Genetically encoded BRET-activated photodynamic therapy for the treatment of deep-seated tumors

• 作者: Elena I.Shramova Stepan P.Chumakov Victoria O.Shipunova Anastasiya V.Ryabova Georgij B.Telegin Andrei V.Kabashin Sergey M.Deyev Galina M.Proshkina
• 来源期刊: 光：科学与应用（英文版）
• 年，卷（期）: 2022,（3）
• 所属期刊栏目: Articles
• 页码范围: 311-323
• 页数: 13页
• 语种: 英文

摘要

Photodynamic therapy (PDT) is one of the most appealing photonic modalities for cancer treatment based on anticancer activity of light-induced photosensitizer-mediated reactive oxygen species (ROS), but a limited depth of light penetration into tissues does not make possible the treatment of deep-seated neoplasms and thus complicates its widespread clinical adoption. Here, we introduce the concept of genetically encoded bioluminescence resonance energy transfer (BRET)-activated PDT, which combines an internal light source and a photosensitizer (PS) in a single-genetic construct, which can be delivered to tumors seated at virtually unlimited depth and then triggered by the injection of a substrate to initiate their treatment. To illustrate the concept, we engineered genetic NanoLuc-miniSOG BRET pair, combining NanoLuc luciferase flashlight and phototoxic flavoprotein miniSOG, which generates ROS under luciferase-substrate injection. We prove the concept feasibility in mice bearing NanoLuc-miniSOG expressing tumor, followed by its elimination under the luciferase-substrate administration. Then, we demonstrate a targeted delivery of NanoLuc-miniSOG gene, via tumor-specific lentiviral particles, into a tumor, followed by its successful elimination, with tumor-growth inhibition (TGI) coefficient exceeding 67％, which confirms a great therapeutic potential of the proposed concept. In conclusion, this study provides proof-of-concept for deep-tissue"photodynamic"therapy without external light source that can be considered as an alternative for traditional PDT.