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.
Highlights
Photodynamic therapy (PDT) presents one of exciting photon therapy implementations, which can combine high efficiency and point localization of therapeutic action[1,2,3]
Later studies reported the development of a series of Bioluminescence Resonance Energy Transfer (BRET)-based agents for PDT, including Renilla reniformis luciferase conjugated to polymer-coated CdSe/ ZnS quantum dots (QDs) emitting at 655 nm (QD655RLuc8)[14,15], Renilla luciferase conjugated to Rose Bengal[16], Renilla luciferase (Rluc8) conjugated carboxylated QD655 and chlorin e617, ferritin-luciferase nanoplatform conjugated to zinc (II)-protoporphyrin IX18, firefly luciferase conjugated with Rose Bengal in complex with biodegradable poly(lactic-co-glycolic acid) (PLGA) nanoparticles[19], etc
Currently available BRET complexes for PDT using chemically assembled compounds based on the conjugation of luciferase with quantum dots[14,15,17] or other substances[16,18,19] still have major problems for potential clinical applications, including the difficulty of structure optimization and stabilization, complicated and costly conjugation protocols, and toxicity of involved compounds
Summary
Photodynamic therapy (PDT) presents one of exciting photon therapy implementations, which can combine high efficiency and point localization of therapeutic action[1,2,3]. Later studies reported the development of a series of BRET-based agents for PDT, including Renilla reniformis luciferase conjugated to polymer-coated CdSe/ ZnS quantum dots (QDs) emitting at 655 nm (QD655RLuc8)[14,15], Renilla luciferase conjugated to Rose Bengal[16], Renilla luciferase (Rluc8) conjugated carboxylated QD655 and chlorin e617, ferritin-luciferase nanoplatform conjugated to zinc (II)-protoporphyrin IX18, firefly luciferase conjugated with Rose Bengal in complex with biodegradable poly(lactic-co-glycolic acid) (PLGA) nanoparticles[19], etc Such compound agents promise the treatment of deep-seated tumors, but their design and applications still face major challenges. The synthesis of these agents requires complicated and costly protocols, while most used compounds included non-biocompatible substances such as highly toxic Cd-containing QDs, which strongly complicates clinical applications prospects
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