Yinyin Chen

UV-Emitting Upconversion-Based TiO2 Photosensitizing Nanoplatform: Near-Infrared Light Mediated in Vivo Photodynamic Therapy via Mitochondria-Involved Apoptosis Pathway

Photodynamic therapy (PDT) is a promising antitumor treatment that is based on the photosensitizers that inhibit cancer cells by yielding reactive oxygen species (ROS) after irradiation of light with specific wavelengths. As a potential photosensitizer, titanium dioxide (TiO2) exhibits minimal dark cytotoxicity and excellent ultraviolet (UV) light triggered cytotoxicity, but is challenged by the limited tissue penetration of UV light. Herein, a novel near-infrared (NIR) light activated photosensitizer for PDT based on TiO2-coated upconversion nanoparticle (UCNP) core/shell nanocomposites (UCNPs@TiO2 NCs) is designed. NaYF4:Yb(3+),Tm(3+)@NaGdF4:Yb(3+) core/shell UCNPs can efficiently convert NIR light to UV emission that matches well with the absorption of TiO2 shells. The UCNPs@TiO2 NCs endocytosed by cancer cells are able to generate intracellular ROS under NIR irradiation, decreasing the mitochondrial membrane potential to release cytochrome c into the cytosol and then activating caspase 3 to induce cancer cell apoptosis. NIR light triggered PDT of tumor-bearing mice with UCNPs@TiO2 as photosensitizers can suppress tumor growth efficiently due to the better tissue penetration than UV irradiation. On the basis of the evidence of in vitro and in vivo results, UCNPs@TiO2 NCs could serve as an effective photosensitizer for NIR light mediated PDT in antitumor therapy.

Ultra-small BaGdF5-based upconversion nanoparticles as drug carriers and multimodal imaging probes.

A new type of drug-delivery system (DDS) was constructed, in which the anti-cancer drug doxorubicin (DOX) was conjugated to the ultra-small sized (sub-10 nm) BaGdF5:Yb(3+)/Tm(3+) based upconversion nanoparticles (UCNPs). This multifunctional DDS simultaneously possesses drug delivery and optical/magnetic/X-ray computed tomography imaging capabilities. The DOX can be selectively released by cleavage of hydrazone bonds in acidic environment, which shows a pH-triggered drug release behavior. The MTT assay shows these DOX-conjugated UCNPs exhibit obvious cytotoxic effect on HeLa cells. Moreover, to improve the upconversion luminescence intensity, core-shell structured UCNPs were constructed. The in vitro upconversion luminescence images of these UCNPs uptaken by HeLa cells show bright emission with high contrast. In addition, these UCNPs were further explored for T1-weighted magnetic resonance (MR) and X-ray computed tomography (CT) imaging in vitro. Long-term in vivo toxicity studies indicated that mice intravenously injected with 10 mg/kg of UCNPs survived for 40 days without any apparent adverse effects to their health. The results indicate that this multifunctional drug-delivery system with optimized size, excellent optical/MR/CT trimodal imaging capabilities, and pH-triggered drug release property is expected to be a promising platform for simultaneous cancer therapy and bioimaging.

Multifunctional upconversion mesoporous silica nanostructures for dual modal imaging and in vivo drug delivery.

Incorporating the agents for magnetic resonance imaging (MRI), optical imaging, and therapy in one nanostructured matrix to construct multifunctional nanomedical platform has attracted great attention for simultaneous diagnostic and therapeutic applications. In this work, a facile methodology is developed to construct a multifunctional anticancer drug nanocarrier by combining the special advantages of upconversion nanoparticles and mesoporous silica. β-NaYF4 :Yb(3+) , Er(3+) @β-NaGdF4 :Yb(3+) is chosen as it can provide the dual modality of upconversion luminescence and MRI. Then mesoporous silica is directly coated onto the upconversion nanoparticles to form discrete, monodisperse, highly uniform, and core-shell structured nanospheres (labeled as UCNPs@mSiO2 ), which are subsequently functionalized with hydrophilic polymer poly(ethylene glycol) (PEG) to improve the colloidal stability and biocompatibility. The obtained multifunctional nanocomposites can be used as an anticancer drug delivery carrier and applied for imaging. The anticancer drug doxorubicin (DOX) is absorbed into UCNPs@mSiO2 -PEG nanospheres and released in a pH-sensitive pattern. In vitro cell cytotoxicity tests on cancer cells verify that the DOX-loaded UCNPs@mSiO2 -PEG has comparable cytotoxicity with free DOX at the same concentration of DOX. In addition, the T1 -weighted MRI that measures in aqueous solutions reveals that the contrast brightening increases with the concentration of Gd(3+) component. Upconversion luminescence images of UCNPs@mSiO2 -PEG uptaken by cells show green emission under 980 nm infrared laser excitation. Finally, the nanocomposites show low systematic toxicity and high in vivo antitumor therapy efficacy. These findings highlight the fascinating features of upconversion-mesoporous nanocomposites as multimodality imaging contrast agents and nanocarrier for drug molecules.

Tailored Synthesis of Octopus‐type Janus Nanoparticles for Synergistic Actively‐Targeted and Chemo‐Photothermal Therapy

A facile, reproducible, and scalable method was explored to construct uniform Au@poly(acrylic acid) (PAA) Janus nanoparticles (JNPs). The as-prepared JNPs were used as templates to preferentially grow a mesoporous silica (mSiO2 ) shell and Au branches separately modified with methoxy-poly(ethylene glycol)-thiol (PEG) to improve their stability, and lactobionic acid (LA) for tumor-specific targeting. The obtained octopus-type PEG-Au-PAA/mSiO2 -LA Janus NPs (PEG-OJNP-LA) possess pH and NIR dual-responsive release properties. Moreover, DOX-loaded PEG-OJNP-LA, upon 808 nm NIR light irradiation, exhibit obviously higher toxicity at the cellular and animal levels compared with chemotherapy or photothermal therapy alone, indicating the PEG-OJNP-LA could be utilized as a multifunctional nanoplatform for in vitro and in vivo actively-targeted and chemo-photothermal cancer therapy.

Multifunctional Core-Shell Structured Nanocarriers for Synchronous Tumor Diagnosis and Treatment In Vivo

Multifunctional, mesoporous, silica-coated upconversion luminescent/magnetic NaGdF4:Yb/Er@NaGdF4:Yb@mSiO2-PEG (referred to as UCNPS; PEG=polyethylene glycol) nanocomposites were fabricated through a phase-transfer-assisted surfactant-templating coating process, followed by hydrophilic polymer (PEG) functionalization to improve the stability and biocompatibility. The UCNP core imparts the nanomaterials with luminescence and magnetic properties for simultaneous upconversion optical and magnetic resonance (MR) imaging, whereas the mesoporous shell affords the nanomaterials the ability to load the anticancer drug doxorubicin. Proof-of-principle in vitro and in vivo experiments are presented to demonstrate that the resultant composite nanomaterials can serve as nanotheranostics for synchronous upconversion luminescence/MR dual modal imaging and anticancer drug delivery; this finally realizes the integration of diagnostics and the treatment of cancers.

Multifunctional electrospinning composite fibers for orthotopic cancer treatment in vivo

A multifunctional, dual-drug carrier platform was successfully constructed. Core-shell structured NaGdF4:Yb/Er@NaGdF4:Yb@mSiO2-polyethylene glycol (abbreviated as UCNPS) nanoparticles loaded with the antitumor drug, doxorubicin (DOX) were incorporated into poly(ɛ-caprolactone) (PCL) and gelatin loaded with antiphlogistic drug, indomethacin (MC) to form nanofibrous fabrics (labeled as MC/UCNPS/DOX) via electrospinning process. The resultant multifunctional spinning pieces can be surgically implanted directly at the tumor site of mice as an orthotopic chemotherapy by controlled-release DOX from mesoporous silicon dioxide (SiO2) and upconversion fluorescence/magnetic resonance dual-model imaging through NaGdF4:Yb/Er@NaGdF4:Yb embedded in MC/UCNPS/DOX in vivo.

808 nm light responsive nanotheranostic agents based on near-infrared dye functionalized manganese ferrite for magnetic-targeted and imaging-guided photodynamic/photothermal therapy

Near-infrared (NIR) light induced phototherapy has attracted considerable attention due to its deep therapeutic depth. To improve the therapeutic outcome and address non-selective side effects, the combination of complementary phototherapeutic strategies in a single nanoagent with precise targeting ability may provide an effective approach for cancer therapy. Thus we have developed an 808 nm NIR light triggered nanosystem based on IR806 dye functionalized MnFe2O4 (MFO-IR) for synchronous magnetic targeted and magnetic resonance (MR) imaging guided in vivo photodynamic/photothermal synergistic therapy. In this construction strategy, carboxylic acid functionalized NIR dye IR806 is explored as an 808 nm NIR-excited photosensitizer (PS) for the first time, which can also provide a conjugation site for MnFe2O4 nanoparticles (MFO NPs). Here, monodisperse MFO NPs have multiple capacities as dye carriers, targeting ligands, MRI contrast agents and photothermal agents. MFO-IR nanocomposites (NCs) with negligible toxicity present efficient NIR-mediated photothermal damage and ROS cytotoxicity via the relevant in vitro experimental investigations. With ideal magnetic targeting effects and remarkable NIR light-responsive properties, these MFO-IR NCs exhibit high in vivo tumor localization and could destroy subcutaneous solid tumors completely under an external magnetic field and 808 nm laser irradiation. Consequently, this magnetic nanosystem has great potential for simultaneous diagnosis and precise cancer phototherapy.

Polyaniline electrospinning composite fibers for orthotopic photothermal treatment of tumors in vivo

A nanocomposite fabricated by electrostatic spinning, which incorporated polyaniline nanoparticles into poly(e-caprolactone) and gelatin (PG), was used to form nanofiber fabrics. Polyaniline nanoparticles have a strong optical absorption at near-infrared (NIR) wavelengths and can convert optical energy into thermal energy under 808 nm laser irradiation, allowing them to ablate tumor cells thermally. Pieces of the nanocomposite were surgically implanted into tumors in mice, and orthotopic photothermal therapy was performed. The experimental results in vivo suggested that polyaniline PG can inhibit tumor growth efficiently by converting optical energy into thermal energy to ablate tumor cells.

Multifunctional polyelectrolyte multilayers coated onto Gd2O3:Yb3+,Er3+@MSNs can be used as drug carriers and imaging agents

Mesoporous silica nanoparticles (MSNs) were firstly functionalized with upconversion luminescent Gd2O3:Yb3+,Er3+ via the Pechini sol–gel method. Then, polyelectrolyte multilayers (PEM) composed of poly(allyamine hydrochloride) (PAH) and poly(styrene sulfonate) (PSS) were coated onto the Gd2O3:Yb3+,Er3+@MSNs using a layer-by-layer (LbL) technique to achieve the pH-responsive properties of the nanocarriers. PEM@Gd2O3:Yb3+,Er3+@MSNs loaded with doxorubicin hydrochloride (DOX) showed pH-responsive release and higher cytotoxicity towards MCF-7 breast cancer cells in vitro. Nanocomposites functionalized with Gd2O3:Yb3+,Er3+ can serve as T1-weighted magnetic resonance imaging (MRI) contrast agents. Nanoparticles emitting red signals under 980 nm laser excitation are suitable for use in potential bioimaging applications. The upconversion luminescent (UCL) intensity of PEM-coated nanocomposites can be adjusted by controlling the number of layers of the PAH/PSS coating. The PEM@Gd2O3:Yb3+,Er3+@MSNs can be used as a potential drug delivery system for MRI, UCL imaging, and pH-responsive chemotherapy.

Stimuli-responsive nanocomposites for magnetic targeting synergistic multimodal therapy and T1/T2-weighted dual-mode imaging

Anticancer drug doxorubicin hydrochloride (DOX)-loaded photothermal nanocomposite MnFe2O4@mSiO2 with magnetic targeting and T1/T2-weighted dual-mode magnetic resonance imaging of MnFe2O4 core and NIR/pH-coupling sensitive mesoporous silica shell nanocarriers was designed and synthesized successfully. The anticancer drug DOX can be absorbed into mesoporous layer of MnFe2O4@mSiO2 nanocomposite, which shows obvious photothermal/chemo dual-modal synergistic therapies triggered by NIR/pH. Under 808 nm irradiation, MnFe2O4 can transform light into thermo, which can not only ablate tumor cells directly but also promote chemotherapy drugs releasing from mesoporous layer to kill tumor cells. The lower pH can also promote DOX releasing from mesoporous layer to enhance tumor inhibitory effect. It is confirmed that biocompatible DOX-MnFe2O4@mSiO2 nanocomposites can act as a potential multifunctional platform for effective magnetic targeting photothermal/chemo dual-modal synergistic therapies with enhanced anti-tumor efficacy and T1/T2-weighted dual-mode magnetic resonance imaging (MRI) applications in vivo.