Russian Journal of BiotherapyRussian Journal of BiotherapyРоссийский биотерапевтический журнал1726-97841726-9792Publishing House ABV Press125510.17650/1726-9784-2021-20-2-31-41REVIEWSОБЗОРЫ ЛИТЕРАТУРЫNOVEL IMMUNOTHERAPEUTIC TARGETED GRANZYME DELIVERY SYSTEMS IN TREATMENT OF MALIGNANT TUMORSСОВРЕМЕННЫЕ ИММУНОТЕРАПЕВТИЧЕСКИЕ ТАРГЕТНЫЕ СИСТЕМЫ ДОСТАВКИ ГРАНЗИМОВ В ЛЕЧЕНИИ ЗЛОКАЧЕСТВЕННЫХ НОВООБРАЗОВАНИЙhttps://orcid.org/0000-0002-3347-9674YaroshI. V.ЯрошИ. В.
Russian Federation

Ilya Valerievich Yarosh

Bld. 2, 8 Trubetskaya St., Moscow 119991

Илья Валерьевич Ярош

119991 Москва, ул. Трубецкая, 8, стр. 2

ilya96yarosh@gmail.comhttps://orcid.org/0000-0002-0762-5631MisyurinV. A.МисюринВ. А.
Russian Federation

24 Kashirskoe Shosse, Moscow 115478

115478 Москва, Каширское шоссе, 24

https://orcid.org/0000-0003-4382-7377KrasnyukI. I.КраснюкИ. И.
Russian Federation

Bld. 2, 8 Trubetskaya St., Moscow 119991

119991 Москва, ул. Трубецкая, 8, стр. 2

I.M. Sechenov First Moscow State Medical University (Sechenov University), Ministry of Health of RussiaФГАОУ ВО Первый Московский государственный медицинский университет им. И. М. Сеченова Минздрава России (Сеченовский Университет)N.N. Blokhin National Medical Research Center of Oncology, Ministry of Health of RussiaФГБУ «Национальный медицинский исследовательский центр онкологии им. Н. Н. Блохина» Минздрава России1407202120231411407202114072021https://bioterapevt.abvpress.ru/jour/article/view/1255

Cytotoxicity is the main human killer cell property. The cytotoxicity reaction of human killer cells is achieved through a complex of molecules, including perforins, granzyme, cathepsin and others. However, only one molecule is enough for target cell death: granzyme. Other molecules are intended for granzyme activation and its delivery to the target cell cytoplasm. Granzymes are a whole family of serine proteases that perform their function in the human body as integral cytolytic effectors during programmed cell death of cancer and pathogen-infected cells. Secreted mainly by cytotoxic T-lymphocytes and NK-cells, granzymes initiate apoptosis via caspase-dependent and caspase-independent pathways. These natural properties make granzymes one of the most promising human enzymes for use in the development of targeted therapeutic strategies in the treatment of various types of cancer.The most promising is granzyme B, because it has the most powerful effector properties. Due to the initiation of cascade reactions that activate apoptosis, granzyme is attractive as a basis for the development of medicines applicable in clinical oncology. At this time, several approaches have been developed for delivering granzyme molecules to tumor cells and facilitating its penetration through the cell membrane. Moreover, some solutions are proposed to overcome the resistance of target cells to granzyme-mediated apoptosis. These approaches are discussed in this review.The purpose of this review was to systematize information on the use of granzyme B as a nanostructured drug delivery system in the treatment of solid and hematological malignancies. In addition, this review discusses ways to overcome the resistance of granzyme penetration into target cells.

Основное свойство, которым обладают киллерные клетки человека, – цитотоксичность. Реакция цитотоксичности киллерных клеток человека достигается при помощи комплекса молекул, в том числе перфоринов, гранзима, катепсина и др. При этом для гибели клеток-мишеней достаточно всего 1 молекулы – гранзима, тогда как остальные молекулы предназначены для его активации и доставки в цитоплазму клеток-мишеней.Предметом настоящего обзора являются гранзимы, которые представляют собой семейство сериновых протеаз и выполняют свою функцию в  организме человека как  интегральные цитолитические эффекторы во время программируемой клеточной смерти раковых и патоген-инфицированных клеток. Секретируемые преимущественно цитотоксическими Т-лимфоцитами и натуральными киллерами, гранзимы осуществляют инициацию апоптоза по каспазозависимым и каспазонезависимым путям. Данные природные свойства делают гранзимы одними из наиболее перспективных человеческих ферментов для использования при разработке целевых терапевтических стратегий в лечении различных видов рака. При  этом наиболее привлекательным является гранзим B, так как он обладает наиболее сильными эффекторными свойствами. К настоящему времени разработано несколько подходов для доставки молекул гранзима к опухолевым клеткам и облегчения его проникновения через клеточную мембрану. Более того, предлагаются некоторые решения по преодолению резистентности клеток-мишеней к гранзим-опосредованному апоптозу.Цель данного обзора литературы – систематизация информации о применении гранзима B в исследованиях как компонента наноструктурных систем доставки лекарственных препаратов для лечения со́лидных и гематологических злокачественных новообразований. Кроме того, в настоящем обзоре рассмотрены преимущества и сложности использования гранзимов.

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