Hypoxia-responsive nanoreactors based on self-enhanced photodynamic sensitization and triggered ferroptosis for cancer synergistic therapy

Xiaoyan Wang,Ming Wu,Xinyi Lin,Jingfeng Liu,Xiaolong Zhang,Feida Li,Yongyi Zeng,Xiaolong Liu

doi:10.1186/s12951-021-00952-y

Abstract

BackgroundPhotodynamic therapy (PDT), a typical reactive oxygen species (ROS)-dependent treatment with high controllability, has emerged as an alternative cancer therapy modality but its therapeutic efficacy is still unsatisfactory due to the limited light penetration and constant oxygen consumption. With the development of another ROS-dependent paradigm ferroptosis, several efforts have been made to conquer the poor efficacy by combining these two approaches; however the biocompatibility, tumor-targeting capacity and clinical translation prospect of current studies still exist great concerns. Herein, a novel hypoxia-responsive nanoreactor BCFe@SRF with sorafenib (SRF) loaded inside, constructed by covalently connecting chlorin e6 conjugated bovine serum albumin (BSA-Ce6) and ferritin through azobenzene (Azo) linker, were prepared to offer unmatched opportunities for high-efficient PDT and ferroptosis synergistic therapy.ResultsThe designed BCFe@SRF exhibited appropriate size distribution, stable dispersity, excellent ROS generation property, controllable drug release capacity, tumor accumulation ability, and outstanding biocompatibility. Importantly, the BCFe@SRF could be degraded under hypoxia environment to release BSA-Ce6 for laser-triggered PDT, ferritin for iron-catalyzed Fenton reaction and SRF for tumor antioxidative defense disruption. Meanwhile, besides PDT effects, it was found that BCFe@SRF mediated treatment upon laser irradiation in hypoxic environment not only could accelerate lipid peroxidation (LPO) generation but also could deplete intracellular glutathione (GSH) and decrease glutathione peroxidase (GPX4) expression, which was believed as three symbolic events during ferroptosis. All in all, the BCFe@SRF nanoreactor, employing multiple cascaded pathways to promote intracellular ROS accumulation, presented remarkably outstanding antitumor effects both in vitro and in vivo.ConclusionBCFe@SRF could serve as a promising candidate for synergistic PDT and ferroptosis therapy, which is applicable to boost oxidative damage within tumor site and will be informative to future design of ROS-dependent therapeutic nanoplatforms.Graphic abstract

Highlights

Photodynamic therapy (PDT), a typical reactive oxygen species (ROS)-dependent treatment with high controllability, has emerged as an alternative cancer therapy modality but its therapeutic efficacy is still unsatisfactory due to the limited light penetration and constant oxygen consumption
A novel protein-based nanoreactor BCFe@ SRF was developed by covalently crosslinking chlorin e6 (Ce6, a typical PS) [8] conjugated bovine serum albumin (BSA) and ferritin by hypoxia-responsive unit azobenzene (Azo), together with the SRF encapsulated inside the protein shell (Fig. 1)
The dynamic light scattering (DLS) data revealed that the hydrodynamic size of BCFe@SRF was 102.6 ± 1.3 nm with polydispersity index (PDI) of 0.28 and the zeta potential changed to − 2.7 ± 0.6 mV (Fig. 2d, e, Additional file 1: Table S1), indicating the successful fabrication of BCFe@SRF

Summary

Introduction

Photodynamic therapy (PDT), a typical reactive oxygen species (ROS)-dependent treatment with high controllability, has emerged as an alternative cancer therapy modality but its therapeutic efficacy is still unsatisfactory due to the limited light penetration and constant oxygen consumption. Reactive oxygen species (ROS)-dependent treatment, as an alternative cancer therapeutic paradigm, has recently gained tremendous attentions [1, 2]. Photodynamic therapy (PDT), a typical oxidative therapeutic modality, employs photo-activated photosensitizers (PSs) to transfer the absorbing laser energy to surrounding oxygen molecules and subsequently generate high levels of 1O2 to kill cancer cells [5, 6]. The low tumor accumulation of PSs after intravenous injection, limited light penetration and the constant oxygen consumption during PDT make it difficult to produce enough ROS in vivo [7,8,9]. Boosting ROS production within tumor sites and simultaneously disrupting the oxidation defense of tumor cells should be a promising strategy to improve the antitumor efficiency

Methods

Results

Conclusion