NIR-II imaging-guided photothermal cancer therapy combined with enhanced immunogenic death.

Photothermal therapy has a remarkable effect on the destruction of tumors. It kills tumor cells by photothermal ablation and induces immunogenic cell death by activating the immune response in tumor tissues. However, inhibition of the tumor immune microenvironment suppresses PTT-induced body-specific anti-tumor immunity. In this study, we designed the GdOF@PDA-HA-R837-hydrogel complex to achieve NIR-II imaging-guided photothermal ablation and enhanced immune response. Due to the doping of Yb and Er elements and the presence of a polydopamine coating, the synthesized nanoparticles enable NIR-II and photoacoustic imaging of tumor tissues, which will help in the integration of multimodal tumor imaging for diagnosis and treatment. Polydopamine is used as a photothermal agent and drug carrier because of its excellent photothermal ability and high drug loading capacity under 808 nm near infrared light. Hyaluronic acid can bind to specific receptors on the surface of cancer cells, allowing nanoparticles to aggregate around the tumor, thus enhancing the targeting ability of nanoparticles. In addition, imiquimod (R837) has been used as an immune response modulator to enhance the immunotherapeutic effect. The presence of a hydrogel enhanced the retention effect of nanoparticles in the tumor. We demonstrate that the combination of photothermal therapy with immune adjuvants effectively induces ICD, which in turn stimulates the activation of specific anti-tumor immunity and enhances the effect of photothermal therapy in vivo.

Recent advances in lanthanide-doped up-conversion probes for theranostics.

Up-conversion (or anti-Stokes) luminescence refers to the phenomenon whereby materials emit high energy, short-wavelength light upon excitation at longer wavelengths. Lanthanide-doped up-conversion nanoparticles (Ln-UCNPs) are widely used in biomedicine due to their excellent physical and chemical properties such as high penetration depth, low damage threshold and light conversion ability. Here, the latest developments in the synthesis and application of Ln-UCNPs are reviewed. First, methods used to synthesize Ln-UCNPs are introduced, and four strategies for enhancing up-conversion luminescence are analyzed, followed by an overview of the applications in phototherapy, bioimaging and biosensing. Finally, the challenges and future prospects of Ln-UCNPs are summarized.

Transferred Photothermal to Photodynamic Therapy Based on the Marriage of Ultrathin Titanium Carbide and Up-Conversion Nanoparticles.

In this research, upconversion nanoparticles (UCNPs) are used as a light conversion carrier, and their deep light source penetrability is closely combined with ultrathin two-dimensional (2D) Ti3C2Tx to explore the application efficiency of the complex in phototherapy. Due to the advantages of 2D Ti3C2Tx with its high absorbance to ultraviolet/visible light, rich atomic defects to load the drugs, and adjustable thinner structure, this 2D material is beneficially applied as the energy donor. UCNPs@Ti3C2Tx with a photothermal conversion efficiency of 20.7% is proven with the ability to generate reactive oxygen species under a 980 nm laser at the cellular level. Importantly, the main photothermal therapy method can be changed to a photodynamic therapy method due to the degradation of Ti3C2Tx to TiO2 under the oxygen-bearing environment. The in vivo experiment was continued to verify that UCNPs@Ti3C2Tx can kill tumor cells and inhibit tumor growth within a certain period. In addition, in vivo treatment with a combination of immunotherapy and phototherapy of UCNPs@ Ti3C2Tx is carried out to achieve stronger tumor inhibition over the prolonged time points.

Lanthanide-Based Nanocomposites for Photothermal Therapy under Near-Infrared Laser: Relationship between Light and Heat, Biostability, and Reaction Temperature.

In this research, typical organic/inorganic photothermal therapy (PTT) agents were designed with a combination of upconversion luminescent (UCL) or near-infrared (NIR) II imaging rare-earth nanomaterials for photo-acoustic (PA)/UCL/NIR II imaging-guided PTT under NIR laser irradiation. The results show the following: (1) The PTT effect mainly comes from NIR absorption and partly from UCL light conversion. (2) Visible UCL emission is mainly quenched by NIR absorption of the coated PTT agent and partly quenched by visible absorption, indicating that excitation may play a more important role than in the UCL emission process. (3) The biostability of the composite might be decided by the synthesis reaction temperature. Among the five inorganic/organic nanocomposites, UCNP@MnO2 is the most suitable candidate for cancer diagnosis and treatment because of its stimuli-response ability to the micro-acid environment of tumor cells and highest biostability. The composites generate heat for PTT after entering the tumor cells, and then, the visible light emission gradually regains as MnO2 is reduced to colorless Mn2+ ions, thereby illuminating the cancer cells after the therapy.

Black Phosphorus Nanosheet with High Thermal Conversion Efficiency for Photodynamic/Photothermal/Immunotherapy.

The synergistic treatment through multiple treatment methods can effectively improve the effect of tumor treatment. Phototherapy and immunotherapy are two innovative and promising cancer diagnosis and treatment methods, so they are good candidates for collaborative diagnosis and treatment. Here we report a new inorganic nanosystem, which uses ultrathin black phosphorus (BP) nanosheets (minimum: 13 nm) as carriers and equips with up-conversion luminescence (UCL) nanoparticles as imaging probes, so that the system can generate photothermal and photodynamic effects to treat tumors together with immunotherapy. Especially, the photothermal conversion efficiency can reach 30.84% under the 980 nm laser, which is significantly higher than the conventional Au nanoparticles including nanostars (22.63%) and Au nanorods (23.33%). When the system works in conjunction with immunotherapy, it not only shows a good ability to treat tumors but also can inhibit tumors for a long time and prevent recurrence. Different from the past, in this work, we not only use this strategy to evaluate the performance during the treatment cycle but also observe the mice after the treatment to verify the long-term effect of suppressing tumors. Overall, this study reveals a new inorganic nanosystem and proposes a new strategy for treating tumors in combination with immunotherapy. The present work illustrates the new opportunities for the treatment of primary tumors.

Hyperthermia and Controllable Free Radical Coenhanced Synergistic Therapy in Hypoxia Enabled by Near-Infrared-II Light Irradiation.

Tumor cell metabolism and tumor blood vessel proliferation are distinct from normal cells. The resulting tumor microenvironment presents a characteristic of hypoxia, which greatly limits the generation of oxygen free radicals and affects the therapeutic effect of photodynamic therapy. Here, we developed an oxygen-independent free radical generated nanosystem (CuFeSe2-AIPH@BSA) with dual-peak absorption in both near-infrared (NIR) regions and utilized it for imaging-guided synergistic treatment. The special absorption provides the nanosystem with high photothermal conversion efficiency and favorably matched photoactivity in both I and II NIR biological windows. Upon NIR light irradiation, the generated heat could prompt AIPH release and decompose to produce oxygen-independent free radicals for killing cancer cells effectively. The contrastive research results show that the enhanced therapeutic efficacy of NIR-II over NIR-I is principally due to its deeper tissue penetration and higher maximum permission exposure that benefits from a longer wavelength. Hyperthermia effect and the production of toxic free radicals upon NIR-II laser illumination are extremely effective in triggering apoptosis and death of cancer cells in the tumor hypoxia microenvironment. The high biocompatibility and excellent anticancer efficiency of CuFeSe2-AIPH@BSA allow it to be an ideal oxygen-independent nanosystem for imaging-guided and NIR-II-mediated synergistic therapy via systemic administration.

Stable ICG-loaded upconversion nanoparticles: silica core/shell theranostic nanoplatform for dual-modal upconversion and photoacoustic imaging together with photothermal therapy.

We report here the design and multiple functions of a new hierarchical nanotheronostic platform consisting of an upconversion nanoparticle (UCNP) core: shell with an additional mesoporous silica (mSiO2) matrix load shell containing sealed, high concentration of ICG molecules. We demonstrate that this UCNP@mSiO2-ICG nanoplatform can perform the following multiple functions under NIR excitation at 800 nm: 1) Light harvesting by the UCNP shell containing Nd and subsequent energy transfer to Er in the Core to produce efficient green and red upconversion luminescence for optical imaging; 2) Efficient nonradiative relaxation and local heating produced by concentration quenching in aggregated ICG imbedded in the mesopourous silica shell to enable both photoacoustic imaging and photothermal therapy. Compared to pure ICG, sealing of mesoporous silica platforms prevents the leak-out and improves the stability of ICG by protecting from rapid hydrolysis. Under 800 nm laser excitation, we performed both optical and photoacoustic (PA) imaging in vitro and in vivo. Our results demonstrated that UCNP@mSiO2-ICG with sealed structures could be systemically delivered to brain vessels, with a long circulation time. In addition, these nanoplatforms were capable of producing strong hyperthermia efforts to kill cancer cells and hela cells under 800 nm laser irradiation.

Dopamine-mediated photothermal theranostics combined with up-conversion platform under near infrared light.

An organic-inorganic hybrid core-shell nanostructure, based on mesoporous silica coated upconversion core-shell nanoparticles (NaGdF4:Yb,Er@NaGdF4:Yb@mSiO2-Dopa abbreviated here as UCNP@mSiO2-Dopa) that stably incorporates dopamine (Dopa) in the silica layer was introduced as a theranostic nanoplatform for optical imaging guided photothermal therapy (PTT) using NIR excitation. Silica-attaching polyethylenimine make the Dopa transforms into an active form (transferred Dopa) that strongly absorbs light under single 980 nm irradiation. We show that the activated UCNP@mSiO2-Dopa nanoplatform is able to produce a pronounced photothermal effect, that elevates water temperature from room temperature to 41.8 °C within 2 minutes, while concurrently emitting strong upconverted luminescence (UCL) for visualized guidance under 980 nm laser. In addition, we demonstrate the application of the same UCNP@mSiO2-Dopa nanoplatform for magnetic resonance imaging (MRI) and x-ray computed tomography (CT) enabled by the gadolinium (Gd) element contained in the UCNP. Importantly, the in vitro and in vivo anti-cancer therapeutic effects have been shown efficacious, implying the use of the described nanoplatform as an effective multi-modal imaging enabled PTT agent. Results from the in vivo biodistribution of UCNPs@mSiO2, cellular live/dead assay, and histologic analysis of main organs of treated mice, reveal that the UCNP@mSiO2-Dopa agents are bio-compatible with low toxicity.

Au25 cluster functionalized metal-organic nanostructures for magnetically targeted photodynamic/photothermal therapy triggered by single wavelength 808 nm near-infrared light.

Near-infrared (NIR) light-induced cancer therapy has gained considerable interest, but pure inorganic anti-cancer platforms usually suffer from degradation issues. Here, we designed metal-organic frameworks (MOFs) of Fe3O4/ZIF-8-Au25 (IZA) nanospheres through a green and economic procedure. The encapsulated Fe3O4 nanocrystals not only produce hyperthemal effects upon NIR light irradiation to effectively kill tumor cells, but also present targeting and MRI imaging capability. More importantly, the attached ultrasmall Au25(SR)18(-) clusters (about 2.5 nm) produce highly reactive singlet oxygen ((1)O2) to cause photodynamic effects through direct sensitization under NIR light irradiation. Furthermore, the Au25(SR)18(-) clusters also give a hand to the hyperthemal effect as photothermal fortifiers. This nanoplatform exhibits high biocompatibility and an enhanced synergistic therapeutic effect superior to any single therapy, as verified by in vitro and in vivo assay. This image-guided therapy based on a metal-organic framework may stimulate interest in developing other kinds of metal-organic materials with multifunctionality for tumor diagnosis and therapy.

Y2O3:Yb,Er@mSiO2-Cu(x)S double-shelled hollow spheres for enhanced chemo-/photothermal anti-cancer therapy and dual-modal imaging.

Multifunctional composites have gained significant interest due to their unique properties which show potential in biological imaging and therapeutics. However, the design of an efficient combination of multiple diagnostic and therapeutic modes is still a challenge. In this contribution, Y2O3:Yb,Er@mSiO2 double-shelled hollow spheres (DSHSs) with up-conversion fluorescence have been successfully prepared through a facile integrated sacrifice template method, followed by a calcination process. It is found that the double-shelled structure with large specific surface area and uniform shape is composed of an inner shell of luminescent Y2O3:Yb,Er and an outer mesoporous silica shell. Ultra small Cu(x)S nanoparticles (about 2.5 nm) served as photothermal agents, and a chemotherapeutic agent (doxorubicin, DOX) was then attached onto the surface of mesoporous silica, forming a DOX-DSHS-Cu(x)S composite. The composite exhibits high anti-cancer efficacy due to the synergistic photothermal therapy (PTT) induced by the attached Cu(x)S nanoparticles and the enhanced chemotherapy promoted by the heat from the Cu(x)S-based PTT when irradiated by 980 nm near-infrared (NIR) light. Moreover, the composite shows excellent in vitro and in vivo X-ray computed tomography (CT) and up-conversion fluorescence (UCL) imaging properties owing to the doped rare earth ions, thus making it possible to achieve the target of imaging-guided synergistic therapy.

An imaging-guided platform for synergistic photodynamic/photothermal/chemo-therapy with pH/temperature-responsive drug release.

To integrate biological imaging and multimodal therapies into one platform for enhanced anti-cancer efficacy, we have designed a novel core/shell structured nano-theranostic by conjugating photosensitive Au25(SR)18 - (SR refers to thiolate) clusters, pH/temperature-responsive polymer P(NIPAm-MAA), and anti-cancer drug (doxorubicin, DOX) onto the surface of mesoporous silica coated core-shell up-conversion nanoparticles (UCNPs). It is found that the photodynamic therapy (PDT) derived from the generated reactive oxygen species and the photothermal therapy (PTT) arising from the photothermal effect can be simultaneously triggered by a single 980 nm near infrared (NIR) light. Furthermore, the thermal effect can also stimulate the pH/temperature sensitive polymer in the cancer sites, thus realizing the targeted and controllable DOX release. The combined PDT, PTT and pH/temperature responsive chemo-therapy can markedly improve the therapeutic efficacy, which has been confirmed by both in intro and in vivo assays. Moreover, the doped rare earths endow the platform with dual-modal up-conversion luminescent (UCL) and computer tomography (CT) imaging properties, thus achieving the target of imaging-guided synergistic therapy under by a single NIR light.

LaF3:Ln mesoporous spheres: controllable synthesis, tunable luminescence and application for dual-modal chemo-/photo-thermal therapy.

In this report, uniform LaF(3):Ln mesoporous spheres have been synthesized by a facile and mild in situ ion-exchange method using yolk-like La(OH)3:Ln mesoporous spheres as templates, which were prepared through a self-produced bubble-template route. It was found that the structures of the final LaF(3):Ln can simply be tuned by adding a polyetherimide (PEI) reagent. LaF(3):Ln hollow mesoporous spheres (HMSs) and LaF(3):Ln flower-like mesoporous spheres (FMSs) were obtained when assisted by PEI and in the absence of PEI. The up-conversion (UC) luminescence results reveal that the doping of Nd(3+) ions in LaF(3):Ln can markedly influence the UC emissions of the products. It is interesting that an obvious thermal effect is achieved due to the energy back-transfer from Tm(3+) to Nd(3+) ions under 980 nm near-infrared (NIR) irradiation. The LaF(3):Yb/Er/Tm/Nd HMSs show good biocompatibility and sustained doxorubicin (DOX) release properties. In particular, upon 980 nm NIR irradiation, the photothermal effect arising from the Nd(3+) doping induces a faster DOX release from the drug release system. Moreover, UC luminescence images of LaF(3):Yb/Er/Tm/Nd HMSs uptaken by MCF-7 cells exhibit apparent green emission under 980 nm NIR irradiation. Such a multifunctional carrier combining UC luminescence and hyperthermia with the chemotherapeutic drugs should be of high potential for the simultaneous anti-cancer therapy and cell imaging.