Выбор и применение антиоксидантов-радиопротекторов в составе терапевтических радиофармпрепаратов (обзор)

Введение. Применение радиофармацевтических препаратов для таргетной радионуклидной терапии (РНТ), эффективность которых была установлена в ходе клинических исследований, является безопасным и эффективным методом терапии различных патологических состояний, в том числе онкологических заболеваний. Основной особенностью терапевтических радиофармацевтических лекарственных препаратов (РФЛП) является использование β^–- и α-излучающих радионуклидов (РН) в готовой лекарственной форме (ГЛФ). Среди радионуклидов, используемых для радионуклидной терапии, лютеций-177 на сегодняшний день является одним из наиболее популярных в клинической практике, что обусловлено его химическими и ядерно-физическими характеристиками. Список разрабатываемых РФЛП на основе лютеция-177 постоянно расширяется, а препараты Lutathera® ([¹⁷⁷Lu]Lu-DOTA-TATE) и Pluvicto™ ([¹⁷⁷Lu]Lu-PSMA-617) уже одобрены для применения в клинической практике ряда стран.

Текст. Ввиду высокой активности РН в одной дозе терапевтического РФЛП (до 8 ГБк в монодозе для ¹⁷⁷Lu) ионизирующее излучение используемых РН приводит к снижению качества РФЛП из-за радиолитической деградации векторной молекулы. Это приводит к снижению специфичного накопления радиоактивности в очагах патологии, снижению терапевтического эффекта и потенциально увеличивает риск радиотоксичности для нецелевых органов и тканей. Степень и интенсивность радиолитической деградации векторной молекулы, а следовательно и срок хранения ГЛФ РФЛП, зависят от многих факторов, среди которых объемная активность радионуклида в препарате, его период полураспада и энергия испускаемых частиц являются наиболее весомыми. Для подавления эффектов радиолиза в составы готовых лекарственных форм вводят различные вспомогательные вещества, проявляющие антиоксидантные (радиопротекторные) свойства. Среди используемых и исследуемых веществ наиболее популярными являются гентизиновая и аскорбиновая кислоты, а также этанол. В данной работе на примерах препаратов лютеция-177 рассмотрены преимущества и недостатки различных антиоксидантов и их комбинаций, используемых в составе терапевтических РФЛП.

Заключение. Подбор оптимального состава лекарственной формы является актуальной задачей, так как позволит обеспечить высокое качество РФЛП как на момент приготовления, так и в течение срока хранения и поставки конечному потребителю, что существенно облегчит применение и централизованную поставку терапевтических РФЛП. Показана необходимость создания унифицированного подхода к подбору антиоксидантов на стадии фармацевтической разработки радиофармпрепаратов. Для достижения этой цели весьма перспективным и доказавшим свою эффективность представляется подход, объединяющий исследования кинетики радикальных реакций с исследованиями радиационно-химических выходов продуктов радиолиза в одинаковых или максимально близких условиях с последующей проверкой стабильности ГЛФ РФЛП. Напротив, эмпирический подход, подразумевающий подбор радиопротекторов на основе прямого исследования их влияния на сохранение уровня радиохимической чистоты, является неоптимальным ввиду высокой рыночной стоимости как радионуклидов, так и нерадиоактивных прекурсоров.

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