Mitochondria-targeted accumulation of oxygen-irrelevant free radicals for enhanced synergistic low-temperature photothermal and thermodynamic therapy

Hongzhi Hu,Qingcheng Song,Wenbo Yang,Zengwu Shao,Jian Zhu,Junzhe Zhang,Yingze Zhang,Xiangtian Deng,Zihui Liang,Weijian Liu,Baichuan Wang,Yiran Zhang,Xin Xing,Shangyu Wang

doi:10.1186/s12951-021-01142-6

Abstract

BackgroundAlthough lower temperature (< 45 °C) photothermal therapy (LPTT) have attracted enormous attention in cancer therapy, the therapeutic effect is still unsatisfying when applying LPTT alone. Therefore, combining with other therapies is urgently needed to improve the therapeutic effect of LPTT. Recently reported oxygen-irrelevant free radicals based thermodynamic therapy (TDT) exhibit promising potential for hypoxic tumor treatment. However, overexpression of glutathione (GSH) in cancer cells would potently scavenge the free radicals before their arrival to the specific site and dramatically diminish the therapeutic efficacy.Methods and resultsIn this work, a core–shell nanoplatform with an appropriate size composed of arginine–glycine–aspartate (RGD) functioned polydopamine (PDA) as a shell and a triphenylphosphonium (TPP) modified hollow mesoporous manganese dioxide (H-mMnO2) as a core was designed and fabricated for the first time. This nanostructure endows a size-controllable hollow cavity mMnO2 and thickness-tunable PDA layers, which effectively prevented the pre-matured release of encapsulated azo initiator 2,2′-azobis[2-(2-imidazolin-2-yl) propane] dihydrochloride (AIBI) and revealed pH/NIR dual-responsive release performance. With the mitochondria-targeting ability of TPP, the smart nanocomposites (AIBI@H-mMnO2-TPP@PDA-RGD, AHTPR) could efficiently induce mitochondrial associated apoptosis in cancer cells at relatively low temperatures (< 45 °C) via selectively releasing oxygen-irrelevant free radicals in mitochondria and facilitating the depletion of intracellular GSH, exhibiting the advantages of mitochondria-targeted LPTT/TDT. More importantly, remarkable inhibition of tumor growth was observed in a subcutaneous xenograft model of osteosarcoma (OS) with negligible side effects.ConclusionsThe synergistic therapy efficacy was confirmed by effectively inducing cancer cell death in vitro and completely eradicating the tumors in vivo. Additionally, the excellent biosafety and biocompatibility of the nanoplatforms were confirmed both in vitro and in vivo. Taken together, the current study provides a novel paradigm toward oxygen-independent free-radical-based cancer therapy, especially for the treatment of hypoxic solid tumors.Graphical

Highlights

Photothermal therapy (PTT) has recently emerged as a promising cancer therapeutic strategy due to its merits of noninvasiveness, specific spatiotemporal selectivity, and negligible drug resistance [1, 2]
The synergistic therapy efficacy was confirmed by effectively inducing cancer cell death in vitro and completely eradicating the tumors in vivo
The current study provides a novel paradigm toward oxygen-independent free-radical-based cancer therapy, especially for the treatment of hypoxic solid tumors

Summary

Introduction

Photothermal therapy (PTT) has recently emerged as a promising cancer therapeutic strategy due to its merits of noninvasiveness, specific spatiotemporal selectivity, and negligible drug resistance [1, 2]. The therapeutic effect is still unsatisfying when applying low-temperature PTT (LPTT) alone, which is ascribed to inducible heat resistance of cancer cells, poor penetration of exogenous light stimulation, and low accumulation of photothermal agents in tumor sites [6]. These strategies still could not move away from the dependence on oxygen fundamentally In this regard, an ingenious strategy by using oxygen-irrelevant free radicals is expected to achieve effective antitumor thermodynamic therapy (TDT) under mild thermal stimulation [4, 12, 13]. We intend to develop a smart therapy strategy, which can selectively accumulate free radicals in mitochondria and simultaneously consume the intracellular GSH, to achieve synergistically enhanced LPTT/TDT. Overexpression of glutathione (GSH) in cancer cells would potently scavenge the free radicals before their arrival to the specific site and dramatically diminish the therapeutic efficacy

Methods

Results

Conclusion