Multifunctional bismuth ferrite nanocatalysts with optical and magnetic functions for ultrasound-enhanced tumor theranostics

Ultrasound (US)-assisted oncotherapy has aroused extensive attention due to its capacities to conquer significant restrictions covering short tissue penetration depth and high phototoxicity in photoinduced therapy. We herein developed a class of pure-phase perovskite-type bimetallic oxide, namely, bismuth ferrite nanocatalysts (BFO NCs), for multimodality imaging-guided and US-enhanced chemodynamic therapy (CDT) against malignant tumors. As-prepared BFO nanoparticles with poly(ethylene glycol)-grafted phosphorylated serine (pS-PEG) modification exhibit satisfactory physiological stability and biocompatibility. The BFO NCs also present high fluorescence emission within the second near-infrared region when irradiated with an 808 nm laser. Intriguingly, the BFO NCs demonstrate highly efficient US-enhanced generation of hydroxyl free radicals, as the cavitation bubbles produced by US trigger partial grievous turbulence and promote the transfer rate of the Fenton reagents. Thus, the BFO NCs enable effective inhibition of tumor growth assisted by external US, and the treatment efficacy can be monitored by computer tomography, magnetic resonance, and fluorescence imaging. Meanwhile, H2O2 and US, as a double logic gate, activate the BFO NCs to trigger the iron-catalyzed and US-enhanced CDT with high specificity and treatment efficiency. Therefore, the BFO NCs as a theranostic agent with an enhanced chemodynamic therapeutic effect assisted by external US and a multimodality imaging capacity are put forward, which show a promising prospect for noninvasive chemodynamic oncotherapy.National Research Foundation (NRF)Accepted versionThe work was financially supported by the National Natural Science Foundation of China (51972075, 51772059, and 51972076), the Natural Science Foundation of Shandong Province (ZR2019ZD29), the Heilongjiang Province Postdoctoral Foundation (LBH-Z19129), and the Fundamental Research Funds for the Central Universities. The work was also supported by the Singapore National Research Foundation Investigatorship (NRF-NRFI2018-03)

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

Hollow Structured Y₂O₃:Yb/Er–Cu_<i>x</i>S Nanospheres with Controllable Size for Simultaneous Chemo/Photothermal Therapy and Bioimaging

To integrate photothermal therapy (PTT) with chemotherapy for improved antitumor efficiency, we designed a novel multifunctional composite by attaching Cu_<i>x</i>S nanoparticles onto the surface of Y₂O₃:Yb/Er hollow spheres through a combined coprecipitation and subsequent hydrothermal route. By altering the initial pH values for the synthesis of precursors, the size and structure properties of the final composites can controllably be tuned. The conjugated folic acid (FA) makes the composite recognize the targeted cancer cells and the attached Cu_<i>x</i>S nanoparticles endow the composite with photothermal function. It is found that the release of doxorubicin (DOX) from the functional carrier could be triggered by both pH value and near-infrared (NIR) radiation. In particular, both PTT and chemotherapy can be simultaneously driven by 980 nm laser irradiation. The synergistic therapeutic effect based on PTT and chemotherapy can lead to low in vitro viability of 12.9% and highly strong inhibition of animal H22 tumor in vivo, which is superior to any individual therapy. Moreover, the composite exhibits the clear in vivo red up-conversion luminescence (UCL). This multifunctional nanocarrier can be applicable as bioimaging agent and effective antitumor agent for the synergistic interaction between PTT and the enhanced chemotherapy

Multifunctional Theranostics for Dual-Modal Photodynamic Synergistic Therapy via Stepwise Water Splitting

Combined therapy using multiple approaches has been demonstrated to be a promising route for cancer therapy. To achieve enhanced antiproliferation efficacy under hypoxic condition, here we report a novel hybrid system by integrating dual-model photodynamic therapies (dual-PDT) in one system. First, we attached core–shell structured up-conversion nanoparticles (UCNPs, NaGdF₄:Yb,Tm@NaGdF₄) on graphitic-phase carbon nitride (<i>g-</i>C₃N₄) nanosheets (one photosensitizer). Then, the as-fabricated nanocomposite and carbon dots (another photosensitizer) were assembled in ZIF-8 metal–organic frameworks through an in situ growth process, realizing the dual-photosensitizer hybrid system employed for PDT via stepwise water splitting. In this system, the UCNPs can convert deep-penetration and low-energy near-infrared light to higher-energy ultraviolet–visible emission, which matches well with the absorption range of the photosensitizers for reactive oxygen species (ROS) generation without sacrificing its efficacy under ZIF-8 shell protection. Furthermore, the UV light emitted from UCNPs allows successive activation of <i>g</i>-C₃N₄ and carbon dots, and the visible light from carbon dots upon UV light excitation once again activate <i>g</i>-C₃N₄ to produce ROS, which keeps the principle of energy conservation thus achieving maximized use of the light. This dual-PDT system exhibits excellent antitumor efficiency superior to any single modality, verified vividly by in vitro and in vivo assay

Lutecium Fluoride Hollow Mesoporous Spheres with Enhanced Up-Conversion Luminescent Bioimaging and Light-Triggered Drug Release by Gold Nanocrystals

Uniform Na₅Lu₉F₃₂ hollow mesoporous spheres (HMSs) have been successfully prepared by a facile and mild (50 °C for 5 h) coprecipitation process, and Au nanocrystals (NCs) with particle size of about 10 nm were conjugated to poly­(ether imide) (PEI) modified HMSs by electrostatic interaction. Compared with Na₅Lu₉F₃₂:Yb/Er HMSs, the up-conversion (UC) luminescence intensity of Na₅Lu₉F₃₂:Yb/Er@Au HMSs was much higher under low pump power due to the local field enhancement (LFE) of Au NCs, and there is a surface plasmon resonance (SPR) effect with nonradiative transitions which generates a thermal effect. These two effects have been proved by theoretical discrete-dipole approximation (DDA) simulation. The good biocompatibility of Na₅Lu₉F₃₂:Yb/Er@Au HMSs indicates them as a promising candidate in the biological field. Particularly, under near-infrared (NIR) laser irradiation, a rapid doxorubicin (DOX) release was achieved due to the thermal effect of Au NCs. In this case, Na₅Lu₉F₃₂:Yb/Er@Au HMSs exhibit an apparent NIR light-controlled “on/off” drug release pattern. In addition, UC luminescent images uptaken by cells show brighter green and red emission under NIR laser excitation. Therefore, this novel multifunctional (mesoporous, enhanced UC luminescent, and light-triggered drug release) material should be potential as a suitable targeted cancer therapy carrier and bioimaging

On-demand generation of peroxynitrite from an integrated two-dimensional system for enhanced tumor therapy

Nanosystem-mediated tumor radiosensitization strategy combining the features of X-ray with infinite penetration depth and high atomic number elements shows considerable application potential in clinical cancer therapy. However, it is difficult to achieve satisfactory anticancer efficacy using clinical radiotherapy for the majority of solid tumors due to the restrictions brought about by the tumor hypoxia, insufficient DNA damage, and rapid DNA repair during and after treatment. Inspired by the complementary advantages of nitric oxide (NO) and X-ray-induced photodynamic therapy, we herein report a two-dimensional nanoplatform by the integration of the NO donor-modified LiYF4:Ce scintillator and graphitic carbon nitride nanosheets for on-demand generation of highly cytotoxic peroxynitrite (ONOO–). By simply adjusting the Ce3+ doping content, the obtained nanoscintillator can realize high radioluminescence, activating photosensitive materials to simultaneously generate NO and superoxide radical for the formation of ONOO– in the tumor. Obtained ONOO– effectively amplifies therapeutic efficacy of radiotherapy by directly inducing mitochondrial and DNA damage, overcoming hypoxia-associated radiation resistance. The level of glutamine synthetase (GS) is downregulated by ONOO–, and the inhibition of GS delays DNA damage repair, further enhancing radiosensitivity. This work establishes a combinatorial strategy of ONOO– to overcome the major limitations of radiotherapy and provides insightful guidance to clinical radiotherapy.Agency for Science, Technology and Research (A*STAR)Submitted/Accepted versionFinancial support from the National Natural Science Foundation of China (51972075, 51972076, and 51772059), the Natural Science Foundation of Shandong Province (ZR2019ZD29), the Natural Science Foundation of Heilongjiang Province (YQ2019E014), the Postdoctoral Scientific Research Developmental Fund (LBH-Q18034), and the Ph.D. Student Research and Innovation Fund of the Fundamental Research Funds for the Central Universities (3072020GIP1016) are greatly acknowledged. This research is also supported by the Singapore Agency for Science, Technology and Research (A*STAR) AME IRG grant (A20E5c0081)

La(OH)₃:Ln³⁺ and La₂O₃:Ln³⁺ (Ln = Yb/Er, Yb/Tm, Yb/Ho) Microrods: Synthesis and Up-conversion Luminescence Properties

One-dimensional La­(OH)₃:Ln³⁺ (Ln = Yb/Er, Yb/Tm, Yb/Ho) microrods have been successfully synthesized using molten composite-hydroxide (NaOH/KOH) as a solvent. La₂O₃:Ln³⁺ nanostructures with retained striplike shape were achieved by a subsequent annealing process. The phase, structure, morphology, and fluorescent properties have been well investigated by various techniques. It is found that the reaction time plays a key role in confining the growth of the microrods. Both La­(OH)₃:Ln³⁺ and La₂O₃:Ln³⁺ nanostructures have rodlike shapes with a typical width of 50–400 nm. The up-conversion (UC) photoluminescence (PL) properties of the samples have been studied in detail. Under 980 nm laser excitation, both La­(OH)₃:Ln³⁺ and La₂O₃:Ln³⁺ microrods exhibit the characteristic emissions of Er³⁺, Tm³⁺, and Ho³⁺ and give green, blue, and blackish green emission colors, respectively. Additionally, the doping concentration of Yb³⁺ has been optimized by fixing the Er³⁺ concentration. It should be noted that the up-conversion emission of La₂O₃:Er³⁺ microrods can be significantly improved in comparison with that of their bulk counterpart under the same excitation conditions

Highly Uniform α‑NaYF₄:Yb/Er Hollow Microspheres and Their Application as Drug Carrier

Highly uniform α-NaYF₄:Yb/Er hollow microspheres have been successfully prepared via a simple two-step route. First, the core–shell structured MF@Y­(OH)­CO₃:Yb/Er precursor was fabricated by a urea-based homogeneous precipitation method using colloidal melamine formaldehyde (MF) microspheres as template. Then the Y­(OH)­CO₃:Yb/Er precursor was transformed into hollow NaYF₄:Yb/Er (α and β mixed phase) by a subsequent solvothermal method, and MF microspheres were dissolved in the solvent simultaneously. The mixed phase of NaYF₄:Yb/Er was transferred into pure α-NaYF₄:Yb/Er by calcination. The as-prepared hollow microspheres were well characterized by X-ray diffraction (XRD), scanning electron microscopy (SEM), transmission electron microscopy (TEM), energy-dispersive X-ray spectrum (EDS), Fourier transform infrared spectroscopy (FT-IR), thermogravimetric analysis (TGA), and upconversion (UC) luminescence spectroscopy. It is found that the template can be removed without additional calcination or etching process. α-NaYF₄:Yb/Er hollow microspheres exhibit bright upconversion (UC) luminescence under 980 nm laser diode (LD) excitation. Furthermore, the hollow microspheres show sustained and pH-dependent doxorubicin hydrochloride (DOX) release properties; in particular, the emission intensity increases with the release amount of drug, making the release process able to be tracked or monitored by the change of the emission intensity, which demonstrates the high potential of this kind of hollow fluorescent material in drug delivery fields

Imaging-Guided and Light-Triggered Chemo-/Photodynamic/Photothermal Therapy Based on Gd (III) Chelated Mesoporous Silica Hybrid Spheres

Exploring a combined anticancer therapeutic strategy to overcome the limitations of a single mode and pursue higher therapeutic efficiency is highly promising in both fundamental and clinical investigations. Herein, a theranostic nanoplatform based on mesoporous silica, which is functionalized by hybrid nanosphere photosensitizer Chlorin e6 (Ce6), photothermal agent carbon dots (CDs), and imaging agent Gd (III) ions has been rationally designed and fabricated. A thermo/pH-coupling sensitive polymer (P­(NIPAm-<i>co</i>-MAA)) coated on a composite acted as a key “gatekeeper” to control drug release at the appropriate time and location. Upon light irradiation, two-mode synergistic therapeutic effect of photodynamic and photothermal therapy can be achieved by photoactive Ce6 and CDs. Meanwhile, the CDs loaded in the channels of mesoporous silica hybrid spheres can also play a role in handling the “gatekeeper” polymer to control the drug release process. Combined with the thermo/pH-sensitive drug release-induced controllable chemotherapy, this platform shows synergistic therapeutic efficacy better than any single/dual therapy, which is confirmed with evidence from in vivo and in vitro assays. Considering the chelated Gd³⁺ simultaneously introduced magnetic resonance imaging (MRI) and computed tomography (CT) properties, this multifunctional platform should have excellent potential in the imaging-guided cancer therapy field