Tumor Microenvironment Cascade‑Responsive Nanodrug with Self‑Targeting Activation and ROS Regeneration for Synergistic Oxidation‑Chemotherapy

Carrier-free nanodrug with exceptionally high drug payload has attracted increasing attentions.Herein,we construct a pH/ROS cascade-responsive nanodrug which could achieve tumor acidity-triggered targeting activation followed by circularly amplified ROS-triggered drug release via positive-feedback loop.The di-selenide-bridged prodrug synthesized from vitamin E succinate and methotrexate(MTX)self-assembles into nanoparticles(VSeM);decorating acidity-cleavable PEG onto VSeM surface temporarily shields the targeting ability of MTX to evade immune clearance and consequently elongate circulation time.Upon reaching tumor sites,acidity-triggered detachment of PEG results in targeting recovery to enhance tumor cell uptake.Afterward,the VSeM could be dissociated in response to intracellular ROS to trigger VES/MTX release;then the released VES could produce extra ROS to accelerate the collapse of VSeM.Finally,the excessive ROS produced from VES could synergize with the released MTX to efficiently suppress tumor growth via orchestrated oxidation-chemotherapy.Our study provides a novel strategy to engineer cascade-responsive nanodrug for synergistic cancer treatment.

2D graphene oxide-L-arginine-soybean lecithin nanogenerator for synergistic photothermal and NO gas therapy

Nitric oxide(NO) gas therapy has been regarded as a promising strategy for cancer treatment. However,its therapeutic efficiency is still unsatisfying due to the limitations of monotherapy. Previous preclinical and clinical studies have shown that combination therapy could significantly enhance therapeutic efficiency. Herein, a graphene oxide(GO)-L-arginine(L-Arg, a natural NO donor) hybrid nanogenerator is developed followed by surface functionalization of soybean lecithin(SL) for synergistic enhancement of cancer treatment through photothermal and gas therapy. The resultant GO-Arg-SL nanogenerator not only exhibited good biocompatibility and excellent endocytosis ability, but also exhibited excellent photothermal conversion capability and high sensitivity to release NO within tumor microenvironment via inducible NO synthase(i NOS) catalyzation. Moreover, the produced hyperthermia and intracellular NO could synergistically kill cancer cells both in vitro and in vivo. More importantly, this nanogenerator can efficiently eliminate tumor while inhibiting the tumor recurrence because of the immunogenic cell death(ICD) elicited by NIR laser-triggered hyperthermia and the immune response activation by massive NO generation. We envision that the GO-Arg-SL nanogenerator could provide a potential strategy for synergistic photothermal and gas therapy.

Imine-Linked Covalent Organic Framework on Surface for Biosensor

Imine-linked covalent organic framework on amino functionalized silicon substrate was constructed via a step-wise reaction between 1,3,5-benzenetricarboxaldehyde and 1,4-diaminobenzene.The obtained material was used as biosensor for bovine serum albumin(BSA)adsorption and probe DNA immobilization,which extended the application of covalent organic frameworks(COFs)to a new field.

Synthesis of NaYF_(4):20% Yb^(3+),2% Er^(3+),2% Ce^(3+)@NaYF_(4) nanorods and their size dependent uptake efficiency under flow condition

Lanthanide doped fluorescent nanoparticles have gained considerable attention in biomedical applications.However,the low uptake efficiency of nanoparticles by cells has limited their applications.In this work,we demonstrate how the uptake efficiency is affected by the size of nanoparticles under flow conditions.Using the same size NaYF_(4):20%Yb^(3+),2%Er^(3+),2%Ce^(3+)(the contents of rare earths elements are in molar fraction)nanoparticles as core,NaYF_(4):20%Yb^(3+),2%Er^(3+),2%Ce^(3+)@NaYF_(4) core-shell structured nanorods(NRs)with different sizes of 60-224 nm were synthesized by thermal decomposition and hot injection method.Under excitation at 980 nm,a strong upconversion green emission(541 nm,^(2)H_(11/2)→^(4) I_(15/2) of Er^(3+))is observed for all samples.The emission intensity for each size nanorod was calibrated and is found to depend on the width of NRs.Under flow conditions,the nanorods with 96 nm show a maximum uptake efficiency by endothelial cells.This work demonstrates the importance of optimizing the size for improving the uptake efficiency of lanthanide-doped nanoparticles.

Optical Spectra and Gain Properties of Ho^(3+)/Pr^(3+)Co-doped LiYF_4 Crystal

The LiYF4 single crystals singly doped Ho3＋ and co-doped Ho3＋, Pr3＋ ions were grown by a modified Bridgman method. The Judd-Ofelt strength parameters （Ω2, Ω4, Ω6） of No3＋ were calculated according to the absorption spectra and the Judd-Ofelt theory, by which the radiative transition probabilities （A）, fluorescence branching ratios （β） and radiative lifetime （τ rad） were obtained. The radiative lifetimes of 5/6 and 5/7 levels in Ho3＋ （1 mol%）：LiYF4 are 10.89 and 20.19 ms, respectively, while 9.77 and 18.50 ms in Ho3＋/pr3＋ doped crystals. Hence, the τ rad of 5/7 level decreases significantly by introduction of Pr3＋ into Ho3＋：LiYF4 crystal which is beneficial to the emission of 2.9 μm. The maximum emission cross section of Ho3＋：LiYF4 crystal located at 2.05 μm calculated by McCumber theory is 0.51 ×10-20 cm2 which is compared with other crystals. The maximum emission cross section at 2948 nm in Ho3＋/pr3＋ co-doped LiYF4 crystal obtained by Fuchtbauer- Ladenburg theory is 0.68 × 10-20 cm2, and is larger than the value of 0.53 × 10-20 cm2 in Ho3＋ singly doped LiYF4 crystal. Based on the absorption and emission cross section spectra, the gain cross section spectra were calculated. In the Ho3- ions singly doped LiYF4 crystal, the gain cross sections for 2.05 μm infrared emission becomes positive once the population inversion level reaches 30%. It means that the pump threshold for obtaining 2.05 μm laser is probably lower which is an advantage for Ho3＋-doped LiYF4 2.05 μm infrared lasers. The calculated gain cross section for 2.9 μm mid-infrared emission does not become positive until the population inversion level reaches 40% in Ho3＋/pr3＋：LiYF4 crystal, but 50% in Ho3＋ singly doped LiYF4 crystal, indicating that a low pumping threshold is achieved for the H03＋：5/6 → 5/7 laser operation with the introduction of Pr3＋ ions. It was also demonstrated that Pr3＋ ion can deplete rapidly the lower laser Ho3＋：5/7 level and has influence on the Ho3＋：5/6 level. The Ho3＋/pr3＋：LiYF4 crystal may be a potential media for 2.9 μm mid-infrared laser.