МЕГАГРАНТЫ

Лаборатория биогибридных медицинских технологий

О лаборатории

Наименование проекта: Биогибридные технологии для современной медицины

№ договора: 14.W03.31.0025

Сайт лаборатории

Наименование ВУЗа: Федеральное государственное бюджетное образовательное учреждение высшего образования "Санкт-Петербургский государственный университет"

Области научных исследований: Химические технологии

Главной целью проекта является создание новой междисциплинарной лаборатории биогибридных технологий как основы современного исследовательского центра в области биоматериалов в Санкт-Петербургском государственном университете. Деятельность данной лаборатория, в кооперации с другими партнерскими исследовательскими центрами, будет сфокусирована на разработке инновационных химических подходов и технологий для создания биоматериалов и биогибридов, предназначенных для применения в многочисленных терапевтических и диагностических областях медицины.

Ведущий учёный

 Arto

ФИО: Уртти Арто Олави

 

Ученые степень и звание: Ph.D., фармацевтическая технология

Занимаемая должность: Профессор, Университет Хельсинки

Области научных интересов: фармакология, фармация, химия, офтальмология, биохимия, молекулярная биология, экспериментальная медицина, генетика наследственности, биотехнология, прикладная микробиология, материалы, технология, химия, радиология, ядерная медицина, медицинская визуализация, клеточная биология, полимеры

Научное признание:
2014 - Членство в совете Европейского общества фармацевтических наук
2003 - Премия Альберта Вуокко выдающимся ученым-фармацевтам
2009 - Премия за выдающиеся достижения тысячелетия Академии технологий Финляндии
2013 - За выдающиеся заслуги, Европейское общество фармацевтических наук
2014 - Золотая медаль Финского научного общества
2014 - Золотая медаль Администрации города Куопио
1998 - Премия за инновации, Foundation for New Technologies in Finland
2010 - История успеха, EUREKA
2012 - Членство в академии Академия наук Финляндии

Научные достижения:
Уртти Арто Олави является изобретателем или соавтором в 24 патентах и патентных заявках. Изобретения и технологии стали коммерциализированными лабораторными продуктами и были использованы в развитии промышленности.
Ведущий ученый возглавляет инновационное развитие инфраструктуры в области химической биологии и скрининга в Университете Хельсинки. Кроме того, он возглавляет фармацевтическую часть сети Drug Discovery and Chemical Biology Network и начал работу по созданию лаборатории визуализации in vivo в Хельсинском университете.

Лехтинен Я., Магаркар А., Стениевски М., Хакола С., Бергман М.,,Рог Т., Улиперттула
М., Уртти А., Бункер А. Анализ причины неудачи в использовании нового нацеливающего пептида в ПЭГ-илированной липосоме: Молекулярное моделирование как рациональный инструмент дизайна в наномедицине 2012 European Journal of Pharmaceutical Science

Субризи А., Туоминен Э., Бункер A., Рог Т., Антопольский М., Уртти А. TAT (48-60) пептидная последовательность аминокислот не является уникальной для проникновения внутрь клетки, а гликозаминогликаны на поверхности клеток ингибируют её поглощение клетками 2012 Journal of Controlled Release

Бхэттэчарья М., Мэлинен М., Лорен П., Лу И.Р., Паррас- Цикуендэс С., Куисма С., Кэннинен Л., Лилль M., Корлу A., Гиллозо К., Лаукканен А., Уртти А., Улиперттула М.
Нанофибриллярный целлюлозный гидрогель способствует формированию трехмерной культуры клеток печени 2012 Journal of Controlled Release

Лехтинен Дж., ракия M., Бергстрем К., Уутела П., Лехтинен К., Hiltunen A., Пиккэрэйнен
Дж., Määttä утра, Кетола Р., Илиперттула М., Вирт Т. и Уртти А. Предварительное нацеливание и прямое иммуно-нацеливание липосомальных систем доставки лекарств на карциному яичников 2012 PLos ONE

Киселев А., Егорова А., Лаукканен А., Баранов В., Уртти А. Характеризация восстанавливаемых пептидных олигомеров в качестве носителей для доставки генов 2013 International Journal of Pharmaceutics

Результаты исследований

Публикации

1. T. Tennikova, A. Urtti. Modified cells as potential ocular drug delivery systems. Drug Discovery Today. 2018. Available online 15 December 2018. doi: 10.1016/j.drudis.2018.12.004.

Drug delivery to ocular targets is problematic, especially in retinal disease treatment. Therefore, targeted drug delivery, prolonged drug action, and minimally invasive treatments are needed. In this review, we describe cell technologies for drug delivery. These technologies are based on genetic engineering and nongenetic-based approaches for cell modification. In principle, cell technologies enable targeted delivery, long drug action, and minimally invasive administration, but they have only been sparsely studied for ocular drug delivery. Herein, these technologies are discussed in the ocular context.
2. A. Urtti. Retinal Bioavailability of Liposomal Minocycline after Sub-conjunctival Administration is Low. Nanomedicine: Nanotechnology, Biology and Medicine. Available online 19 January 2019. doi: 10.1016/j.nano.2018.12.012.

Letter to editor. Intravitreal injection is the method of choice in the retinal drug delivery, for example, in the treatment of age-related macular degeneration. Obviously, there is scientific interest and clinical need for alternative and less invasive ways to deliver drugs to the retina.
3. Krasavin M., Shetnev A., Sharonova T., Baykov S., Kalinin S., Nocentini A., Sharoyko V., Poli G., Tuccinardi T., Presnukhina S., Tennikova T.B., Supuran C.T. Continued exploration of 1,2,4-oxadiazole periphery for carbonic anhydrase targeting primary arene sulfonamides: discovery of sub-nanomolar inhibitors of membrane-bound hCA IX isoform that selectively kills cancer cells in hypoxic environment. European Journal of Medicinal Chemistry. 2018. V.164. P.92-105. doi: 10.1016/j.ejmech.2018.12.049.

An expanded set of diversely substituted 1,2,4-oxadiazole-containing primary aromatic sulfonamides was synthesized and tested for inhibition of human carbonic anhydrase I, II, IX and XII isoforms. The initial biochemical profiling revealed a significantly more potent inhibition of cancer-related, membranebound isoform hCA IX (reaching into submicromolar range), on top of potent inhibition of hCA XII that is another cancer target. The observed structure-activity relationships have been rationalized by molecular modeling. Comparative single-concentration profiling of the carbonic anhydrase inhibitors synthesized for antiproliferative effects against normal (ARPE-19) and cancer (PANC-1) cell lines under chemically induced hypoxia conditions revealed several candidate compounds selectively targeting cancer cells. More in-depth characterization of these leads revealed two structurally related compounds that showed promising selective cytotoxicity against pancreatic cancer (PANC-1) and melanoma (SK-MEL-2) cell lines.
4. Petrova V.A., Panevin A.A., Zhuravskii S.G., Gasilova E.R., Vlasova E.N., Romanov D.P., Poshina D.N., Skorik Y.A. Preparation of N-succinyl chitin nanoparticles and their applications in otoneurological pathology. International Journal of Biological Macromolecules. 2018. V.120. P.1023-1029. doi: 10.1016/j.ijbiomac.2018.08.180.

Succinyl-chitin (SCH) nanoparticleswere obtained by acylation of partially deacetylated chitin (DCH) nanofibers. Introduction of the succinyl moiety induced a partial amorphization of DCH, as viewed by X-ray diffraction, and increased the fractal dimension of the colloids from df=1.2 (DCH) to 1.5–1.7 (SCH), as revealed by light scattering. The spherically symmetric form of the colloids remained almost unchanged, as indicated by the range of structure-sensitive ratios 1.0 b Rg/Rh b 1.2; the hydrodynamic diameter ranged from 200 to 300 nm. The cytoprotective activity of the SCH nanoparticles was evaluated in vivo in an acute hearing pathology model (220–250 g male Wistar rats, n = 90) following prophylactic and therapeutic administrations. Ototropic action was estimated using the amplitude of otoacoustic emissions at the frequency of the distortion product optoacoustic emissions in the range of 4–6.4 kHz before acoustic stimulation, as well as at 1 h, 24 h, and 7 days after acoustic stimulation. A dispersion of 0.3% SCH nanoparticles demonstrated prolonged ototropic action and earlier regeneration of hearing functions when compared to a meglumine sodium succinate solution. Thus, intravenous administration of the SCH nanoparticles increases the cycling time of exogenous succinate and improves biodistribution in tissues possessing a hemato-labyrinth barrier.
5. L. Churilov, V. Korzhikov-Vlakh, E. Sinitsyna, D. Polyakov, O. Darashkevich, M. Poida, G. Platonova, T. Vinogradova, V. Utekhin, N. Zabolotnykh, V. Zinserling, P. Yablonsky, A. Urtti, T. Tennikova. Enhanced delivery of 4-thioureidoiminomethylpyridinium perchlorate in tuberculosis models with IgG functionalized poly(lactic acid) based particles. Pharmaceutics. 2019. V.11. I.1. P.2. doi: 10.3390/pharmaceutics11010002.

The compound 4-thioureidoiminomethylpyridinium perchlorate (perchlozone©) is a novel anti-tuberculosis drug that is active in multiple drug resistance cases, but the compound is hepatotoxic. To decrease the systemic load and to achieve targeting, we encapsulated the drug into poly(lactic acid)-based micro- (1100 nm) and nanoparticles (170 nm) that were modified with single-chain camel immunoglobulin G (IgG) for targeting. Both micro- and nanoparticles formed stable suspensions in saline solution at particle concentrations of 10–50 mg/mL. The formulations were injected intraperitoneally and intravenously into the mice with experimental tuberculosis. The survival of control animals was compared to that of mice which were treated with daily oral drug solution, single intraperitoneal administration of drug-loaded particles, and those treated both intravenously and intraperitoneally by drug-loaded particles modified with polyclonal camel IgGs. The distribution of particles in the organs of mice was analyzed with immunofluorescence and liquid chromatography/mass spectrometry. Morphological changes related to tuberculosis and drug toxicity were registered. Phagocytic macrophages internalized particles and transported them to the foci of tuberculosis in inner organs. Nanoparticle-based drug formulations, especially those with IgG, resulted in better survival and lower degree of lung manifestations than the other modes of treatment.
6. A.-K. Rimpelä, I. Kiiski, F. Deng, H. Kidron, A. Urtti. Pharmacokinetic Simulations of Intravitreal Biologicals: Aspects on Drug Delivery to the Posterior and Anterior Segments. Pharmaceutics. 2019. V.11. I. 1. P.9. doi: 10.3390/pharmaceutics11010009.

Biologicals are important ocular drugs that are be delivered using monthly and bimonthly intravitreal injections to treat retinal diseases, such as age-related macular degeneration. Long acting delivery systems are needed for prolongation of their dosing interval. Intravitreal biologicals are eliminated from the eye via the aqueous humor outflow. Thus, the anterior and posterior segments are exposed to the drug. We utilized a kinetic simulation model to estimate protein drug concentrations in the vitreous and aqueous humor after bolus injection and controlled release administration to the vitreous. The simulations predicted accurately the experimental levels of 5 biologicals in the vitreous and aqueous humor. The good match between the simulations and experimental data demonstrated almost complete anterior segment bioavailability, and major dose sparing with ocular controlled release systems. Overall, the model is a useful tool in the design of intraocular delivery of biologicals.
7. A. Subrizi, E. M. del Amo, V. Korzhikov-Vlakh, T. Tennikova, M. Ruponen, A. Urtti. (2019). Design principles of ocular drug delivery systems: importance of drug payload, release rate, and material properties. Drug Discovery Today, Accepted for publication - In press. https://doi.org/10.1016/j.drudis.2019.02.001.

Ocular drugs are usually delivered locally to the eye. Required drug loading, release rate, and ocular retention time of drug delivery systems depend on the potency, bioavailability, and clearance of the drug at the target site. Drug-loading capacity of the formulation is limited by the material properties and size constraints of the eye. The design aid described herein for ocular drug delivery systems guides the calculation of steady-state drug concentrations in the ocular compartments, taking into account drug dose, bioavailability, and clearance. The dosing rate can be adjusted to reach the target drug concentrations, thereby guiding the design of drug delivery systems for topical, intravitreal, and subconjunctival administration. The simple design aid can be used at early stages of drug development by investigators without expertise in pharmacokinetic and pharmacodynamic modeling.

Back to top