Tumor microenvironment responsive hollow mesoporous Co9S8@MnO2-ICG/DOX intelligent nanoplatform for synergistically enhanced tumor multimodal therapy.

The development of multifunctional nanoplatform with combination of tumor microenvironment (TME)-responsive dual T1/T2 magnetic resonance (MR) imaging and synergistically self-enhanced photothermal/photodynamic/chemo-therapy is of significant importance for tumor theranostic, which still remains a great challenge. Herein, a novel hollow mesoporous double-shell Co9S8@MnO2 nanoplatform loaded with photodynamic agent of indocyanine green molecules (ICG) and chemotherapy drug of doxorubicin (DOX) was designed for TME responsive dual T1/T2 enhanced MR imaging and synergistically enhanced anti-tumor therapy. The designed nanoplatform with MnO2 shell can act as a TME-responsive oxygen self-supplied producer to alleviate tumor hypoxia and simultaneously improve photodynamic therapy (PDT) efficiency. Moreover, the TME-induced MnO2 dissolving and near-infrared (NIR) triggered photothermal nature from Co9S8 shell can further promote the tumor-targeted DOX release, leading to the synergistically improved anti-tumor efficacy. And the simultaneous enhancement in dual T1/T2 MR signal was achieved for highly specific tumor diagnosis. The in vivo and in vitro results confirmed that the designed TME-triggered nanoplatform with synergistic combination therapy presented good biocompatibility, and superior inhibition of tumor growth than monotherapy. This study provides the opportunities of designing intelligent TME-activated nanoplatform for highly specific tumor MR imaging and collaborative self-enhanced tumor therapy.

Low dose soft X-ray-controlled deep-tissue long-lasting NO release of persistent luminescence nanoplatform for gas-sensitized anticancer therapy.

Nitric oxide (NO)-based gas therapy is emerged as a new adjunct anti-tumor treatment method, which has triggered a great research interest. Nevertheless, due to the short half-life of NO gas in vivo, it is of significance to develop NO-gas based gasotransmitter with controllable NO release for deep-tissue anti-tumor therapy. Herein, a novel soft X-ray activated persistent luminescence nanotransducer is designed for controllable and long-lasting NO release and deep-tissue anti-cancer therapy by integrating ZnGa2O4:Mn (ZGO:Mn) nanoparticles with light-responsive NO donor (RBS). With the merits of the ultra-low dosage (down to 0.9 mGy) soft X-ray activated persistent luminescence from small sized ZGO:Mn, continuous NO release is achieved for about 40 min after stopping the irradiation of X-ray. Moreover, the green persistent luminescence can be renewably activated by in-situ soft X-ray irradiation, leading to the repeatable long-lasting NO release in deep tissue (up to 24 mm). And the designed NO-releasing platform presents efficient in vitro and in vivo anti-cancer therapy. Therefore, the designed persistent luminescence-based NO gasotransmitter provides a new NO-releasing strategy for depth-independent gas-sensitized therapeutic applications.

808 nm light triggered lanthanide nanoprobes with enhanced down-shifting emission beyond 1500 nm for imaging-guided resection surgery of tumor and vascular visualization.

Lanthanide based nanoprobe with high efficient down-shifting second near-infrared (NIR-II, 1000-1700 nm) emission has emerged as a promising agent for tumor-associated vascular visualization. However, most of the developed lanthanide-based NIR-II-emissive probes are activated by 980 nm laser, leading to the concern of biological overheating effect. Herein, the high quality 808 nm laser activated NaYF4:Gd/Yb/Er/Nd/Ce@NaYF4:Nd core-shell nanoprobes with significantly improved NIR-II emission beyond 1500 nm and eliminated overheating effect were developed for imaging-guided resection surgery of tumor and vascular visualization. Methods: The core-shell nanoprobe with boosted NIR-II emission and eliminated heating effect was achieved with combination of Nd-sensitizing and Ce-doping strategies. The NIR-II optical imaging and toxicity assessment were demonstrated by in vivo and in vitro experiments. Results: The designed core-shell nanoprobe presented superior NIR-II emission beyond 1500 nm than the core only nanoparticle and NIR-II emission intensity was improved up to 11.0 times by further suppressing the upconversion (UC) pathway through doping Ce3+. More importantly, non-invasive tumor vascular imaging and NIR-II optical imaging-guided surgical resection of tumor were successfully achieved. Conclusion: It is expected that the Nd-sensitized lanthanide-based nanoprobe with significant improvement in NIR-II emission and eliminated overheating effect is a highly promising probe for NIR-II imaging, making it more competitive in non-invasive vascular imaging and imaging-guided tumor resection surgery.

Hollow Mesoporous Bi@PEG-FA Nanoshell as a Novel Dual-Stimuli-Responsive Nanocarrier for Synergistic Chemo-Photothermal Cancer Therapy.

The development of stimuli-responsive multifunctional nanocarriers for therapeutic drug delivery is extremely desirable for highly specific treatment of disease. Herein, thiol-polyethylene glycol-folate acid-modified hollow mesoporous bismuth nanoshells (HM-Bi@PEG-FA NSs) were developed as the new dual-stimuli-responsive single-"elemental" photothermal nanocarriers for synergistic chemo-photothermal therapy of tumor. The designed hollow-mesoporous-type nanocarriers present excellent photothermal conversion capacity (∼34.72%) and good biocompatibility. Meanwhile, acidic pH and near-infrared (NIR) laser dual-stimulated doxorubicin (DOX) release is successfully achieved. More importantly, the DOX-loaded HM-Bi@PEG-FA NSs hold an efficient in vitro/in vivo antitumor effect through the synergistic chemo-photothermal therapy. Therefore, our findings provide the possibility of designing a dual-stimuli-responsive hollow mesoporous Bi-based photothermal nanocarrier for synergistically enhanced antitumor therapy.

A general strategy for designing NIR-II emissive silk for the in vivo monitoring of an implanted stent model beyond 1500 nm.

Silk fibroin-based materials spun by silkworms present excellent biocompatible and biodegradable properties, endowing them with broad applications for use in in vivo implanted devices. Therefore, it is highly desirable to explore functionalized silk with additional optical bioimaging abilities for the direct in situ monitoring of the status of implanted devices in vivo. Herein, a new type of silk material with a second near-infrared (NIR-II, 1000-1700 nm) emission is explored for the real-time observation of a biological stent model using a general route of feeding larval silkworms with lanthanide-based NaYF4:Gd3+/Yb3+/Er3+@SiO2 nanocrystals. After being fed lanthanide nanocrystals, the silk spun by silkworms shows efficient NIR-II emission beyond 1500 nm. Moreover, NIR-II bio-imaging guided biological stent model monitoring presents a superior signal-to-noise (S/N) ratio compared to the traditional optical imaging by utilizing the upconversion (UC) region. These findings open up the possibility of designing NIR-II optically functionalized silk materials for highly sensitive and deep-tissue monitoring of the in vivo states of the implanted devices.

808 nm laser-triggered NIR-II emissive rare-earth nanoprobes for small tumor detection and blood vessel imaging.

Optical bioimaging in second near-infrared window (NIR-II, 1000-1700 nm) has been emerged as an indispensable tool for highly sensitive disease detection. In this work, intense NIR-II emissive polyacrylic acid (PAA) modified NaLuF4: Gd/Nd nanorods (PAA-NRs) with pure hexagonal phase and uniform size were explored for high sensitivity in vivo NIR-II bioimaging and optical imaging-guided small tumor detection. The NIR-II emission of the NaLuF4: Gd host can be readily adjusted by doping Nd3+, making it promising emission centered at 1056 nm and 1328 nm with high photo-stability. The time-dependent in vivo tracking results validate that the PAA-NRs are mainly accumulated in the reticuloendothelial system (RES) and excreted through the hepatic pathway. In addition, NIR-II optical imaging-guided small tumor (down to 5 mm) diagnosis was successfully achieved. Remarkably, in vivo small blood vessel with high spatial resolution (~105 µm) was detected clearly. And the histological tests reveal that our designed hydrophilic NRs present negligible toxicity effects and good biocompatibility in living animals. Besides the NIR-II emission, the PAA-NRs also present X-ray absorption features for X-ray bioimaging. These findings demonstrate that the explored lanthanide-based NRs with controllable size, efficient NIR-II emission and decent biocompatibility are promising NIR-II contrast agents for future biomedical applications, such as, early diagnosis of small tumor, vascular related disease imaging and angiogenesis diagnosis.

A high performance Sc-based nanoprobe for through-skull fluorescence imaging of brain vessels beyond 1500 nm.

Optical bioimaging that works in the second near infrared region (NIR-II, 1000-1700 nm) has emerged as a next generation imaging technique with superior imaging sensitivity and spatial resolution compared to traditional optical imaging utilizing visible and near-infrared lights (below 900 nm). Herein, a new Sc-based NIR-II probe was explored for high performance NIR-II in vivo bioimaging and optical imaging-guided non-invasive brain blood vessel visualization. The lanthanide doped Sc-based probes (KSc2F7:Yb3+/Er3+) possess a pure orthorhombic phase structure with size control by adjusting the F- ion content. These probes present a dominant red upconversion (UC) emission, which is significantly different from the traditional NaYF4:Yb/Er host, which usually has a green UC emission. More importantly, apart from the dominant red UC emission, these probes also possess a strong NIR-II downconversion (DC) emission centered at 1525 nm, which is usually ignored for bioimaging applications. In vivo NIR-II imaging reveals that our explored Sc-based nanorods are promising probes for highly sensitive optical imaging. Moreover, non-invasive through-skull fluorescence bioimaging of brain vessels with high spatial resolution was demonstrated. Therefore, it is expected that Sc-based nanomaterials with unique dominant red UC and DC NIR-II emissions beyond 1500 nm are ideal probes for bio-applications.

Second near-infrared emissive lanthanide complex for fast renal-clearable in vivo optical bioimaging and tiny tumor detection.

In vivo optical imaging by using a new imaging window located at short-wavelength infrared region (1000-1700 nm, named as NIR II) presents an unprecedented improvement in imaging sensitivity and spatial resolution over the traditional visible and near-infrared light. However, the most developed NIR II-emitters are hardly excreted from live animals, leading to unknown long-term toxicity concerns, which hinder the widespread applications of this advanced imaging technology. Here, we developed a new generation molecular NIR II-emitting probe based on Nd-diethylene triamine pentacetate acid (DTPA) complex. The designed molecular Nd-DTPA probe with bright narrow band emission at 1330 nm is successfully used for highly sensitive in vivo NIR II bioimaging with rapid renal excretion, high biocompatibility and optical-guided tiny tumor (down to ∼3 mm) detection for the first time. Moreover, the Nd-DPTA complex also holds great promise as an X-ray contrast agent. These findings open up the possibility for designing a new generation of multi-modal small molecular probe for early tumor diagnosis and favor the clinic translation of the advanced NIR II imaging method.

Non-invasive through-skull brain vascular imaging and small tumor diagnosis based on NIR-II emissive lanthanide nanoprobes beyond 1500 nm.

Optical bioimaging by using the new short-wavelength infrared window (SWIR, also named as NIR-II, 1000-1700 nm) is emerged as a next generation imaging technique for disease diagnosis owing to the unprecedented improvements in imaging sensitivity and spatial resolution. However, it is challenging to search new imaging agents with highly biocompatible and bright narrow-band emission located in the 1500-1700 nm (referred as NIR-IIb) region. Here we developed high quality polyacrylic acid (PAA) modified NaYF4:Gd/Yb/Er nanorods (PAA-NRs) with remarkably enhanced NIR-IIb emission and decent bio-compatibility for in vivo cerebral vascular bioimaging and small tumor visualization. These PAA-NRs present efficient narrow-band NIR-IIb emission centered at 1520 with 182 nm of band-width. Owing to the highly efficient NIR-IIb emission, NIR-IIb imaging-guided small tumor (4 mm in diameter) detection is achieved. More importantly, non-invasive optical brain vessel bioimaging with high spatial (∼43.65 µm) and temporal resolution through scalp and skull is obtained without craniotomy. These findings open up the opportunity of designing non-invasive approach for visualization the brain vasculature and tumor in biomedical application.

Short-wave near-infrared emissive GdPO4:Nd3+ theranostic probe for in vivo bioimaging beyond 1300 nm.

The optical probes working in the second near-infrared (NIR-II) window have attracted increasing research interest for their advantages of high tissue penetration depth, low autofluorescence, and unprecedentedly improved imaging sensitivity and spatial resolution. Therefore, it is of great significance to design a new nanoplatform by integration of NIR-II optical imaging and drug delivery functions. Herein, a multifunctional nanoplatform based on GdPO4:Nd3+ yolk-shell sphere was developed for dual-modal in vivo NIR-II/X-ray bioimaging and pH-responsive drug delivery. The in vivo NIR-II bioimaging and real-time tracking presented that these probes were mainly accumulated in liver and spleen. Moreover, owing to the large X-ray absorption coefficient of Gd3+, these probes are successfully used as superior X-ray imaging agents than iobitridol. The in vivo toxicity assessments demonstrate the low biotoxicity of the GdPO4:Nd3+ spheres in living animals. More importantly, apart from the excellent dual-modal bioimaging, these yolk-shell-structured probes were also used as ideal nanotransducer for pH-responsive drug delivery of doxorubicin (DOX). These findings open up the opportunity of designing theranostic nanoplatform with integration of imaging-based diagnosis and therapy.

Soft X-ray activated NaYF4:Gd/Tb scintillating nanorods for in vivo dual-modal X-ray/X-ray-induced optical bioimaging.

Lanthanide (Ln) nanocrystals using soft X-ray as an excitation source have received significant research interest due to the advantages of unlimited penetration depth of X-ray light. In this study, we demonstrated an efficient scintillator based on NaYF4:Gd nanorods (denoted as NRs) doped with different contents of terbium (Tb) ions for optical bioimaging under X-ray irradiation. The experimental results showed that the emission intensity was correlated to the doping contents of Tb3+, and the largest emission intensity was achieved by doping 15% Tb under excitation by soft X-ray light. In addition, the emission intensity of the as-prepared NRs can be significantly improved by increasing the excitation power and irradiation times of the X-ray. Owing to the efficient X-ray-induced emission, these NRs were successfully used as probes for X-ray-induced optical bioimaging with high sensitivity. In addition, the dual-modal X-ray imaging and X-ray induced optical bioimaging were performed on a mouse, which indicated that the NRs were promising dual-modal bioprobes. Therefore, the X-ray activation nature of the designed NRs makes them promising probes for biomedicine and X-ray-induced photodynamic therapy (PDT) applications owing to the unlimited penetration depth of X-ray excitation source and absence of autofluorescence.

X-ray-Activated Near-Infrared Persistent Luminescent Probe for Deep-Tissue and Renewable in Vivo Bioimaging.

Near-infrared (NIR) persistent luminescence nanoparticles (PLNPs) are considered as new alternative optical probes due to being free of autofluorescence, benefited from the self-sustained emission after excitation and high signal-to-noise ratio. However, the NIR-emitted PLNPs always present a short decay time and require excitation by ultraviolet or visible light with a short penetrable depth, remarkably hindering their applications for in vivo long-term tracking and imaging. Therefore, it is important to develop NIR-emitted PLNPs with in vivo activation nature by new excitation sources with deeper penetrating depths. Here, we propose a new type of X-ray-activated ZnGa2O4:Cr PLNPs (X-PLNPs) with efficient NIR persistent emission and rechargeable activation features, in which both the excitation and emission possess a high penetrable nature in vivo. These X-PLNPs exhibit long-lasting, up to 6 h, NIR emission at 700 nm after the stoppage of the X-ray excitation source. More importantly, the designed X-PLNPs can be readily reactivated by a soft X-ray excitation source with low excitation power (45 kVp, 0.5 mA) to restore in vivo bioimaging signals even at 20 mm depth. Renewable in vivo whole-body bioimaging was also successfully achieved via intravenous injection/oral administration of X-PLNPs after in situ X-ray activation. This is the first time that NIR-emitted PLNPs have been demonstrated to be recharged by X-ray light for deep-tissue in vivo bioimaging, which paves the way for in vivo renewable bioimaging using PLNPs and makes the PLNPs more competitive in bioimaging area.

A 980 nm laser-activated upconverted persistent probe for NIR-to-NIR rechargeable in vivo bioimaging.

Long-lasting persistent luminescent nanoparticles (PLNPs) with efficient near-infrared (NIR) emission have emerged as a new generation of probes for in vivo optical bioimaging owing to their advantages of zero-autofluorescence benefited from the self-sustained emission after excitation, deep penetration depth, and a high signal-to-noise ratio. However, most of the PLNPs are charged by ultraviolet (UV) or visible light, remarkably limiting their applications for in vivo long-term bioimaging. Here we demonstrate 980 nm laser activated upconversion-PLNPs (UC-PLNPs) with efficient NIR emission. The NIR-emitting UC-PLNPs (Zn3Ga2GeO8:Yb/Er/Cr) were synthesized by a sol-gel method with subsequent calcination. Owing to the efficient energy-transfer between Er and Cr ions, these UC-PLNPs present long-lasting up to 15 h NIR emission at 700 nm after the excitation of a 980 nm laser; in which both excitation and emission bands fall within the biological transparent window. The results of in vitro/in vivo toxicity assessments indicate that UC-PLNPs after surface modification present low biotoxicity and side effects in living animals. More importantly, the synthesized UC-PLNPs can be effectively recharged by 980 nm laser to restore in vivo persistent bioimaging signals and can also be employed as nanoprobes for in vivo UC optical bioimaging. This is the first demonstration of rechargeable UC-PLNPs for NIR-to-NIR in vivo bioimaging. We believe that the synthesized UC-PLNPs by combining UC and persistent luminescence properties into a single host may have potential applications in the bioimaging area and pave the way for widely using PLNPs for in vivo renewable long-lasting bioimaging.

Multifunctional BaYbF5: Gd/Er upconversion nanoparticles for in vivo tri-modal upconversion optical, X-ray computed tomography and magnetic resonance imaging.

Development of high-quality upconversion nanoparticles (UCNPs) with combination of the merits of multiple molecular imaging techniques, such as, upconversion luminescence (UCL) imaging, X-ray computed tomography (CT), and magnetic resonance (MR) imaging, could significantly improve the accuracy of biological diagnosis. In this work, multifunctional BaYbF5: Gd/Er (50:2mol%) UCNPs were synthesized via a solvothermal method using oleic acid (OA) as surface ligands (denoted as OA-UCNPs). The OA-UCNPs were further treated by diluted HCl to form ligand-free UCNPs (LF-UCNPs) for later bioimaging applications. The cytotoxicity assay in HeLa cells shows low cell toxicity of these LF-UCNPs. Owing to the efficient UCL of BaYbF5: Gd/Er, the LF-UCNPs were successfully used as luminescent bioprobe in UCL bioimaging. And, X-ray CT imaging reveals that BaYbF5: Gd/Er UCNPs can act as potential contrast agents for detection of the liver and spleen in the live mice owing to the high-Z elements (e.g., Ba, Yb, and Gd) in host matrix. Moreover, with the addition of Gd, the as-designed UCNPs exhibit additional positive contrast enhancement in T1-weighted MR imaging. These findings demonstrate that BaYbF5: Gd/Er UCNPs are potential candidates for tri-modal imaging.

M2+ Doping Induced Simultaneous Phase/Size Control and Remarkable Enhanced Upconversion Luminescence of NaLnF4 Probes for Optical-Guided Tiny Tumor Diagnosis.

Doping has played a vital role in constructing desirable hybrid materials with tunable functions and properties via incorporating atoms into host matrix. Herein, a simple strategy for simultaneously modifying the phase, size, and upconversion luminescence (UCL) properties of the NaLnF4 (Ln = Y, Yb) nanocrystals by high-temperature coprecipitation through nonequivalent M2+ doping (M = Mg2+ , Co2+ ) has been demonstrated. The phase transformation from cubic to hexagonal is readily achieved by doping M2+ . Compared with Mg-free sample, a remarkable enhancement of overall UCL (≈27.5 times) is obtained by doping Mg2+ . Interestingly, owing to the efficient UCL, red UCL-guided tiny tumor (down to 3 mm) diagnosis is demonstrated for the first time. The results open up a new way of designing high efficient UCL probe with combination of hexagonal phase and small size for tiny tumor detection.

Upconversion optical/magnetic resonance imaging-guided small tumor detection and in vivo tri-modal bioimaging based on high-performance luminescent nanorods.

In this work, we demonstrated multifunctional NaYbF4: Tm3+/Gd3+ upconversion (UC) nanorods (UCNRs) with near-infrared (NIR)-to-NIR emission and controlled phase and size for UC optical and T1/T2 dual-weighted magnetic resonance (MR) imaging-guided small tumor detection and tri-modal bioimaging. Cell toxicity and post-injection histology results revealed that our designed UCNRs present low biotoxicity and good biocompatibility in living animals. Real-time tracking based on UCNRs in living mice demonstrated that the UCNRs were mainly accumulated in the reticuloendothelial system (RES) and excreted through the hepatic pathway. Additionally, the UCNRs exhibited high X-ray absorption coefficient and large K-edge value, resulting in efficient in vivo CT imaging. A new type of binary (Yb3+/Gd3+) MR contrast agent for simultaneous T1/T2 dual-weighted MR imaging was achieved by doping Gd3+ into NaYbF4 host. Importantly, a small tumor (5 mm in diameter) could be detected in vivo by intravenously injecting UCNRs under UC optical and MR imaging modalities. Therefore, these multifunctional nanoprobes based on NaYbF4:Tm3+/Gd3+ UCNRs with remarkable NIR-to-NIR emission provide potential applications for tri-modal UC optical, CT, binary T1/T2 MR imaging, and early-stage tumor detection in nanomedicine.