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

Elena I. Shramova; Stepan P. Chumakov; Victoria O. Shipunova; Anastasiya V. Ryabova; Georgij B. Telegin; Andrei V. Kabashin; Sergey M. Deyev; Galina M. Proshkina

doi:10.1038/s41377-022-00729-4

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

Articles

- Genetically encoded BRET-activated photodynamic therapy for the treatment of deep-seated tumors
- Light: Science & Applications Vol. 11, Issue 3, Pages: 311-323(2022)
- Affiliations：
  
  1.Shemyakin–Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, 16/10 Miklukho-Maklaya Street, Moscow, 117997, Russia
  2.MEPhI (Moscow Engineering Physics Institute), Institute of Engineering Physics for Biomedicine (PhysBio), 31 Kashirskoe shosse, Moscow, 115409, Russia
  3.Prokhorov General Physics Institute, Russian Academy of Sciences, Vavilova, 38, Moscow, 119991, Russia
  4.Branch of Shemyakin and Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, Prospect Nauki 6, Pushchino, 142290, Russia
  5.Aix Marseille University, CNRS, LP3, 163 Ave. De Luminy, Case 917, 13288, Marseille, France
- Author bio：
  
  Sergey M. Deyev (biomem@mail.ru)
  Galina M. Proshkina (gmb@ibch.ru)
- Funds：
- DOI：10.1038/s41377-022-00729-4
  CLC：
- Published：31 March 2022，
  
  Published Online：21 February 2022，
  
  Received：17 June 2021，
  
  Revised：17 January 2022，
  
  Accepted：31 January 2022
- Accepted：
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Shramova, E. I. et al. Genetically encoded BRET-activated photodynamic therapy for the treatment of deep-seated tumors. Light: Science & Applications, 11, 311-323 (2022).
DOI：

Shramova, E. I. et al. Genetically encoded BRET-activated photodynamic therapy for the treatment of deep-seated tumors. Light: Science & Applications, 11, 311-323 (2022). DOI： 10.1038/s41377-022-00729-4.

摘要

Abstract

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.

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references

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