Psychological Status, Influencing Factors and Intervention Countermeasures of Hospital Pharmacists in Extreme Working Environments in the Post-Pandemic Era--An Embedded Mixed Study.

Objective: The study explores the psychological state and related influences of hospital pharmacists enclosed in extreme work environments in the post-epidemic era, and also explores potential measures to alleviate negative emotions. Methods: An embedded mixed research methodology was used. In the qualitative research phase, semi-structured interviews were carried out with 30 pharmacists consistently confined to their work environments. The data were managed and analyzed using NVivo12 software. In the quantitative research phase, 146 pharmacists with experience in extreme work environments were selected, and the data were collected through questionnaires (GAD-7 and CD-RISC-25) and self-administered questions generated during the qualitative phase. The Shapiro-Wilk test was utilized to assess data normality. Spearman correlation was conducted to evaluate correlations among self-designed questions, resilience, and anxiety. Results: The results from interviews with 30 pharmacists revealed four factors influencing the psychological state of pharmacists in the post-epidemic era: personal factors, interpersonal relationships, environmental factors, and policy and public opinion. Mitigation measures for negative emotions encompass material security, life adjustment, epidemic prevention policy, public opinion information, and organizational management. The results of a quantitative study of 146 pharmacists showed that only 1% had severe anxiety, but the psychological resilience scores were generally low, and 62% had poor psychological resilience, with scores below 73. Simultaneously, it was observed that, except religious beliefs, factors influencing psychological status in extreme work environments were significantly negatively correlated with personal anxiety levels and significantly positively correlated with psychological resilience. Conclusion: Our study holds significance in unraveling the psychological aspects of pharmacists as healthcare workers. It also offers insights into how healthcare organizations respond to the negative emotions experienced by healthcare workers in emergencies or extreme environments.

In Situ Autophagy Disruption Generator for Cancer Theranostics.

Cancer remains a serious clinical disease awaiting new effective treatment strategies. Autophagy modulation has emerged as a novel and promising pharmacologic target critical to future drug development and anti-cancer therapy applications. Herein, we constructed an in situ autophagy disruption generator to break the balance of autophagy flow for tumor-targeting therapy. Hollow mesoporous manganese trioxide (Mn2O3) nanoparticles (NPs) were synthesized and conjugated with hyaluronic acid (HA) to form tumor-targeting drug carriers. Then, traditional autophagy inhibitor hydroxychloroquine (HCQ) was loaded into the hollow core of HA-Mn2O3, to form a multifunctional theranostics platform (HA-Mn2O3/HCQ). This nanoplatform displayed specific localization and retention in lysosomes after entering tumor cells. The synchronous release of HCQ and manganese ion (Mn2+) induced lysosomal alkalization and osmotic pressure elevation. Significantly greater lysosomal deacidification and autophagy blockade effect emerged after treatment by this nanoplatform, with in vitro tumor inhibition rate of 92.2%. Imaging experiment proved that it could selectively deliver HCQ to tumor sites and further degrade to realize simultaneous release of Mn2+ and HCQ. Micromorphological and immunofluorescence analysis demonstrated that in situ high concentrations of these two substances would achieve effective autophagy blockade. Pharmacodynamics test showed that this nanogenerator displayed the best therapeutic efficacy with 5.08-fold tumor inhibition ratio compared with the HCQ group. Moreover, the generated Mn2+ can be used as T1 contrast agent for visualizing tumor lesions and monitoring therapeutic effects. Overall, the as-made multifunctional drug-delivery system might provide a promising platform for cancer theranostics upon in situ autophagy disruption.

Construction of a water-soluble and photostable rubropunctatin/ß-cyclodextrin drug carrier.

The purpose of the current study was to construct a ß-cyclodextrin drug carrier for rubropunctatin to improve its water solubility and light stability for future cytotoxicity studies. The inclusion complexation behavior of rubropunctatin with ß-cyclodextrin was investigated using FESEM, FT-IR and XRD. A molecular docking study was performed to elucidate the most probable inclusion structure. The inclusion complex could be completely dispersed in water and had a small size of 121.87 ± 2.13 nm (n = 3), a good PDI (0.320 ± 0.017), and an acceptable potential value of -27.7 ± 0.32 mV (n = 3). Furthermore, the stability of the rubropunctatin in water under light irradiation was found to be greatly enhanced after being encapsulated in cyclodextrin, and it exhibited a retention rate of over 70% vs. 10.17%. In addition, the cytotoxicity of the inclusion complex was evaluated by MTT assay and Annexin V-FITC/PI detection using cervical adenocarcinoma HeLa cells. The results showed that the inclusion complex had comparable toxicity compared to rubropunctatin solubilized with 0.4% DMSO. More importantly, the formation of the inclusion complex contributed greatly to the intensification of the bioavailability of rubropunctatin because the use of organic solvent was avoided.

Monascus pigment rubropunctatin derivative FZU-H reduces Aß(1-42)-induced neurotoxicity in Neuro-2A cells.

Alzheimer's disease (AD) is an extremely complex disease, characterized by several pathological features including oxidative stress and amyloid-ß (Aß) aggregation. Blockage of Aß-induced injury has emerged as a potential therapeutic approach for AD. Our previous efforts resulted in the discovery of Monascus pigment rubropunctatin derivative FZU-H with potential neuroprotective effects. This novel lead compound significantly diminishes toxicity induced by Aß(1-42) in Neuro-2A cells. Our further mechanism investigation revealed that FZU-H inhibited Aß(1-42)-induced caspase-3 protein activation and the loss of mitochondrial membrane potential. In addition, treatment of FZU-H was proven to attenuate Aß(1-42)-induced cell redox imbalance and Tau hyperphosphorylation which caused by okadaic acid in Neuro-2A cells. These results indicated that FZU-H shows promising neuroprotective effects for AD.

A "protective umbrella" nanoplatform for loading ICG and multi-modal imaging-guided phototherapy.

In order to prevent the aggregation of ICG and enhance its stability, a novel nanoplatform (TiO2:Yb,Ho,F-ß-CD@ICG/HA) was designed for NIR-induced phototherapy along with multi-mode imaging(UCL/MRI/Flu). In this nanosysytem: TiO2:Yb,Ho,F was used as upconversion materials and applied in vivo for the first time; ß-CD acted as a "protective umbrella" to load separated ICG and avoid the low phototherapy efficiency because of its aggregation; HA was the capping agent of ß-CD to prevent ICG unexpected leaking and a target to recognize CD44 receptor. The nanosystem exhibited excellent size (~200 nm) and photo- and thermal-stability, preferable reactive oxygen yield and temperature response (50.4 °C) under 808 nm laser. It could efficiently target and suppress tumor growth. The imaging ability (UCL/MRI) of TiO2:Yb,Ho,F could facilitate diagnosis of the tumor, especially for deep tissues. Altogether, our work successfully improved the phototherapy efficacy through incorporating the ICG into the cavity of ß-CD and applied TiO2:Yb,Ho,F for upconversion imaging in vivo.

Single-walled carbon nanotube-loaded doxorubicin and Gd-DTPA for targeted drug delivery and magnetic resonance imaging.

An aspargine-glycine-arginine (NGR) peptide modified single-walled carbon nanotubes (SWCNTs) system, developed by a simple non-covalent approach, could be loaded with the anticancer drug doxorubicin (DOX) and magnetic resonance imaging (MRI) contrast agent gadolinium-diethylenetriamine pentaacetic acid (Gd-DTPA). This DOX- and Gd-DTPA-loaded NGR functionalized SWCNTs (DOX/NGR-SWCNTs/Gd-DPTA) retained both cytotoxicity of DOX and MRI contrast effect of Gd-DPTA. This drug delivery system showed excellent stability in physiological solutions. This DOX/NGR-SWCNTs/Gd-DPTA system could accumulate in tumors and enter into tumor cells, which facilitated combination chemotherapy with diagnosis of tumor in one system. An excellent in vitro anti-tumor effect was shown in MCF-7 cells treated by DOX/NGR-SWCNTs/Gd-DPTA, compared with DOX solution, DOX/SWCNTs and DOX/SWCNTs/Gd-DPTA. In vivo data of DOX/NGR-SWCNTs/Gd-DPTA group in tumor-bearing mice further confirmed that this system performed much higher tumor targeting capacity and anti-tumor efficacy than other control groups.

Construction of magnetic-carbon-quantum-dots-probe-labeled apoferritin nanocages for bioimaging and targeted therapy.

Carbon dots (CDs) are one of the most highlighted carbon-based materials for biological applications, such as optical imaging nanoprobes, which are used for labeling cells in cancer treatment mainly due to their biocompatibility and unique optical properties. In this study, gadolinium (Gd)-complex-containing CDs were obtained through a one-step microwave method to develop multimodal nanoprobes integrating the advantages of optical and magnetic imaging. The obtained Gd-CDs exhibited highly fluorescent properties with excellent water solubility and biological compatibility. Natural apoferritin (AFn) nanocages, an excellent drug delivery carrier, are hollow in structure, with their pH-dependent, unfolding-refolding process at pH 2.0 and 7.4. The chemotherapeutic drug doxorubicin (DOX) can be highly effective and encapsulated into AFn cavity. A widely used tumor-targeting molecule, folic acid (FA), functionalized the surface of AFn to obtain an active tumor targeting effect on MCF-7 cells and malignant tumors in mice models. In this study, an AFn nanocarrier encapsulating high concentration of DOX labeled with magnetic and fluorescent Gd-CDs probe was developed. Gd-CDs exhibited a unique green photoluminescence and almost no toxicity compared with free GdCl3. Furthermore, Gd-doped CDs significantly increased the circulation time and decreased the toxicity of Gd3+ in in vitro and in vivo magnetic resonance imaging, which demonstrated that the AFn nanocages labeled with Gd-CD compounds could serve as an excellent T1 contrast agent for magnetic resonance imaging. The self-assembling multifunctional Gd-CDs/AFn (DOX)/FA nanoparticles have a great potential for cancer theranostic applications.

Single-walled carbon nanotubes mediated targeted tamoxifen delivery system using aspargine-glycine-arginine peptide.

An aspargine-glycine-arginine (NGR) peptide modified single-walled carbon nanotubes (SWCNTs) system, developed by a simple non-covalent approach, could be loaded with the anticancer drug tamoxifen (TAM). This TAM-loaded NGR modified SWCNTs (TAM/NGR-SWCNTs) not only retained both optical properties of SWCNTs and cytotoxicity of TAM, but also could accumulate in tumors and enter into 4T1 cells, which facilitated combination chemotherapy with photothermal therapy in one targeting system. Enhanced cellular uptake, antitumor effect and cell apoptosis of TAM/NGR-SWCNTs on 4T1 cells were observed in vitro, compared with the TAM solution, TAM/SWCNTs and photothermal therapy alone. In vivo investigation of TAM/NGR-SWCNTs in tumor-bearing mice further confirmed that this system possessed much higher tumor targeting capacity and antitumor efficacy than the control, especially with the near-infrared-laser irradiation treatment. Moreover, it demonstrated negligible systematic toxicity through the histopathological analysis. All these results suggest TAM/NGR-SWCNTs are promising for high targeted efficiency and treatment efficacy and low side effects of future cancer therapy by synergistic effect of chemo-photothermal combination.

Single-walled carbon nanotubes mediated neovascularity targeted antitumor drug delivery system.

PURPOSE: The aim of this study was to prepare a new neovascularity targeting antitumor drug delivery system mediated by single-walled carbon nanotubes (SWNTs). METHODS: In this study, antiangiogenesis agent 2-methoxyestradiol was loaded by SWNTs via π~π accumulation. The SWNTs were then linked with NGR (Asn-Gly-Arg) peptide, which could target tumor angiogenesis. This drug delivery system was characterized by transmission electron microscope, scanning electron microscopy, and atomic force microscope analysis. The suppression efficacy of tumor growth in cultured breast cancer cell line was evaluated by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. The in vivo antitumor activity was evaluated on the Sarcoma (S180) tumor-bearing mice model. RESULTS: The characteristics of this drug delivery system showed that the particle of complex was 190 ± 4.3 nm in size distribution and 23.56 ± 2.03 mV in zeta potential. The inhibition ratio of this SWNTs drug delivery system at 24, 48, and 72 h was about 57.7%, 83.6%, and 88.2%. Compared with normal saline group, the relative tumor volumes in the 2ME, SWNTs-2ME, and NGR-SWNTs-2ME groups were decreased 1 week after administration. CONCLUSION: This novel neovascularity targeting drug delivery system containing NGR-SWNTs-2ME may be beneficial to improve treatment efficacy and minimize side effects in future cancer therapy.

Synergistic anticancer effect of RNAi and photothermal therapy mediated by functionalized single-walled carbon nanotubes.

Single-walled carbon nanotubes (SWNTs) are special nano-materials which exhibit interesting physical and chemical properties, presenting new opportunities for biomedical research and applications. In this study, we have successfully adopted a novel strategy to chemically functionalize SWNTs with polyethylenimine (PEI) through purification, oxidation, amination and polymerization, which were then bound by DSPE-PEG2000-Maleimide for further conjugation with the tumor targeting NGR (Cys-Asn-Gly-Arg-Cys-) peptide via the maleimide group and sulfhydryl group of cysteine, and finally hTERT siRNA was loaded to obtain a novel tumor targeting siRNA delivery system, designated as SWNT-PEI/siRNA/NGR. The results showed that SWNT-PEI/siRNA/NGR could efficiently cross cell membrane, induced more severe apoptosis and stronger suppression in proliferation of PC-3 cells in vitro. Furthermore, in tumor-bearing mice model the delivery system exhibited higher antitumor activity due to more accumulation in tumor without obvious toxicity in main organs. The combination of RNAi and near-infrared (NIR) photothermal therapy significantly enhanced the therapeutic efficacy. In conclusion, SWNT-PEI/siRNA/NGR is a novel and promising anticancer system by combining gene therapy and photothermal therapy.

PEI-derivatized fullerene drug delivery using folate as a homing device targeting to tumor.

Fullerene (C60) has shown great potential in drug delivery. In this study, firstly, amine-functionalized C60 (C60-NH(2)) was achieved by introducing ethylenediamine onto the surface of C60, and then PEI-derivatized C60 (C60-PEI) was performed via a cationic polymerization of aziridine on the surface of C60-NH(2); FT-IR and TGA results verified the structure of water-soluble C60-PEI. C60-PEI was encapsulated with folic acid (FA) through an amide linker, and then docetaxel (DTX) was conjugated to C60-PEI-FA and obtained a drug delivery system, C60-PEI-FA/DTX. Compared with free DTX, the tumor targeting drug delivery could efficiently cross cell membranes, lead to more apoptosis and afford higher antitumor efficacy in a cultured PC3 cells in vitro. Furthermore, compared with free DTX in an in vivo murine tumor model, C60-PEI-FA/DTX afforded higher antitumor efficacy without obvious toxic effects to normal organs owing to its prolonged blood circulation and 7.5-fold higher DTX uptake of tumor, demonstrating that C60-PEI-FA/DTX may be promising for high treatment efficacy with minimal side effects in future therapy.

Targeting and hyperthermia of doxorubicin by the delivery of single-walled carbon nanotubes to EC-109 cells.

A targeting and photothermal drug delivery system of doxorubicin (DOX) was successfully developed based on the AS1411 aptamer modified single wall carbon nanotubes (SWNTs). In this study, DOX was efficiently loaded onto SWNTs (DOX-AS1411-SWNTs) with drug loading of 121% and released from DOX-AS1411-SWNTs in a pH-dependent manner. Internalization analysis demonstrated that the tertiary complex (DOX-AS1411-SWNTs) could transfer into the cell through the AS1411-mediated endocytosis in 2 h. Moreover, the cytotoxicity test of DOX-AS1411-SWNTs showed higher inhibition effect on EC-109 cells compared to DOX control group. Meanwhile, 808 nm near-infrared laser was used here for photothermal treatment, and AS1411-SWNTs were proved to have a strong efficacy on tumor hyperthermia. Furthermore, with a focus on the G2-M phase, we found DOX-AS1411-SWNTs capable of altering G2-M cell-cycle phase, owing to the hyperthermia and synergistic effect.

In vivo controlled release and prolonged antitumor effects of 2-methoxyestradiol solid lipid nanoparticles incorporated into a thermosensitive hydrogel.

A two-phase delivery system involving local injections of solid lipid nanoparticles (SLNs) -loaded hydrogel was developed using 2-methoxyestradiol as a model anticancer drug. This approach improves the effectiveness of conventional treatments for subcutaneous tumors and avoids that solid lipid nanoparticles are rapidly cleared from the circulation following systemic administration. The specific aim of the study presented in this article was to investigate the in vivo release, delivery and antitumor effects of 2-ME SLNs entrapped in a hydrogel. The results indicated that the hydrogel could deliver fluorescence-marked SLNs to tumor masses and cancer cells, exhibiting a controlled release of 2-ME SLNs over 46 days following a zero-order model. After treatment with the 2-ME SLN-loaded hydrogel, BALB/c mice that had been inoculated with syngeneic 4T1 breast cancer cells displayed significantly more tumor growth suppression for at least 21 days than those treated with a hydrogel containing the free drug, which was consistent with the in vitro cytotoxicity of 2-ME SLNs. This experiment demonstrated the efficacy of the hydrogel as a depot of 2-ME SLNs. Additionally, the mice treated with the hydrogel did not exhibit a loss of body weight or abnormal levels of white blood cells compared to the control group. These experiments demonstrated the potential value of 2-ME SLN hydrogel local injections as a safer and more effective method for the chemotherapy of subcutaneous tumors.

Preparation, characterization and in vivo evaluation of 2-methoxyestradiol-loaded liposomes.

This study systematically investigated the intravenous injection formulation of liposomes loaded with 2-methoxyestradiol (2-ME), a poor water soluble anti-tumor drug. The objective of this study was to design passive targeting nanoliposome which could improve therapeutic efficacy and liver first pass effect. Based on the optimized conditions of single-factor and orthogonal design, 2-ME-loaded liposomes were prepared by the aether injection method. The formulated liposomes were found to be relatively uniform in size with a negative zeta potential. The average drug entrapment efficiency and loading were 85% and 8%, respectively. The overall targeting efficiency (TE(C)) of the 2-ME-loaded liposomes was enhanced from 40.29% to 88.32% in the lung. The lung damage caused by liposomes was less severe than that by solution. These results indicated that 2-ME liposomes could mainly deliver the drug to the lungs and make the drug accumulate in the lungs, which changed the disposition behavior in vivo, decreased the toxic and side effects on other tissues and reduced the severity of damage to lungs following intravenous injection.