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

Light(Science & Applications) 2022年第3期11卷 22-34页

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 Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry Russian Academy of Sciences16/10 Miklukho-Maklaya StreetMoscow 117997Russia MEphI(Moscow Engineering physics Institute) Institute of Engineering Physics for Biomedicine(PhysBio)31 Kashirskoe shosseMoscow 115409Russia prokhorov General physics Institute Russian Academy of SciencesVavilova38Moscow 119991Russia Branch of Shemyakin and Ovchinnikov Institute of Bioorganic Chemistry Russian Academy of SciencesProspect Nauki 6Pushchino 142290Russia Aix Marseille University CNRSLP3163 Ave.De LuminyCase 91713288 MarseilleFrance

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 ***,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 *** illustrate the concept,we engineered genetic NanoLuc-miniSOG BRET pair,combining NanoLuc luciferase flashlight and phototoxic flavoprotein miniSOG,which generates ROS under luciferase-substrate *** prove the concept feasibility in mice bearing NanoLuc-miniSOG expressing tumor,followed by its elimination under the luciferase-substrate ***,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 *** 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.

关键词： neoplasms injection treatment

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