Mitochondria-targeting graphene oxide nanocomposites for fluorescence imaging-guided synergistic phototherapy of drug-resistant osteosarcoma.

BACKGROUND: Osteosarcoma (OS) is the most common primary malignant bone tumor occurring in children and young adults. Drug-resistant osteosarcoma often results in chemotherapy failure. Therefore, new treatments aimed at novel therapeutic targets are urgently needed for the treatment of drug-resistant osteosarcoma. Mitochondria-targeted phototherapy, i.e., synergistic photodynamic/photothermal therapy, has emerged as a highly promising strategy for treating drug-resistant tumors. This study proposed a new nano-drug delivery system based on near-infrared imaging and multifunctional graphene, which can target mitochondria and show synergistic phototherapy, with preferential accumulation in tumors. METHODS AND RESULTS: Based on our previous study, (4-carboxybutyl) triphenyl phosphonium bromide (TPP), a mitochondria-targeting ligand, was conjugated to indocyanine green (ICG)-loaded, polyethylenimine-modified PEGylated nanographene oxide sheets (TPP-PPG@ICG) to promote mitochondrial accumulation after cellular internalization. Thereafter, exposure to a single dose of near-infrared irradiation enabled synergistic photodynamic and photothermal therapy, which simultaneously inhibited adenosine triphosphate synthesis and mitochondrial function. Induction of intrinsic apoptosis assisted in surmounting drug resistance and caused tumor cell death. After fluorescence imaging-guided synergistic phototherapy, the mitochondria-targeting, multifunctional graphene-based, drug-delivery system showed highly selective anticancer efficiency in vitro and in vivo, resulting in marked inhibition of tumor progression without noticeable toxicity in mice bearing doxorubicin-resistant MG63 tumor cells. CONCLUSION: The mitochondria-targeting TPP-PPG@ICG nanocomposite constitutes a new class of nanomedicine for fluorescence imaging-guided synergistic phototherapy and shows promise for treating drug-resistant osteosarcoma.

Surface plasmon-enhanced nanoporous GaN-based green light-emitting diodes with Al2O3 passivation layer.

A surface plasmon (SP)-enhanced nanoporous GaN-based green LED based on top-down processing technology has been successfully fabricated. This SP-enhanced LED consists of nanopores passing through the multiple quantum wells (MQWs) region, with Ag nanorod array filled in the nanopores for SP-MQWs coupling and thin Al(2)O(3) passivation layer for electrical protection. Compared with nanoporous LED without Ag nanorods, the electroluminescence (EL) peak intensity for the SP-enhanced LED was greatly enhanced by 380% and 220% at an injection current density of 1 and 20A/cm(2), respectively. Our results show that the increased EL intensity is mainly attributed to the improved internal quantum efficiency of LED due to the SP coupling between Ag nanorods and MQWs.

[Raman spectra analysis of GaN : Er films prepared by ion implantation].

U-, n- and p-GaN : Er films were prepared by ion implantation method. Three carrier types of samples were studied by Raman spectra analysis. After Er+ ion implantation into GaN samples, new Raman peaks at wavenumber of 293, 362 (see text) 670 cm-1 appeared, where 293 cm-1 was considered as disordered activation of Raman scattering (DARS), 362 and 670 cm-1 may be associated with GaN lattice defects formed after ion implantation. The Ez (high) characteristic peak moves to the high frequency before and after GaN : Er samples annealing at 800 C, indicating that GaN lattice is under the compressive stress. The Lorenz fitting was used to analysed the occurrences of A1 (LO) peak in different samples which is composed of the uncoupled mode LO and the plasmon coupling mode LPP+, qualitatively pointing out the carrier concentration variation of a series of GaN : Er samples.

Intra-articular Injection of Kartogenin-Enhanced Bone Marrow-Derived Mesenchymal Stem Cells in the Treatment of Knee Osteoarthritis in a Rat Model.

BACKGROUND: In this study, we investigated the in vitro and in vivo chondrogenic capacity of kartogenin (KGN)-enhanced bone marrow-derived mesenchymal stem cells (BMSCs) for cartilage regeneration. PURPOSE: To determine (1) whether functionalized nanographene oxide (NGO) can effectively deliver KGN into BMSCs and (2) whether KGN would enhance BMSCs during chondrogenesis in vitro and in vivo in an animal model. STUDY DESIGN: Controlled laboratory study. METHODS: Functionalized NGO with line chain amine-terminated polyethylene glycol (PEG) and branched polyethylenimine (BPEI) were used to synthesize biocompatible NGO-PEG-BPEI (PPG) and for loading hydrophobic KGN molecules noncovalently via π-π stacking and hydrophobic interactions (PPG-KGN). Then, PPG-KGN was used for the intracellular delivery of hydrophobic KGN by simple mixing and co-incubation with BMSCs to acquire KGN-enhanced BMSCs. The chondrogenic efficacy of KGN-enhanced BMSCs was evaluated in vitro. In vivo, osteoarthritis (OA) was induced by anterior cruciate ligament transection in rats. A total of 5 groups were established: normal (OA treated with nothing), phosphate-buffered saline (PBS; intra-articular injection of PBS), PPG-KGN (intra-articular injection of PPG-KGN), BMSCs (intra-articular injection of BMSCs), and BMSCs + PPG-KGN (intra-articular injection of PPG-KGN-preconditioned BMSCs). At 6 and 9 weeks after the surgical induction of OA, the rats received intra-articular injections of PPG-KGN, BMSCs, or KGN-enhanced BMSCs. At 14 weeks after the surgical induction of OA, radiographic and behavioral evaluations as well as histological analysis of the knee joints were performed. RESULTS: The in vitro study showed that PPG could be rapidly uptaken in the first 4 hours after incubation, reaching saturation at 12 hours and accumulating in the lysosome and cytoplasm of BMSCs. Thus, PPG-KGN could enhance the efficiency of the intracellular delivery of KGN, which showed a remarkably high chondrogenic differentiation capacity of BMSCs. When applied to an OA model of cartilage injuries in rats, PPG-KGN-preconditioned BMSCs contributed to protection from joint space narrowing, pathological mineralization, OA development, and OA-induced pain, as well as improved tissue regeneration, as evidenced by radiographic, weightbearing, and histological findings. CONCLUSION: Our results demonstrate that KGN-enhanced BMSCs showed markedly improved capacities for chondrogenesis and articular cartilage repair. We believe that this work demonstrates that a multifunctional nanoparticle-based drug delivery system could be beneficial for stem cell therapy. Our results present an opportunity to reverse the symptoms and pathophysiology of OA. CLINICAL RELEVANCE: The intracellular delivery of KGN to produce BMSCs with enhanced chondrogenic potential may offer a new approach for the treatment of OA.

Transmissibility of COVID-19 in 11 major cities in China and its association with temperature and humidity in Beijing, Shanghai, Guangzhou, and Chengdu.

BACKGROUND: The new coronavirus disease COVID-19 began in December 2019 and has spread rapidly by human-to-human transmission. This study evaluated the transmissibility of the infectious disease and analyzed its association with temperature and humidity to study the propagation pattern of COVID-19. METHODS: In this study, we revised the reported data in Wuhan based on several assumptions to estimate the actual number of confirmed cases considering that perhaps not all cases could be detected and reported in the complex situation there. Then we used the equation derived from the Susceptible-Exposed-Infectious-Recovered (SEIR) model to calculate R0 from January 24, 2020 to February 13, 2020 in 11 major cities in China for comparison. With the calculation results, we conducted correlation analysis and regression analysis between R0 and temperature and humidity for four major cities in China to see the association between the transmissibility of COVID-19 and the weather variables. RESULTS: It was estimated that the cumulative number of confirmed cases had exceeded 45 000 by February 13, 2020 in Wuhan. The average R0 in Wuhan was 2.7, significantly higher than those in other cities ranging from 1.8 to 2.4. The inflection points in the cities outside Hubei Province were between January 30, 2020 and February 3, 2020, while there had not been an obvious downward trend of R0 in Wuhan. R0 negatively correlated with both temperature and humidity, which was significant at the 0.01 level. CONCLUSIONS: The transmissibility of COVID-19 was strong and importance should be attached to the intervention of its transmission especially in Wuhan. According to the correlation between R0 and weather, the spread of disease will be suppressed as the weather warms.

[Elevating the accuracy rate for nurses' changes of patients' positions].

The incidence of pressure sores among inpatients had increased in our ward month by month. Clinical checklists and data analysis showed that the accuracy rate for nurses' changes of patients' positions was 12%. The investigation of reasons for this low accuracy rate included: (1) A flawed nursing standard for position changes. (2) Lack of training for position changing. (3) Lack of quality management and control of position changes. (4) Lack of practice and unfamiliarity with the procedures for position changing. (5) Poor quality of pressure-reducing surfaces. (6) Shortage of pressure-reducing surfaces. (7) Inappropriate method of use of pressure-reducing surfaces. (8) Non-inclusion by management of incidence of pressure sores within the scope of quality control. After a review of literature and group discussion, strategies were adopted to: (1) Establish a detailed explanation of standards for position changes. (2) Arrange lectures and promotional campaigns. (3) Add more pillows and water cushions. (4) Conduct case analysis when a patient develops a new pressure sore. After completion of this project, the accuracy rate for nurses' changes of patients' positions increased from 12% to 88%, and the incidence of pressure sores decreased from 0.47% to 0.05%. The result shows that accuracy of position change may affect the rate of pressure sore. We expect this project to serve as a reference in clinical practice for promotion of the quality of patient care.

Nanoceria-Mediated Drug Delivery for Targeted Photodynamic Therapy on Drug-Resistant Breast Cancer.

Photodynamic therapy (PDT) has shown great potential for overcoming drug-resistant cancers. Here, we report a multifunctional drug delivery system based on chlorin e6 (Ce6)/folic acid (FA)-loaded branched polyethylenimine-PEGylation ceria nanoparticles (PPCNPs-Ce6/FA), which was developed for targeted PDT to overcome drug-resistant breast cancers. Nanocarrier delivery and FA targeting significantly promoted the cellular uptake of photosensitizers (PSs), followed by their accumulation in lysosomes. PPCNPs-Ce6/FA generated reactive oxygen species (ROS) after near-infrared irradiation (NIR, 660 nm), leading to reduced P-glycoprotein (P-gp) expression, lysosomal membrane permeabilization (LMP), and excellent phototoxicity toward resistant MCF-7/ADR cells, even at ultralow doses. Moreover, we identified NIR-triggered lysosomal-PDT using the higher dose of PPCNPs-Ce6/FA, which stimulated cell death by plasma membrane blebbing, cell swelling, and energy depletion, indicating an oncosis-like cell death pathway, despite the occurrence of apoptotic or autophagic mechanisms at lower drug doses. In vivo studies showed prolonged blood circulation times, low toxicity in mice, and high tumor accumulation of PPCNPs-Ce6/FA. In addition, using NIR-triggered PDT, PPCNPs-Ce6/FA displayed excellent potency for tumor regression in the MCF-7/ADR xenograft murine model. This study suggested that multifunctional PPCNPs-Ce6/FA nanocomposites are a versatile and effective drug delivery system that may potentially be exploited for phototherapy to overcome drug-resistant cancers, and the mechanisms of cell death induced by PDT should be considered in the design of clinical protocols.

A folic acid conjugated polyethylenimine-modified PEGylated nanographene loaded photosensitizer: photodynamic therapy and toxicity studies in vitro and in vivo.

Targeted cancer therapies are currently a strong focus in biomedical research. Our recent studies have demonstrated that polyethylenimine-modified PEGylated nanographene loaded chlorin e6 (PPG-Ce6) shows excellent photodynamic efficacy because of the significantly enhanced intracellular targeted delivery of Ce6 to lysosomes. Based on our previous research, in this work, a novel nanographene-based tumor targeting delivery system was developed to selectively transport the photosensitizer into the tumor cells. In brief, we describe that the folic acid (FA) conjugated polyethylenimine-modified PEGylated nanographene system (PPG-FA) delivered in a targeted manner chlorin e6 (Ce6) to the tumor to simultaneously achieve targeted photodynamic therapy and biological imaging. The cellular internalization and the cellular uptake of PPG-FA-Ce6 were assessed, which indicated that the intracellular uptake of PPG-FA-Ce6 was target-specific. In vitro and in vivo photodynamic therapy results showed that PPG-FA-Ce6 exhibits excellent targeted delivery of Ce6, leading to simultaneous significant targeted photodynamic therapy and imaging. More importantly, the toxicity studies showed that PPG-FA-Ce6 had low toxicity as evidenced by blood biochemistry, hematological analysis, and histological examination. Our present work demonstrates that PPG-FA-Ce6 has high photodynamic therapy efficacy with no obvious toxicity because of its good tumor targeting property which can be potentially utilized in the biomedicine field.

Photosensitizer-Loaded Branched Polyethylenimine-PEGylated Ceria Nanoparticles for Imaging-Guided Synchronous Photochemotherapy.

A multifunctional theranostic platform based on photosensitizer (chlorin e6, Ce6)-loaded branched polyethylenimine-PEGylated ceria nanoparticles (PPCNPs-Ce6) was created for the development of effective cancer treatments involving the use of imaging-guided synchronous photochemotherapy. PPCNPs-Ce6 with high Ce6 photosensitizer loading (Ce6: cerium ∼40 wt %) significantly enhanced the delivery of Ce6 into cells and its accumulation in lysosomes, remarkably improving photodynamic therapeutic (PDT) efficacy levels compared to those in the administration of free Ce6 at ultralow drug doses (∼200 nM). Interestingly, PPCNPs-Ce6 efficiently induced HeLa cell death even at low concentrations (∼10 µM) without the use of laser irradiation and exhibit chemocytotoxicity. Inductively coupled plasma mass spectrometry (ICP-MS) and biology transmission electron microscopy (Bio-TEM) analyses demonstrated that ceria nanoparticles enter cells abundantly and accumulate in lysosomes or large vesicles. We then evaluated the effects of the different materials on lysosomal integrity and function, which revealed that PPCNPs-Ce6 catastrophically impaired lysosomal function compared to results with PPCNPs and Ce6. Studies of apoptosis revealed greater induction of apoptosis by PPCNPs-Ce6 treatment. This multifunctional nanocarrier also exhibited a high degree of solubility and stability in aqueous solutions, suggesting its applicability for extensive biomedical application.

PEGylated ceria nanoparticles used for radioprotection on human liver cells under γ-ray irradiation.

Ceria nanoparticles (CNPs) have recently been shown to protect cells and animals from radiation-induced damage. However, most of the CNPs used in previous studies were either naked or weakly protected by surfactants, which inevitably encounter many obstacles in biological applications. Here, alendronate was used as an ideal anchor to graft polyethylene glycol (PEG) onto CNPs, leading to enhanced stability, reduced cytotoxicity, and improved biological properties. Further investigation assessed the protective ability of the nanoparticles against radiation-induced effects for human normal liver cells (L-02), indicating that the PEGylated CNPs (CNPs-AL-PEG) were more efficient than naked CNPs. We determined that enhanced Ce(3+)/Ce(4+) ratios improved intracellular dispersion and that the ameliorated intracellular distribution of CNPs-AL-PEG contributes to the elevated expression of SOD2, which leads to increased protection of normal cells against ROS and reduces the oxidatively generated DNA damage. These studies hold tremendous promise for radioprotection and biological applications.