Biodegradable reduce expenditure bioreactor for augmented sonodynamic therapy via regulating tumor hypoxia and inducing pro-death autophagy

Weijuan Zou,Jianrong Wu,Bing Hu,Xiaojun Cai,Yuanyi Zheng,Junnian Hao,Zhigang Wang

doi:10.1186/s12951-021-01166-y

Abstract

BackgroundsSonodynamic therapy (SDT) as an emerging reactive oxygen species (ROS)-mediated antitumor strategy is challenged by the rapid depletion of oxygen, as well as the hypoxic tumor microenvironment. Instead of the presently available coping strategies that amplify the endogenous O2 level, we have proposed a biodegradable O2 economizer to reduce expenditure for augmenting SDT efficacy in the present study.ResultsWe successfully fabricated the O2 economizer (HMME@HMONs-3BP-PEG, HHBP) via conjugation of respiration inhibitor 3-bromopyruvate (3BP) with hollow mesoporous organosilica nanoparticles (HMONs), followed by the loading of organic sonosensitizers (hematoporphyrin monomethyl ether; HMME) and further surface modification of poly(ethylene glycol) (PEG). The engineered HHBP features controllable pH/GSH/US-sensitive drug release. The exposed 3BP could effectively inhibit cell respiration for restraining the oxygen consumption, which could alleviate the tumor hypoxia conditions. More interestingly, it could exorbitantly elevate the autophagy level, which in turn induced excessive activation of autophagy for promoting the therapeutic efficacy. As a result, when accompanied with suppressing O2-consumption and triggering pro-death autophagy strategy, the HHBP could achieve the remarkable antitumor activity, which was systematically validated both in vivo and in vitro assays.ConclusionsThis work not only provides a reduce expenditure means for enduring SDT, but also represents an inquisitive strategy for tumor treatments by inducing pro-death autophagy.Graphical

Highlights

As an emerging cancer-treatment modality, sonodynamic therapy (SDT) employs sonosensitizers that are activated by ultrasound (US) in the presence of oxygen, which enables the generation of highly toxic reactive oxygen species (ROS) in cancer cells, primarily singlet oxygen (1O2) [1,2,3]
These characterization results above image of HHBP. h Hydrodynamic diameter of hollow mesoporous organosilica nanoparticles (HMONs), HMONs-NH2, HMONs-3BP, and HHBP. i The UV-vis absorption spectra of 3BP, hematoporphyrin monomethyl ether (HMME), HMONs, HMONs-3BP, HMME@HMONs-poly(ethylene glycol) (PEG), and HHBP. j The release profiles of HMME from HHBP at different pHs and GSH concentrations with or without US irradiation (1.0 W/cm2, 1.0 MHz, 50% duty circle, 1 min, n = 3). k Time-dependent oxidation of DPBF indicating 1O2 generation by HHBP under US irradiation. l electron spin resonance (ESR) spectra demonstrating 1O2 generation for different groups confirmed the porosity and hollow feature of the as-prepared HMONs-3BP, which is remained highly suitable for the encapsulation of hydrophobic molecules
transmission electron microscopy (TEM) observations revealed that the surface engineering and drug loading exhibited a negligible change in morphology (Fig. 2g), while the hydrodynamic diameter of HHBP was increased to 142 nm (Fig. 2h), which is slightly larger than that of HMONs-3BP

Summary

Introduction

As an emerging cancer-treatment modality, sonodynamic therapy (SDT) employs sonosensitizers that are activated by ultrasound (US) in the presence of oxygen, which enables the generation of highly toxic reactive oxygen species (ROS) in cancer cells, primarily singlet oxygen (1O2) [1,2,3]. The efficacy of SDT mainly depends on oxygen content inside the solid tumors, while several solid tumors often feature hypoxia triggered by the limited oxygen diffusion and the rapid proliferation of cancer cells [8,9,10,11]. This situation is further challenged by the fact that hypoxia gets further intensified during the SDT process, triggering SDT resistance. Promoted by the significant advances in nanomedicine, several expectant strategies aimed at modulating the level of oxygen in a solid tumor, such as delivering O2 to the hypoxic regions via oxygen-carrying nanomaterials and the in situ generations of O 2 by nanocatalysts/nanozymes-mediated hydrogen peroxide (H2O2) decomposition, have been exploited [11, 15,16,17,18,19,20]

Methods

Results

Conclusion