity of the bulk rocks. All arc front olivines have low CaO (0.135 ± 0.029 wt %) relative to rear-arc olivines which have the higher CaO (0.248 ± 0.028 wt %) of olivines from mid-ocean ridge basalts. Olivine 3He/4He–δ18O isotope systematics confirm that the olivine+Cr-spinels are not, or negligibly, affected by crustal basement contamination, and thus preserve compositional characteristics of primary arc magmas. Variations in melt H2O contents in the arc front series and the decoupling of olivine CaO and Ni are inconsistent with controls on the olivine CaO by melt water and/or secondary mantle pyroxenites. Instead, we propose that low olivine CaO reflects the typical low melt CaO of high-Mg# arc magmas erupting through thick crust. We interpret the inverse correlation of olivine CaO and Cr-spinel Cr# over a broad range of Cr# (~10–70) as co-variations of CaO, Al and Cr of their (near) primary host melts, which derived from a mantle that has been variably depleted by slab-flux driven serial melt extraction. Our results obviate the need for advecting depleted residual mantle from rear- and back-arc region, but do not upset the larger underlying global variations of melt CaO high-Mg# arc magmas worldwide, despite leading to considerable regional variations of melt CaO at the arc front of the Trans-Mexican Volcanic Belt

Low-frequency magnetic sensing by magnetoelectric metglas/bidomain LiNbO3 long bars

We present an investigation into the magnetic sensing performance of magnetoelectric bilayered metglas / bidomain LiNbO3 long thin bars operating in a cantilever or free vibrating regime and under quasi-static and low-frequency resonant conditions. Bidomain single crystals of Y+128o-cut LiNbO3 were engineered by an improved diffusion annealing technique with a polarization macrodomain structure of the “head-to-head” and “tail-to-tail” type. Long composite bars with lengths of 30, 40 and 45 mm, as well as with and without attached small tip proof masses, were studied. ME coefficients as large as 550 V/cm∙Oe, corresponding to a conversion ratio of 27.5 V/Oe, were obtained under resonance conditions at frequencies of the order of 100 Hz in magnetic bias fields as low as 2 Oe. Equivalent magnetic noise spectral densities down to 120 pT/Hz1/2 at 10 Hz and to 68 pT/Hz1/2 at a resonance frequency as low as 81 Hz were obtained for the 45 mm long cantilever bar with a tip proof mass of 1.2 g. In the same composite without any added mass the magnetic noise was shown to be as low as 37 pT/Hz1/2 at a resonance frequency of 244 Hz and 1.2 pT/Hz1/2 at 1335 Hz in a fixed cantilever and free vibrating regimes, respectively. A simple unidimensional dynamic model predicted the possibility to drop the low-frequency magnetic noise by more than one order of magnitude in case all the extrinsic noise sources are suppressed, especially those related to external vibrations, and the thickness ratio of the magnetic-to-piezoelectric phases is optimized. Thus, we have shown that such systems might find use in simple and sensitive room-temperature low-frequency magnetic sensors, e.g., for biomedical applications.publishe

Использование и перераспределение земель сельскохозяйственного назначения в Томском районе

Актуальность темы магистерской диссертацией связана с неэффективностью использования земель СХНО как основы продовольственной безопасности Томской области. Объектом исследования являются земли сельскохозяйственного назначения Томского района Томской области Цель работы – обоснование комплексного подхода к решению сложившихся проблем использования земель СХН и разработка его алгоритма на примере Томского района Томской области. В ходе работы были рассмотрены почвенные и климатические условия Томского района, их влияние на земли СХН.Object of research are the earth of agricultural purpose of the Tomsk region of the Tomsk region The work purpose – justification of an integrated approach to the solution of the developed problems of use of lands of agricultural tenure and development of his algorithm on the example of the Tomsk region of the Tomsk region. During work soil and climatic conditions of the Tomsk area, their influence on lands of SHN have been considered. The analysis of the possible reasons promoting reduction of the areas and decrease in fertility of this category, standard and legal base is carried out, and the existing problems of use and non-use of lands of agricultural purpose on the example of the Tomsk area are also revealed and proved. As a result of research the scheme covering in itself the factor

Magnetoelectric metglas/bidomain y + 140°-cut lithium niobate composite for sensing fT magnetic fields

We investigated the magnetoelectric properties of a new laminate composite material based on y+140°-cut congruent lithium niobate piezoelectric plates with an antiparallel polarized “head-to-head” bidomain structure and metglas used as a magnetostrictive layer. A series of bidomain lithium niobate crystals were prepared by annealing under conditions of Li2O outdiffusion from LiNbO3 with a resultant growth of an inversion domain. The measured quasi-static magnetoelectric coupling coefficient achieved |αE31| = 1.9 V·(cm·Oe)–1. At a bending resonance frequency of 6862 Hz, we found a giant |αE31| value up to 1704 V·(cm·Oe)–1. Furthermore, the equivalent magnetic noise spectral density of the investigated composite material was only 92 fT/Hz1/2, a record value for such a low operation frequency. The magnetic-field detection limit of the laminated composite was found to be as low as 200 fT in direct measurements without any additional shielding from external noises.publishe

Salivary gland immunohistochemistry vs substantia nigra sonography: comparative analysis of diagnostic significance

Introduction. Parkinson's disease (PD) urges for new instrumental methods of diagnosis. Transcranial sonography of the substantia nigra (SN TCS) is an established method for early PD diagnosis but its application is limited. Recently, biopsies (primarily that of salivary gland) and test for abnormal -synuclein are suggested to verify PD. Materials and methods. We assessed 12 individuals with PD, HoehnYahr 2.3 0.4. The assessments included: UPDRS, NMSQ, NMSS, RBDSQ, PDQ-8, MoCA, and HADS scoring; SN TCS; and sublingual gland immunohistochemistry for phosphorylated -synuclein (PS-129) with automated morphometric analysis. Results. Substantia nigra hyperechogenicity was shown in 75% of patients whereas biopsy revealed PS-129 in 100% of patients. Echogenic area of the substantia nigra was 0.24 [0.21; 0.3] cm2. PS-129 inclusion area varied from 28.47 [27.55; 96.26] to 238.77 [234.13; 272.49] m2, and PS-129 proportion varied from 13.4% to 93.4% of the nervous fiber area across the patients. We found relations between PS-129 and NMSQ (r = 0.8; p 0.001), NMSS (r = 0.9; p 0.001), PDQ-8 (r = 0.7; p = 0.003), UPDRS-I (r = 0.7; p = 0.009), UPDRS-II (r = 0.6; p = 0.03), and HADS (anxiety r = 0.8; p = 0.002; depression r = 0.6; p = 0.04) scores. Conclusion. The results demonstrate a higher biopsy sensitivity as compared to SN TCS. Automated morphometric analysis has been newly applied to assess PS-129 occurrence. Immunohistochemistry results are directly related to non-motor symptom severity, which may indicate high probability of PS-129 presence and diagnosis confirmation in early disease

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

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

Functional classification of proteins based on projection of amino acid sequences: application for prediction of protein kinase substrates

<p>Abstract</p> <p>Background</p> <p>The knowledge about proteins with specific interaction capacity to the protein partners is very important for the modeling of cell signaling networks. However, the experimentally-derived data are sufficiently not complete for the reconstruction of signaling pathways. This problem can be solved by the network enrichment with predicted protein interactions. The previously published <it>in silico </it>method PAAS was applied for prediction of interactions between protein kinases and their substrates.</p> <p>Results</p> <p>We used the method for recognition of the protein classes defined by the interaction with the same protein partners. 1021 protein kinase substrates classified by 45 kinases were extracted from the Phospho.ELM database and used as a training set. The reasonable accuracy of prediction calculated by leave-one-out cross validation procedure was observed in the majority of kinase-specificity classes. The random multiple splitting of the studied set onto the test and training set had also led to satisfactory results. The kinase substrate specificity for 186 proteins extracted from TRANSPATH^®database was predicted by PAAS method. Several kinase-substrate interactions described in this database were correctly predicted. Using the previously developed ExPlain™ system for the reconstruction of signal transduction pathways, we showed that addition of the newly predicted interactions enabled us to find the possible path between signal trigger, TNF-alpha, and its target genes in the cell.</p> <p>Conclusions</p> <p>It was shown that the predictions of protein kinase substrates by PAAS were suitable for the enrichment of signaling pathway networks and identification of the novel signaling pathways. The on-line version of PAAS for prediction of protein kinase substrates is freely available at <url>http://www.ibmc.msk.ru/PAAS/</url>.</p