Cytosolic NQO1 Enzyme-Activated Near-Infrared Fluorescence Imaging and Photodynamic Therapy with Polymeric Vesicles

Abstract

The utilization of enzymes as a triggering module could endow responsive polymeric nanostructures with selectivity in a site-specific manner. On the basis of the fact that endogenous NAD­(P)­H:quinone oxidoreductase isozyme 1 (NQO1) is overexpressed in many types of tumors, we report on the fabrication of photosensitizer-conjugated polymeric vesicles, exhibiting synergistic NQO1-triggered turn-on of both near-infrared (NIR) fluorescence emission and a photodynamic therapy (PDT) module. For vesicles self-assembled from amphiphilic block copolymers containing quinone trimethyl lock-capped self-immolative side linkages and quinone-bridged photosensitizers (coumarin and Nile blue) in the hydrophobic block, both fluorescence emission and PDT potency are initially in the “off” state due to “double quenching” effects, that is, dye-aggregation-caused quenching and quinone-rendered PET (photoinduced electron transfer) quenching. After internalization into NQO1-positive vesicles, the cytosolic NQO1 enzyme triggers self-immolative cleavage of quinone linkages and fluorogenic release of conjugated photosensitizers, leading to NIR fluorescence emission turn-on and activated PDT. This process is accompanied by the transformation of vesicles into cross-linked micelles with hydrophilic cores and smaller sizes and triggered dual drug release, which could be directly monitored by enhanced magnetic resonance (MR) imaging for vesicles conjugated with a DOTA­(Gd) complex in the hydrophobic bilayer. We further demonstrate that the above strategy could be successfully applied for activated NIR fluorescence imaging and tissue-specific PDT under both cellular and in vivo conditions.

Engineering Intelligent Nanosystems for Enhanced Medical Imaging

“…While many efforts are dedicated to sensing pH and hydrogen peroxide, many more biomedically relevant analytes may be measured, such as levels of ions, [63,[234][235][236][237] reactive oxygen or nitrogen species, [238][239][240][241][242][243][244][245][246] enzymes, [81,[247][248][249][250][251][252][253][254] glutathione, [255][256][257][258][259][260] and other biomarkers. [261][262][263] An example is the ratiometric hypochlorite sensor developed by Zou et al for the detection of arthritis ( Figure 11A).…”

Stimulus-Responsive Nanomedicines for Disease Diagnosis and Treatment

“…Without being triggered by NQO1, both fluorescence emission and photodynamic therapy (PDT) capability were turned off due to the “double quenching” effect. Upon cellular uptake, highly expressed NQO1 triggered the self-immolative cleavage of the quinone trimethyl lock, which then led to the release of photosensitizers, near infrared (NIR) emission and PDT activation, thereby realizing real-time monitoring and treatment of cancers [ 100 ].…”

Tumor Microenvironment-Responsive Nanomaterials as Targeted Delivery Carriers for Photodynamic Anticancer Therapy

“…Numerous studies have shown that NQO1 is upregulated in breast cancer, pancreatic cancer, colorectal cancer, cervical cancer, and lung cancer (Ma et al, 2014 ; Yang et al, 2014 ). Yao et al ( 2020 ) reported that NQO1-responsive multifunctional polymer vesicles (named BCPs) covalently conjugated with PS (coumarin and Nile Blue). In the absence of NQO1, due to the “dual quenching” effect, that is to say, the quenching caused by aggregation caused by photoinduced electron transfer (PET) and the quenching of quinone production, the fluorescence emission and PDT efficiency were in the “off” state.…”