Tumor Microenvironment-Activated Degradable Multifunctional Nanoreactor for Synergistic Cancer Therapy and Glucose SERS Feedback

Abstract

Integration of disease diagnosis and therapy in vivo by nanotechnology is a challenge in the design of multifunctional nanocarriers. Herein, we report an intelligent and degradable nanoreactor, an assembly of the 4-mercaptobenzonitrile-decorated silver nanoparticles (AgNPs@MBN) and the glucose oxidase (GOx)-loaded metal-organic-framework (ZIF-8@GOx), which can be activated by tumor microenvironment to start the catalytic cascade-enhanced chemo-starvation synergistic therapy and simultaneous self-sense of cellular glucose level. Under the mild acidic microenvironment of tumor, the nanoreactor will collapse to release GOx that triggers a catalytic cascade reaction in vivo, depleting glucose, etching AgNPs@MBN, and producing toxic H 2 O 2 , Ag + , and Zn 2+ ions, all of which work together to inhibit tumor growth. The AgNPs@MBN as SERS nanoprobe reads out glucose concentration noninvasively in tumor to achieve instant feedback of therapeutic progression. This work proposes a promising example of using enzyme-encapsulated biomineralized MOFs as an effective anticarcinogen for clinical applications.Recently, glucose oxidase (GOx)-based cancer starvation therapy that depletes glucose and engenders toxic H 2 O 2 /gluconic acid in the presence of oxygen has been explored (Chang et al., 2017;Wang et al., 2016; Zhang et al., 2018a) as a targeting therapeutic strategy for cancers due to its powerful ability to change tumor microenvironments. Moreover, the generated H 2 O 2 not only markedly enhances tumor oxidative stress but also can be converted into $OH radicals to kill cancer cells (Wang et al., 2019b). Thus this strategy can be further integrated with other therapeutic methods to achieve enhanced synergistic therapeutic effects (Wang et al., 2019c;Ma et al., 2019;Tang et al., 2019). The naked GOx exposed in biological environments is particularly prone to inactivation. Also, it has the weaknesses of short in vivo half-life, immunogenicity, and systematic toxicity (Fu et al., 2018). Thus, nanocarriers (inorganic or organic) for GOx (Wang et al., 2016; Zhang et al., 2018a) are highly suggested in many GOx-based starvation therapeutic strategies. However, these nanocarriers are usually undegradable in vivo, and hence may cause biotoxicity. Therefore, a degradable and intelligent nanocarrier for precise GOx-based starvation therapy is urgently desired.Metal-organic frameworks (MOFs) are a class of highly crystalline, porous, and degradable solid-state materials constructed by metal ions and organic linkers (Wang et al., 2019a;Schoedel et al., 2016). It affords a promising biomedical nanocarrier platform for encapsulating drugs, antibodies, genes, enzymes, etc. (Feng et al., 2018;Chen et al., 2019) for in vivo drug delivery. These MOF cages can protect proteins from the attack of proteases and the clearance of the mononuclear phagocyte system in physiological environments (

Glucose Metabolism Intervention-Facilitated Nanomedicine Therapy

“… 173 , 174 Sun et al developed ZIF-8@GOx-AgNPs@MBN based on ZIF-8 MOF, co-delivering GOx and AgNPs. 175 Owing to its acidic breakdown property, ZIF-8 crumbled to release cargos while generating Zn 2+ , realizing spatial tumor treatment. Zn 2+ , along with Ag + generated from AgNPs, served as metal-ion therapy agents.…”

Recent Advances in Metal Organic Frameworks Based Surface Enhanced Raman Scattering Substrates: Synthesis and Applications

“…In situ synthesis of SERS-active metal NPs on the surface of MOFs is easy to conduct but facing difficulties in controlling the size and distribution of NPs. Different strategies for assembling as-prepared SERS-active metal NPs on the surface of MOFs were reported, such as chemical bond connection [ 54 ], electrodeposition [ 32 ], and electrostatic affinity [ 55 ]. In these methods, the morphology and coverage of SERS-active metal NPs can be well controlled.…”

“…MOF based SERS substrates have been explored in the design of versatile nanocarriers for cancer diagnosis and therapy. For example, a degradable nanoreactor was constructed by assembling Ag NP@4-mercaptobenzonitrile (MBN) SERS tags on the surface of ZIF8@Glucose oxidase (GOx) and was used for synergistic cancer therapy and simultaneous glucose monitoring by SERS [ 55 ]. This nanoreactor can be activated by tumor microenvironment to start the catalytic enhanced metal ion poisoning and starvation synergistic therapy and to be used as SERS substrate for monitoring of cellular glucose level.…”

Recent progress of surface-enhanced Raman spectroscopy for subcellular compartment analysis

“…The surface element (AgNPs@MBN) of the nanoreactor has the function of in-situ SERS reporting glucose level in cells based on a ''turn-off'' mechanism (intensity decrease) of the Raman reporter (MBN) induced by the H 2 O 2 etching effect on the AgNPs. Thus, the enzymatic activity of GOx and the degradability of the nanoreactor in an acidic environment can be monitored; that is, this nanosensor can immediately feedback the curative effect by SERS 138 .…”