Моноклональные антитела к фактору роста эндотелия сосудов как векторы для доставки контейнерных систем в интракраниальную глиому C6 тема диссертации и автореферата по ВАК РФ 03.01.04, кандидат биологических наук Шеин, Сергей Александрович

• Шеин, Сергей Александрович
• кандидат биологических наук
• 2012

Оглавление диссертации кандидат биологических наук Шеин, Сергей Александрович

Список сокращений.

Актуальность.

Глава I. Обзор литературы: Фактор роста эндотелия сосудов как мишень противоопухолевой терапии.

Введение диссертации (часть автореферата) на тему «Моноклональные антитела к фактору роста эндотелия сосудов как векторы для доставки контейнерных систем в интракраниальную глиому C6»

Функции VEGF.10

Роль VEGF в развитии опухолей.18

Бевацизумаб в клинических исследованиях.24

Механизмы резистентности.28

Опухолевые стволовые клетки.34

Иммунолипосомы для адресной доставки лекарств.35

Заключение диссертации по теме «Биохимия», Шеин, Сергей Александрович

Выводы.

1. Модифицированный способ иммунизации мышей рекомбинантным препаратом VEGF-164 позволил получить В-лимфоциты селезенки, способные при слиянии с клетками миеломной культуры Sp2/0-Agl4 образовывать гибридные клетки, продуцирующие моноклональные анти-VEGF антитела изотипа G2a, характеризующиеся константой аффинности - 1,37±0,15х108 М"1. Полученные моноклональные анти-VEGF антитела способны специфично распознавать рекомбинантный и нативный VEGF в иммуноблот анализе, а также визуализировать VEGF-позитивные клетки.

2. Препарат моноклональных анти-VEGF антител, меченных флуорохромом Alexa Fluor 488 и введенных внутривенно, способен захватываются клетками интракраниальной глиомы и накапливаться в опухолевой ткани, визуализируясь в иммунофлуоресцентном анализе.

3. Терапия препаратом моноклональных анти-VEGF антител крыс с ортотопиче-ской глиомой С6 в концентрации 3 и 10 мг/кг при внутривенном введении не оказывает влияния на выживаемость экспериментальных животных и объем опухоли.

4. Конъюгация моноклональных анти-VEGF антител с магнитными наночастицами оксида железа (гидродинамический диаметр 90±5 нм), и холестерин- фосфатидилхолино-выми липосомами (210±10 нм) объективно повышает уровень их накопления в опухолевой ткани при внутривенном введении и качество визуализации глиом методами МРТ исследования в режиме SWI и флуоресцентного анализа.

5. Внутривенное введение крысам с интракраниальной глиомой С6 ПЭГилирован-ных липосом, конъюгированных с моноклональными анти-VEGF антителами (2,58±0,17 нмоль антител), приводит к их специфичному захвату клетками глиомы и реактивными астроцитами, а также позволяет визуализировать накопление в опухолевой ткани.

Благодарности.

Автор выражает искреннюю благодарность научным руководителям Владимиру Павловичу Чехонину и Ольге Ивановне Гуриной за неоценимую помощь на протяжении всей работы и ценные советы, Наталье В. Нуколовой за помощь в работе с липосомами, Максиму А. Абакумову за помощь в работе с наночастицами, Анне В. Леопольд за помощь в наработке и очистке рекомбинантного VEGF, Надежде Е. Волгиной за помощь в работе к культурой HUVEC, Карине ТУТ. Кардашовой за помощь в работе с гибридными клетками, Владимиру Павловичу Баклаушеву и Гаухар Маратовне Юсубалиевой за помощь в освоении иммунохимических и хирургических методов, Надежде Филипповне Гриненко за помощь в работе с культурами клеток, Клавдии Павловне Ионовой и сотрудникам вивария за помощь в работе с животными, Кристине В. Новиковой и Анне А. Корчагиной за помощь в работе по исследованию биологической активности антител in vitro, Михаилу В. Гуляеву за помощь в МРТ сканировании животных при антиангиогенной терапии, Мельникову Павлу за помощь в лазерной конфокальной микроскопии.

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