Endogenous H2S-Triggered In Situ Synthesis of NIR-II-Emitting Nanoprobe for In Vivo Intelligently Lighting Up Colorectal Cancer

摘要

class="head no_bottom_margin" id="sec1title">IntroductionAmong adults older than 50 years, colorectal cancer incidence rates had increased by 22% from 2000 to 2013, which was one of the most common malignancies in the world (, ). Also, some clinical diagnostic methods for colorectal cancer such as colonoscopy, surgical procedures, and carcinoembryonic antigen are well explored (, , , , ). However, all these traditional methods still suffer from some inevitable drawbacks, including extensive medical experience needed, low sensitivity, and great pain to patients (, , , , ). Therefore the development of a non-invasive early diagnostic technique with high sensitivity is urgently demanded for specific visualization of colorectal cancer.Optical imaging method capable of providing direct visualization of disease with high spatial/temporal resolution and high sensitivity has emerged as an indispensable tool for non-invasive disease diagnosis (, , , href="#bib49" rid="bib49" class=" bibr popnode">Zhao et al., 2016). Differing from conventional optical imaging by using the visible and first near-infrared (NIR-I, 700–900 nm) regions, second NIR (NIR-II) optical imaging with emission ranging from 1,000 to 1,700 nm is considered as the next-generation advanced optical imaging technique with superior imaging sensitivity and significant improvement in spatial resolution owing to the remarkably reduced scattering losses (href="#bib19" rid="bib19" class=" bibr popnode">Hong et al., 2012a, href="#bib20" rid="bib20" class=" bibr popnode">Hong et al., 2012b, href="#bib21" rid="bib21" class=" bibr popnode">Hong et al., 2014a, href="#bib22" rid="bib22" class=" bibr popnode">Hong et al., 2014b, href="#bib31" rid="bib31" class=" bibr popnode">Naczynski et al., 2013, href="#bib9" rid="bib9" class=" bibr popnode">Dang et al., 2016, href="#bib50" rid="bib50" class=" bibr popnode">Zhao et al., 2018). In vivo NIR-II imaging began with the utilization of single-walled carbon nanotubes (href="#bib21" rid="bib21" class=" bibr popnode">Hong et al., 2014a, href="#bib22" rid="bib22" class=" bibr popnode">Hong et al., 2014b, href="#bib23" rid="bib23" class=" bibr popnode">Hong et al., 2015, href="#bib10" rid="bib10" class=" bibr popnode">Diao et al., 2015); since then, several other probes including small-molecule dyes (href="#bib46" rid="bib46" class=" bibr popnode">Yang et al., 2018), semiconductor quantum dots (href="#bib2" rid="bib2" class=" bibr popnode">Bruns et al., 2017, href="#bib19" rid="bib19" class=" bibr popnode">Hong et al., 2012a, href="#bib20" rid="bib20" class=" bibr popnode">Hong et al., 2012b), and rare-earth-doped materials (href="#bib55" rid="bib55" class=" bibr popnode">Zhong et al., 2017, href="#bib27" rid="bib27" class=" bibr popnode">Li et al., 2018, href="#bib28" rid="bib28" class=" bibr popnode">Li et al., 2019, href="#bib45" rid="bib45" class=" bibr popnode">Xue et al., 2018) have been explored for in vivo NIR-II imaging. However, most of the developed NIR-II probes presented low specificity for tumor diagnosis, resulting in the absence of targeting visualization of colorectal cancer. Therefore the development of probe with high sensitivity, excellent spatial resolution, and tumor-targeted properties holds great significance for improving the diagnostic sensitivity.It is well known that colon cancer cells overexpress cystathionine-β-synthase, resulting in larger amounts of H2S in tumor than the adjacent normal tissue or non-transformed cells (href="#bib36" rid="bib36" class=" bibr popnode">Szabo et al., 2013). Various fluorescent probes for H2S intracellular imaging were successfully developed by using the visible and NIR-I region (href="#bib30" rid="bib30" class=" bibr popnode">Lin et al., 2015, href="#bib48" rid="bib48" class=" bibr popnode">Yu et al., 2014, href="#bib40" rid="bib40" class=" bibr popnode">Wang et al., 2013a, href="#bib41" rid="bib41" class=" bibr popnode">Wang et al., 2013b, href="#bib38" rid="bib38" class=" bibr popnode">Wang et al., 2018, href="#bib42" rid="bib42" class=" bibr popnode">Wang et al., 2019, href="#bib34" rid="bib34" class=" bibr popnode">Shi et al., 2017, href="#bib52" rid="bib52" class=" bibr popnode">Zhang et al., 2017a, href="#bib53" rid="bib53" class=" bibr popnode">Zhang et al., 2017b). However, few probes have been employed for in vivo H2S-stimulated imaging owing to the limitations of penetration depth and poor spatial resolution by using the traditional visible and NIR-I optical imaging (href="#bib30" rid="bib30" class=" bibr popnode">Lin et al., 2015, href="#bib48" rid="bib48" class=" bibr popnode">Yu et al., 2014, href="#bib40" rid="bib40" class=" bibr popnode">Wang et al., 2013a, href="#bib41" rid="bib41" class=" bibr popnode">Wang et al., 2013b). Undoubtedly, H2S-activated emissions in NIR-II window can provide valuable insight into the accurate and specific diagnosis of colorectal cancers in vivo. Nevertheless, in situ endogenous H2S-activated NIR-II-emissive probes for targeting diagnosis of colon cancer was still scarcely explored. Very recently, a conceptual study was proposed by designing an H2S-activated NIR-II optical probe based on the core-shell silica nanocomposites encapsulating an H2S-responsive organic molecule for detection of colon cancer in vivo (href="#bib44" rid="bib44" class=" bibr popnode">Xu et al., 2018). However, this NIR-II fluorescence imaging probe suffers from some intrinsic problems, such as the complex synthesis process, photo-bleaching, and low photo-stability of organic molecular probes, which impede its further applications in bioimaging fields (href="#bib17" rid="bib17" class=" bibr popnode">He et al., 2018, href="#bib35" rid="bib35" class=" bibr popnode">Shi et al., 2018). Therefore, developing a new H2S-activated inorganic nanoparticulate probe with highly simple synthesis method, non-photo-bleaching nature, high quantum yield (QY), and high photo-stability is highly desirable.Biomolecule-assisted synthesis (href="#bib56" rid="bib56" class=" bibr popnode">Zhou et al., 2015, href="#bib11" rid="bib11" class=" bibr popnode">Dickerson et al., 2008, href="#bib40" rid="bib40" class=" bibr popnode">Wang et al., 2013a, href="#bib41" rid="bib41" class=" bibr popnode">Wang et al., 2013b, href="#bib3" rid="bib3" class=" bibr popnode">Chen et al., 2015a, href="#bib4" rid="bib4" class=" bibr popnode">Chen et al., 2015b, href="#bib5" rid="bib5" class=" bibr popnode">Chen et al., 2015c, href="#bib15" rid="bib15" class=" bibr popnode">Gao et al., 2014) has been demonstrated to be an excellent and useful method for the preparation of inorganic nanomaterials with good biocompatibility and stability in biomedical applications. For example, bovine serum albumin (BSA), tryptophan-based peptides, and chicken egg white (CEW) have been used to prepare carbon-, noble metal-, and metal-based oxide or sulfide nanomaterials (href="#bib7" rid="bib7" class=" bibr popnode">Chong et al., 2015, href="#bib39" rid="bib39" class=" bibr popnode">Wang et al., 2012, href="#bib43" rid="bib43" class=" bibr popnode">Wang et al., 2015, href="#bib3" rid="bib3" class=" bibr popnode">Chen et al., 2015a, href="#bib4" rid="bib4" class=" bibr popnode">Chen et al., 2015b, href="#bib32" rid="bib32" class=" bibr popnode">Reithofer et al., 2014, href="#bib54" rid="bib54" class=" bibr popnode">Zhang et al., 2014, href="#bib25" rid="bib25" class=" bibr popnode">Jana et al., 2014). Among these biomolecules, the CEW complex consists of multiple proteins and is extremely cheap and easily available in daily life (href="#bib56" rid="bib56" class=" bibr popnode">Zhou et al., 2015, href="#bib11" rid="bib11" class=" bibr popnode">Dickerson et al., 2008). Thus, exploring new H2S-activatable NIR-II probe via CEW complex is highly desirable for specific colon cancer detection.Herein, endogenous H2S-triggered NIR-II-emitting nanoprobe based on Ag-CEW complex (href="/pmc/articles/PMC6625970/figure/sch1/" target="figure" class="fig-table-link figpopup" rid-figpopup="sch1" rid-ob="ob-sch1" co-legend-rid="lgnd_sch1">Scheme 1) for specific visualization of colorectal cancer was designed via in situ chemical reaction between Ag-CEW and overexpressed H2S gas in colorectal cancer. The Ag-CEW complex was synthesized by an environment-friendly method by using CEW as the surface ligands for chelating Ag⁺ at room temperature. More importantly, in situ H2S-activatable NIR-II-emitting nanoprobe for in vivo specific diagnosis of colorectal cancer was achieved. In vivo histological examination was carried out to evaluate the biotoxicity of the Ag-CEW complex.href="/pmc/articles/PMC6625970/figure/sch1/" target="figure" rid-figpopup="sch1" rid-ob="ob-sch1">class="inline_block ts_canvas" href="/core/lw/2.0/html/tileshop_pmc/tileshop_pmc_inline.html?title=Click%20on%20image%20to%20zoom&p=PMC3&id=6625970_sc1.jpg" target="tileshopwindow">target="object" href="/pmc/articles/PMC6625970/figure/sch1/?report=objectonly">Open in a separate windowclass="figpopup" href="/pmc/articles/PMC6625970/figure/sch1/" target="figure" rid-figpopup="sch1" rid-ob="ob-sch1">Scheme 1Schematic Illustration of the Synthesis Procedure of Ag-CEW Complex and Endogenous H2S-Triggered In Situ Synthesis of Ag2S QDs from Ag-CEW Complex for Highly Specific Visualization of Colon Cancer