Generic synthesis of small-sized hollow mesoporous organosilica nanoparticles for oxygen-independent X-ray-activated synergistic therapy

Wenpei Fan ,Yang Zhang ,Wei Tang ,Guangming Lu ,Nan Lü ,Zijian Zhou ,Zhantong Wang ,Bo Shen ,Orit Jacobson ,Niveen M Khashab ,Zhaowen Cui ,Weijing Yang ,Yijing Liu ,Liwen Zhang ,Jibin Song ,Ping Hu ,Zhèn Yáng ,Zheyu Shen ,Maria A Aronova ,Lingling Shan ,Xiaoyuan Chen

doi:10.1038/s41467-019-09158-1

Abstract

The success of radiotherapy relies on tumor-specific delivery of radiosensitizers to attenuate hypoxia resistance. Here we report an ammonia-assisted hot water etching strategy for the generic synthesis of a library of small-sized (sub-50 nm) hollow mesoporous organosilica nanoparticles (HMONs) with mono, double, triple, and even quadruple framework hybridization of diverse organic moieties by changing only the introduced bissilylated organosilica precursors. The biodegradable thioether-hybridized HMONs are chosen for efficient co-delivery of tert-butyl hydroperoxide (TBHP) and iron pentacarbonyl (Fe(CO)5). Distinct from conventional RT, radiodynamic therapy (RDT) is developed by taking advantage of X-ray-activated peroxy bond cleavage within TBHP to generate •OH, which can further attack Fe(CO)5 to release CO molecules for gas therapy. Detailed in vitro and in vivo studies reveal the X-ray-activated cascaded release of •OH and CO molecules from TBHP/Fe(CO)5 co-loaded PEGylated HMONs without reliance on oxygen, which brings about remarkable destructive effects against both normoxic and hypoxic cancers.

Highlights

The success of radiotherapy relies on tumor-specific delivery of radiosensitizers to attenuate hypoxia resistance
The large-sized hollow mesoporous organosilica nanoparticles (HMONs) over hundreds of nanometers suffer from short blood circulation and poor tumor accumulation[14,17], which underscores the need for small-sized HMONs below 50 nm for considerable tumor accumulation by achieving the win–win between the decreased RES uptake and the increased EPR effect[18,19,20]
Some methods have been reported for the preparation of HMONs14,21–23, it is still essential to work out a generic strategy to synthesize a library of sub-50 nm HMONs with multiple framework hybridization of diverse organic moieties, which may broaden their wide applications

Summary

Introduction

The success of radiotherapy relies on tumor-specific delivery of radiosensitizers to attenuate hypoxia resistance. To verify the advantage of this ammonia-assisted hot water etching strategy in the generic synthesis of a library of sub-50 nm HMONs with multiple framework hybridization, four kinds of representative bissilylated organosilica precursors (BTES with thioether moiety, BTEB with phenylene moiety, BTEE with ethane moiety, BTEEE with ethylene moiety) were adopted to form the outer MON layer.

Results

Conclusion