Insight into the Luminescence Alternation of Sub-30 nm Upconversion Nanoparticles with a Small NaHoF4 Core and Multi-Gd3+ /Yb3+ Coexisting Shells.

It is absolutely imperative for development of material science to adjust upconversion luminescence (UCL) properties of highly doped upconversion nanoparticles (UCNPs) with special optical properties and prominent application prospects. In this work, featuring NaHoF4 @NaYbF4 (Ho@Yb) structures, sub-30 nm core-multishell UCNPs are synthesized with a small NaHoF4 core and varied Gd3+ /Yb3+ coexisting shells. X-ray diffraction, transmission electron microscopy, UCL spectrum, UCL lifetime, and pump power dependence are adhibited for characterization. Compared with the former work, except for a smaller total size, tunable emission in color from red to yellow to green, and intensity from low to stronger than that of traditional UCNPs is achieved for ≈10 nm NaHoF4 core size by means of changing number of layers and Gd3+ /Yb3+ concentration ratios in different layers. Besides, simultaneously doping Ho3+ into the shells will result in lowered UCL intensity and lifted green/red ratio. Surface energy loss and sensitizing energy supply, which can be modulated with inert shielding of Gd3+ and sensitization of Yb3+ , are proved to be the essential determinant. More UCL properties of these peculiar Ho@Yb UCNPs are uncovered and detailedly summarized, and the findings can help to expand the application scope of NaHoF4 into photoinduced therapy.

Glutathione Mediated Size-Tunable UCNPs-Pt(IV)-ZnFe2 O4 Nanocomposite for Multiple Bioimaging Guided Synergetic Therapy.

Here a multifunctional nanoplatform (upconversion nanoparticles (UCNPs)-platinum(IV) (Pt(IV))-ZnFe2 O4 , denoted as UCPZ) is designed for collaborative cancer treatment, including photodynamic therapy (PDT), chemotherapy, and Fenton reaction. In the system, the UCNPs triggered by near-infrared light can convert low energy photons to high energy ones, which act as the UV-vis source to simultaneously mediate the PDT effect and Fenton's reaction of ZnFe2 O4 nanoparticles. Meanwhile, the Pt(IV) prodrugs can be reduced to high virulent Pt(II) by glutathione in the cancer cells, which can bond to DNA and inhibit the copy of DNA. The synergistic therapeutic effect is verified in vitro and in vivo results. The cleavage of Pt(IV) from UCNPs during the reduction process can shift the larger UCPZ nanoparticles (NPs) to the smaller ones, which promotes the enhanced permeability and retention (EPR) and deep tumor penetration. In addition, due to the inherent upconversion luminescence (UCL) and the doped Yb3+ and Fe3+ in UCPZ, this system can serve as a multimodality bioimaging contrast agent, covering UCL, X-ray computed tomography, magnetic resonance imaging, and photoacoustic. A smart all-in-one imaging-guided diagnosis and treatment system is realized, which should have a potential value in the treatment of tumor.

Multifunctional Theranostic Nanoplatform Based on Fe-mTa2O5@CuS-ZnPc/PCM for Bimodal Imaging and Synergistically Enhanced Phototherapy.

Multifunctional nanotheranostic agent with high performance for tumor site-specific generation of singlet oxygen (1O2) as well as imaging-guidance is crucial to laser-mediated photodynamic therapy. Here, we introduced a versatile strategy to design a smart nanoplatform using phase change material (PCM) to encapsulate photosensitizer (zinc phthalocyanine, ZnPc) in copper sulfide loaded Fe-doped tantalum oxide (Fe-mTa2O5@CuS) nanoparticles. When irradiated by 808 nm laser, the PCM is melted due to the hyperthermia effect from CuS nanoparticles, inducing the release of ZnPc to produce toxic 1O2 triggered by 650 nm light with very low power density (5 mW/cm2). Then, the produced heat and toxic 1O2 can kill tumor cells in vitro and in vivo effectively. Furthermore, the special properties of Fe-mTa2O5 endow the nanoplatform with excellent computed tomography (CT) and T1-weighted magnetic resonance imaging ( T1-MRI) performance for guiding and real-time monitoring of therapeutic effect. This work presents a feasible way to design smart nanoplatform for controllable generation of heat and 1O2, achieving CT/ T1-MRI dual-modal imaging-guided phototherapy.

Au Nanoclusters Sensitized Black TiO2-x Nanotubes for Enhanced Photodynamic Therapy Driven by Near-Infrared Light.

The low reactive oxygen species production capability and the shallow tissue penetration of excited light (UV) are still two barriers in photodynamic therapy (PDT). Here, Au cluster anchored black anatase TiO2-x nanotubes (abbreviated as Au25 /B-TiO2-x NTs) are synthesized by gaseous reduction of anatase TiO2 NTs and subsequent deposition of noble metal. The Au25 /B-TiO2-x NTs with thickness of about 2 nm exhibit excellent PDT performance. The reduction process increased the density of Ti3+ on the surface of TiO2 , which effectively depresses the recombination of electron and hole. Furthermore, after modification of Au25 nanoclusters, the PDT efficiency is further enhanced owing to the changed electrical distribution in the composite, which forms a shallow potential well on the metal-TiO2 interface to further hamper the recombination of electron and hole. Especially, the reduction of anatase TiO2 can expend the light response range (UV) of TiO2 to the visible and even near infrared (NIR) light region with high tissue penetration depth. When excited by NIR light, the nanoplatform shows markedly improved therapeutic efficacy attributed to the photocatalytic synergistic effect, and promotes separation or restrained recombination of electron and hole, which is verified by experimental results in vitro and in vivo.

Construction of thiol-capped ultrasmall Au-Bi bimetallic nanoparticles for X-ray CT imaging and enhanced antitumor therapy efficiency.

Thiol capped gold nanoparticles with small size, high dispersity, and broad light absorption covering ultraviolet (UV) to near infrared (NIR) region have been developed for catalysis, fluorescence imaging and photodynamic therapy (PDT). The constitution of the metal core in such nanoparticles can strongly influence the luminescence, catalysis, and stability properties. However, to date, a corresponding investigation of the influence of the metallic core on the generation of reaction oxygen species (ROS) and its therapeutic efficiency towards tumor cells remains to be lacking. Herein, we fabricated bimetallic nanoparticles by introducing bismuth into captopril capped gold nanoparticles. Surprisingly, the introduction of the Bi was found enhance the photothermal effect of the nanoparticles to a great extent, and the variation trends for the thermal effect, ROS generation rate, and tumor cell inhibition effect were found to disparate with the changes in the Au and Bi composition. The origin of the photothermal effect was deduced through density functional theory calculations based on microscopic construction. Combined with the intrinsic photodynamic effect, the bimetallic nanoparticles showed an outstanding tumor cell inhibition effect. Furthermore, due to the excellent CT imaging property, our designed nanoparticles provide the exciting possibility to realize CT imaging guided and light-mediated tumor therapy.

Rapid Decomposition and Catalytic Cascade Nanoplatforms Based on Enzymes and Mn-Etched Dendritic Mesoporous Silicon for MRI-Guided Synergistic Therapy.

The endogenous tumor microenvironment (TME) can signally influence the therapeutic effects of cancer, so it is necessary to explore effective synergistic therapeutic strategies based on changing of the TME. Here, a catalytic cascade nanoplatform based on manganese (Mn)-etched dendritic mesoporous silicon nanoparticles (designated as DMMnSiO3 NPs) loaded with indocyanine green (ICG) and natural glucose oxidase (GOD) is established (designated as DIG nanocomposites). As the Mn-O bonds in DMMnSiO3 NPs are susceptive to mildly acidic and reducing environments, the DIG nanocomposites can be rapidly decomposed because of the biodegradation of DMMnSiO3 NPs once internalized into the tumor by the consumption of glutathione (GSH) in TME to weaken the antioxidant capability of the tumors. The released Mn2+ could catalyze endogenous hydrogen peroxide (H2O2) to generate oxygen (O2) to relieve the hypoxia in TME. The generation of O2 may promote the catalyzed oxidation of glucose by GOD, which will cut off nutrient supplies, accompanied by the regeneration of H2O2. The regenerated H2O2 could be sequentially catalyzed by Mn2+ to compensate for the consumed O2, and thus, the catalytic cascade process between Mn2+ and GOD was set up. As a result, a synergistic therapeutic strategy based on T1-weighted magnetic resonance imaging (MRI) of Mn2+, starvation therapy by O2-compensation enhanced catalyzing glucose, dual-model (GSH consumption and O2 compensation) enhanced photodynamic therapy, and effective photothermal therapy of ICG (η = 23.8%) under 808 nm laser irradiation has been successfully established.

Switchable up-conversion luminescence bioimaging and targeted photothermal ablation in one core-shell-structured nanohybrid by alternating near-infrared light.

In photothermal therapy (PTT), simultaneous achievement of imaging and hyperthermia mediated by a single laser inevitably risks damaging normal tissues before treatment. Herein, a core-shell-structured GdOF:Yb/Er@(GNRs@BSA) nanohybrid was designed and fabricated by conjugating gold nanorods (GNRs) on the surfaces of GdOF:Yb/Er nanoparticles by a facile procedure. By alternating near-infrared (NIR) light appropriately, high photothermal efficiency for PTT and good up-conversion luminescence (UCL) imaging can be achieved in this structure, which can substantially solve the heat-induced risk during the theranostic process. Furthermore, good biocompatibility and phagocytosis can be realized by modifying bovine serum albumin (BSA) on the surface of the GNRs, and the conjugation of folic acid (FA) endows this nanohybrid with targeting function. It is noted that the size of the GNRs prepared by the one-pot method is much smaller than that by the seed-mediated method, which is not only conducive to uniform heat distribution during intratumoral therapy, but also contributes to the nanohybrid metabolic decomposition and fluorescence tracing after treatment. Moreover, this product can also be utilized as a good magnetic resonance imaging (MRI) and computed tomography (CT) contrast agent, which can provide versatile imaging properties in the field of cancer clinical treatment.

A smart tumor microenvironment responsive nanoplatform based on upconversion nanoparticles for efficient multimodal imaging guided therapy.

Near-infrared (NIR) light-induced imaging-guided cancer therapy has been studied extensively in recent years. Herein, we report a novel theranostic nanoplatform by modifying polyoxometalate (POM) nanoclusters onto mesoporous silica-coated upconversion nanoparticles (UCNPs), followed by loading doxorubicin (DOX) in the mesopores and coating a folate-chitosan shell onto the surface. In this nanoplatform, the core-shell structured UCNPs (NaYF4:Yb,Er@NaYF4:Yb,Nd) showed special upconverting luminescence (UCL) when irradiated with high-penetration 808 nm NIR light, and the doped Yb and Nd ions endowed the sample with CT imaging properties, thus achieving a dual-mode imaging function. Moreover, the simultaneously generated heat mediated by the 808 nm NIR light may coordinate with the chemotherapy generated from the released DOX to realize an efficient synergistic therapy, verified by diverse in vitro and in vivo assays. The coated folate-chitosan shell can target the platform to tumor tissues when it was transported in the blood vessels and accumulated in tumor sites via the enhanced permeability and retention effect (EPR). Due to the acidic and reductive microenvironment of the tumor, the DOX released quickly with the dissolved folate-chitosan shell, exhibiting obvious tumor microenvironment (TME) responsive properties. The smart imaging-guided therapeutic nanoplatform should be highly promising in TME responsive therapy.

Upconversion-mediated ZnFe2O4 nanoplatform for NIR-enhanced chemodynamic and photodynamic therapy.

ZnFe2O4, a semiconductor catalyst with high photocatalytic activity, is ultrasensitive to ultraviolet (UV) light and tumor H2O2 for producing reactive oxygen species (ROS). Thereby, ZnFe2O4 can be used for photodynamic therapy (PDT) from direct electron transfer and the newly defined chemodynamic therapy (CDT) from the Fenton reaction. However, UV light has confined applicability because of its high phototoxicity, low penetration, and speedy attenuation in the biotissue. Herein, an upconversion-mediated nanoplatform with a mesoporous ZnFe2O4 shell was developed for near-infrared (NIR) light enhanced CDT and PDT. The nanoplatform (denoted as Y-UCSZ) was comprised of upconversion nanoparticles (UCNPs), silica shell, and mesoporous ZnFe2O4 shell and was synthesized through a facile hydrothermal method. The UCNPs can efficiently transfer penetrable NIR photons to UV light, which can activate ZnFe2O4 for producing singlet oxygen thus promoting the Fenton reaction for ROS generation. Besides, Y-UCSZ possesses enormous internal space, which is highly beneficial for housing DOX (doxorubicin, a chemotherapeutic agent) to realize chemotherapy. Moreover, the T 2-weighted magnetic resonance imaging (MRI) effect from Fe3+ and Gd3+ ions in combination with the inherent upconversion luminescence (UCL) imaging and computed tomography (CT) from the UCNPs makes an all-in-one diagnosis and treatment system. Importantly, in vitro and in vivo assays authenticated excellent biocompatibility of the PEGylated Y-UCSZ (PEG/Y-UCSZ) and high anticancer effectiveness of the DOX loaded PEG/Y-UCSZ (PEG/Y-UCSZ&DOX), indicating its potential application in the cancer treatment field.

Carbon-Dot-Decorated TiO2 Nanotubes toward Photodynamic Therapy Based on Water-Splitting Mechanism.

The use of visible light to produce reactive oxygen species (ROS) from renewable water splitting is a highly promising means in photodynamic therapy (PDT). Up to date, diverse inorganic-organic hybrid materials developed as photosensitizers still undergo low therapeutic efficiency and/or poor stability. Herein, a kind of carbon-nanodot-decorated TiO2 nanotubes (CDots/TiO2 NTs) composite is developed and applied for photodynamic therapy. Upon 650 nm laser light excitation, the emissions with short wavelengths (325-425 nm) from the CDots as a result of upconversion process excite TiO2 NTs to form electron/hole (e- /h+ ) pairs, triggering the reaction with the adsorbed oxidants to produce ROS. Moreover, the CDots deposited on the surface of TiO2 NTs markedly enhance the light absorption response and narrow the band gap compared with anatase TiO2 nanoparticles, thereby increasing the photosensitizing efficiency. Besides, the CDots show high chemical catalytic activity for H2 O2 decomposition even if no light is needed, which is essential for PDT. The excellent therapeutic performance actuated by 650 nm light is demonstrated by in vitro and in vivo assays. This photosensitizer comprises low-cost, earth-abundant, environment-friendly merits, and especially excellent stability, implying its feasible application in biomedical field.

Polypyrrole-coated UCNPs@mSiO2@ZnO nanocomposite for combined photodynamic and photothermal therapy.

Designing multifunctional nanoplatforms for the purpose of simultaneous theranostic modalities is critical to address the challenges of cancer therapy. Also, single modalities of phototherapy, including photothermal therapy (PTT) and photodynamic therapy (PDT), cannot meet the requirements of highly efficient treatment. Here, a core-shell-shell nanostructure consisting of a core of upconversion nanoparticles (UCNPs), a layer of mesoporous silica with anchored ZnO nanodots, and an outer layer of polypyrrole (PPy) was developed. In the proposed construct, the emitted ultraviolet (UV) light from the UCNPs core upon 980 nm near-infrared light irradiation can trigger the ZnO nanodots to activate ambient O2 molecules around cancerous tissues to produce toxic reactive oxygen species (ROS), realizing the PDT function. On the other hand, the coated PPy layer can concurrently give rise to an obvious heat effect upon NIR light illumination, thus achieving synergistic PDT and PTT effects; this results in excellent anti-tumor efficiency in vitro and in vivo. Furthermore, in hand with the upconversion luminescence (UCL) and computed tomography (CT) imaging derived from the UCNPs core, dual-mode imaging directed cancer therapy has been realized.

Lanthanide-doped bismuth oxobromide nanosheets for self-activated photodynamic therapy.

Low tissue penetration depth of the excited light and complicated synthetic procedures greatly hinder the clinical application of photodynamic therapy (PDT). Here we present a facile and mass production route to fabricate Yb3+/Tm3+ co-doped BiOBr nanosheets. In contrast to the complicated combination of photosensitizers (PSs) with up-conversion nanoparticles (UCNPs), which generates a PDT effect by a fluorescence resonance energy transfer process from UCNPs to PSs upon near-infrared light excitation, this as-synthesized material can be self-activated by deep-penetrating 980 nm laser light to produce a large amount of reactive oxygen species, giving rise to a high PDT efficiency which has been proven by in vitro and in vivo therapeutic assays. Surface modification of the BiOBr:Yb,Tm nanosheets with polyethylene glycol endows the system with improved biocompatibility. Through the combination of inherent fluorescence and CT imaging properties, an imaging-monitored therapeutic system has been realized. The system overcomes the problems of low tissue penetration depth, complicated structure-induced low efficiency, and potential safety concerns. Our finding presents the first demonstration of a self-activated nanoplatform for targeted and noninvasive deep-cancer therapy.

Multifunctional mesoporous ZrO2 encapsulated upconversion nanoparticles for mild NIR light activated synergistic cancer therapy.

Desirable nanosystem that could not only deliver drugs safely and effectively into tumor sites, but also be expected to serve as photosensitizer to realize the photodynamic therapeutic function, would be of great significance in the synergistic cancer therapy. To perform this task, a multifunctional nanosystem has been developed for markedly enhanced cancer therapeutic efficacy by loading chemotherapy agent (doxorubicin hydrochloride, DOX) and photosensitive drug chlorin e6 (Ce6) into the channels of mesoporous zirconium dioxide (ZrO2) layer which coats on Nd3+-doped upconversion nanoparticles (UCNPs). As a temperature sensitive phase change material (PCM), the loaded tetradecanol was served as switch for control release of DOX and reactive oxygen species (ROS) in the condition of enhanced temperature triggered by the near infrared (NIR) light irradiation. The hyperthermia generated from the UCNPs cores exposed to NIR laser could raise the temperature of tumor location to 47.8 °C. The as-synthesized UCNPs@ZrO2-Ce6/DOX/PCM nanosystem demonstrates an excellent in vivo synergistic effect by administrating into U14 tumor-bearing mice via intravenous injection, under mild NIR laser irradiation (0.5 W cm-2, 5 min break after 5 min irradiation). In a word, our experimental results indicate that the finely designed UCNPs@ZrO2-Ce6/DOX/PCM may act as an ideal nanoplatform for multiple imaging guided tumor therapy.

Multifunctional UCNPs@MnSiO3@g-C3N4 nanoplatform: improved ROS generation and reduced glutathione levels for highly efficient photodynamic therapy.

Photodynamic therapy (PDT) is a novel technique that has been extensively employed in cancer treatment; it utilizes reactive oxygen species to kill malignant cells. However, poor performance of the photosensitizer itself, limited penetration depth and the overexpression of glutathione (GSH) in cancer cells are the major obstacles facing the actual clinical application of PDT. Inspired by the challenges mentioned above, here we propose multifunctional nanoparticles utilizing mesoporous manganese silicate (MnSiO3)-coated upconversion nanoparticles (UCNPs) as nanocarriers for loading highly fluorescent graphitic-phase carbon nitride quantum dots (g-C3N4 QDs) to simultaneously act as a photosensitive drug and imaging agent. Surface modification of the nanoparticles with polyethylene glycol (PEG) endows the samples (denoted as UMCNs-PEG) with excellent biocompatibility and long-term in vivo circulation. Taking advantage of the inherent performance of the as-synthesized nanoparticles, multimodality imaging, including upconversion luminescence (UCL), computed tomography (CT) and magnetic resonance imaging (MRI), has been achieved; this is conducive to providing effective treatment information by real-time monitoring. In vivo photodynamic therapy to achieve effective tumor inhibition was then realized without inducing significant toxicity to treated mice. As a result, this work provides a novel paradigm with highly integrated functionalities which not only exhibits excellent prospects for imaging-guided photodynamic anticancer therapy but also encourages further exploration of new types of multifunctional nanoparticles for biomedical applications.

Doxorubicin-conjugated CuS nanoparticles for efficient synergistic therapy triggered by near-infrared light.

To integrate photothermal therapy (PTT) with chemotherapy for improving anticancer efficiency, we developed a novel and multifunctional doxorubicin (DOX) conjugated copper sulfide nanoparticle (CuS-DOX NP) drug delivery system using hydrazone bonds to conjugate carboxyl-functionalized copper sulfide nanoparticles (CuS NPs) and DOX. On the other hand, the hydrazone bonds could be used for improving the DOX release rate (88.0%) by cleavage in a mildly acidic environment irradiated by 808 nm laser light, which could greatly promote chemo-therapeutic efficacy. Simultaneously, CuS NPs which can absorb near infrared (NIR) light produce a clear thermal effect, giving rise to a synergistic therapeutic effect combined with enhanced chemo-therapy. The DOX-conjugated CuS NPs display an evident in vitro cytotoxicity to HeLa cancer cells under 808 nm light irradiation. High tumor inhibition efficacy has been achieved after 14 day in vivo treatment, performed with intravenous administration of CuS-DOX NPs with 808 nm laser irradiation on H22 tumor-bearing mice. The multifunctional system which was achieved by a facile route should be a potential candidate in the anti-cancer field due to the synergistic therapeutic effect, which is superior to any single approach.

Synthesis, luminescence, and anti-tumor properties of MgSiO3:Eu-DOX-DPP-RGD hollow microspheres.

In this report, MgSiO3:Eu-DOX-DPP-RGD hollow microspheres employed for simultaneous imaging and anti-cancer therapy have been designed by sequentially loading the anti-tumor drugs doxorubicin (DOX), light-activated platinum(iv) pro-drug PPD, and a targeted peptide of NH2-Gly-Arg-Gly-Asp-Ser (RGD) onto MgSiO3:Eu mesoporous hollow spheres, which were synthesized using solid SiO2 spheres as sacrificed template by a facile hydrothermal process based on the Kirkendall effect. The photoluminescence intensity of MgSiO3:Eu has been optimized, which can emit a recognized red signal in vitro and in vivo under modest ultraviolet (UV) irradiation. It was found that the platform has high biocompatibility and could become intracellular through fast and effective endocytosis with the aid of the targeted peptide RGD, and chemotherapeutic drugs DOX and light-activated platinum(iv) pro-drug DPP that can be released from the carrier to induce an obvious inhabitation effect to HeLa cancer cells (survival rate of only 17.4%), which has been verified by in vitro and in vivo results. Moreover, the in vitro result using a photosensitizer ZnPc loaded carrier shows that the system is not suitable for ZnPc induced photodynamic therapy. The apparent imaging effect and high anti-tumor efficacy of this functional system give it great potential in actual clinical applications.