Procedurally Targeted Delivery of Antitumor Drugs Using FAPα-Responsive TPGS Dimer-Based Flower-like Polymeric Micelles.

To overcome the intestinal epithelium barrier and achieve a better antitumor effect, the procedurally targeting flower-like nanomicelles for oral delivery of antitumor drugs were designed based on FAPα-responsive TPGS1000 dimer (TPGS-Gly-Pro-TPGS) and L-carnitine linked poly(2-ethyl-2-oxazoline)-b-poly(D, l-lactide) (Car-PEOz-b-PLA). As expected, compared with unmodified polymeric micelles (TT-PMs) composed of TPGS-Gly-Pro-TPGS, L-carnitine conjugated polymeric micelles (CTT-PMs) formed from both TPGS-Gly-Pro-TPGS and Car-PEOz-b-PLA with favorable stability in simulated gastrointestinal fluid and FAPα-dependent release capability exhibited remarkably enhanced cellular uptake and transmembrane transport through OCTN2 mediation confirmed by fluorescence immunoassay, which was intuitively evidenced by stronger fluorescence within epithelial cells, and the basal side of small intestinal epithelium of mice being given intragastric administration of DiI-labeled micelles. The transport of CTT-PMs across the intestinal epithelium in an intact form was mediated by clathrin along the intracellular transport pathway of endosome-lysosome-ER-Golgi apparatus. Furthermore, both the increased uptake by FAPα-positive U87MG cells and unchangeable uptake by FAPα-negative C6 cells for coumarin-6 (C-6)/CTT-PMs compared with C-6/TT-PMs evidenced the targeting ability of CTT-PMs to FAPα-positive tumor cells. Both OCTN2-mediation and FAPα-responsiveness were beneficial for polymeric micelles to improve the delivery and therapeutic efficiency of antitumor agents, which was further supported by the remarkable enhancement in in vivo antitumor efficacy via promoting apoptosis of tumor cells for paclitaxel (PTX)-loaded CTT-PMs (PTX/CTT-PMs) with low toxicity compared with PTX/TT-PMs. Our findings offered an alternative design strategy for procedurally targeted delivery of chemotherapeutics by an oral route.

Uncovering the Mechanisms of Active Components from Toad Venom against Hepatocellular Carcinoma Using Untargeted Metabolomics.

Toad venom, a dried product of secretion from Bufo bufo gargarizans Cantor or Bufo melanostictus Schneider, has had the therapeutic effects of hepatocellular carcinoma confirmed. Bufalin and cinobufagin were considered as the two most representative antitumor active components in toad venom. However, the underlying mechanisms of this antitumor effect have not been fully implemented, especially the changes in endogenous small molecules after treatment. Therefore, this study was designed to explore the intrinsic mechanism on hepatocellular carcinoma after the cotreatment of bufalin and cinobufagin based on untargeted tumor metabolomics. Ultraperformance liquid chromatography with tandem mass spectrometry (UHPLC-MS/MS) was performed to identify the absorbed components of toad venom in rat plasma. In vitro experiments were determined to evaluate the therapeutic effects of bufalin and cinobufagin and screen the optimal ratio between them. An in vivo HepG2 tumor-bearing nude mice model was established, and a series of pharmacodynamic indicators were determined, including the body weight of mice, tumor volume, tumor weight, and histopathological examination of tumor. Further, the entire metabolic alterations in tumor after treating with bufalin and cinobufagin were also profiled by UHPLC-MS/MS. Twenty-seven active components from toad venom were absorbed in rat plasma. We found that the cotreatment of bufalin and cinobufagin exerted significant antitumor effects both in vitro and in vivo, which were reflected in inhibiting proliferation and inducing apoptosis of HepG2 cells and thereby causing cell necrosis. After cotherapy of bufalin and cinobufagin for twenty days, compared with the normal group, fifty-six endogenous metabolites were obviously changed on HepG2 tumor-bearing nude mice. Meanwhile, the abundance of α-linolenic acid and phenethylamine after the bufalin and cinobufagin intervention was significantly upregulated, which involved phenylalanine metabolism and α-linolenic acid metabolism. Furthermore, we noticed that amino acid metabolites were also altered in HepG2 tumor after drug intervention, such as norvaline and Leu-Ala. Taken together, the cotreatment of bufalin and cinobufagin has significant antitumor effects on HepG2 tumor-bearing nude mice. Our work demonstrated that the in-depth mechanism of antitumor activity was mainly through the regulation of phenylalanine metabolism and α-Linolenic acid metabolism.

Hydrogel-Based Stimuli-Responsive Micromotors for Biomedicine.

The rapid development of medical micromotors draws a beautiful blueprint for the noninvasive or minimally invasive diagnosis and therapy. By combining stimuli-sensitive hydrogel materials, micromotors are bestowed with new characteristics such as stimuli-responsive shape transformation/morphing, excellent biocompatibility and biodegradability, and drug loading ability. Actuated by chemical fuels or external fields (e.g., magnetic field, ultrasound, light, and electric field), hydrogel-based stimuli-responsive (HBSR) micromotors can be utilized to load therapeutic agents into the hydrogel networks or directly grip the target cargos (e.g., drug-loaded particles, cells, and thrombus), transport them to sites of interest (e.g., tumor area and diseased tissues), and unload the cargos or execute a specific task (e.g., cell capture, targeted sampling, and removal of blood clots) in response to a stimulus (e.g., change of temperature, pH, ion strength, and chemicals) in the physiological environment. The high flexibility, adaptive capacity, and shape morphing property enable the HBSR micromotors to complete specific medical tasks in complex physiological scenarios, especially in confined, hard-to-reach tissues, and vessels of the body. Herein, this review summarizes the current progress in hydrogel-based medical micromotors with stimuli responsiveness. The thermo-responsive, photothermal-responsive, magnetocaloric-responsive, pH-responsive, ionic-strength-responsive, and chemoresponsive micromotors are discussed in detail. Finally, current challenges and future perspectives for the development of HBSR micromotors in the biomedical field are discussed.

Yohimbine hydrochloride inhibits skin melanin synthesis by regulating wnt/ß-catenin and p38/MAPK signal pathways.

BACKGROUND: Yohimbine hydrochloride (YH) is a prescription drug to treat erectile dysfunction. It also had potential in fighting high blood pressure and diabetic neuropathy as well as promoting weight loss. OBJECTIVE: The aim of the study is to investigate the anti-melanogenic function of yohimbine hydrochloride and reveal its underlying molecular mechanism. METHODS: B16F10 mouse melanoma cells, Melan-A murine melanocyte, Zebrafish embryos and C57BL/6 mouse ear skins were treated with different concentrations of YH. The extracellular and cellular melanin content was detected by spectrometry. The expression of microphthalmia-associated transcription factor (MITF), tyrosinase and the activities of Wnt/ß-catenin and p38/MAPK signal pathways were determined by RT-qPCR, Western blot analysis and immunofluorescent staining. RESULTS: Melanin production could be effectively inhibited by YH at the safe concentration in vitro and in vivo. Q-PCR and WB results showed that the expression of MITF and tyrosinase were strongly downregulated after YH treatments along with the reduction of tyrosinase activity. YH markedly inhibited ß-catenin nuclear accumulation and p38 phosphorylation in B16F10 cells compared with the untreated controls. Importantly, the increase of MITF expression induced by ß-catenin activator BIO and p38 activator anisomycin could be fully reversed by YH treatments. CONCLUSIONS: These results indicate that YH can function as an anti-melanogenic agent, at least in part, by inhibiting Wnt/ß-catenin and p38/MAPK signal pathways. Therefore, YH may be potentially used as a skin-whitening compound for preventing hyperpigmentation disorders in the future.

Design and Application of Near-Infrared Nanomaterial-Liposome Hybrid Nanocarriers for Cancer Photothermal Therapy.

Liposomes are attractive carriers for targeted and controlled drug delivery receiving increasing attention in cancer photothermal therapy. However, the field of creating near-infrared nanomaterial-liposome hybrid nanocarriers (NIRN-Lips) is relatively little understood. The hybrid nanocarriers combine the dual superiority of nanomaterials and liposomes, with more stable particles, enhanced photoluminescence, higher tumor permeability, better tumor-targeted drug delivery, stimulus-responsive drug release, and thus exhibiting better anti-tumor efficacy. Herein, this review covers the liposomes supported various types of near-infrared nanomaterials, including gold-based nanomaterials, carbon-based nanomaterials, and semiconductor quantum dots. Specifically, the NIRN-Lips are described in terms of their feature, synthesis, and drug-release mechanism. The design considerations of NIRN-Lips are highlighted. Further, we briefly introduced the photothermal conversion mechanism of NIRNs and the cell death mechanism induced by photothermal therapy. Subsequently, we provided a brief conclusion of NIRNs-Lips applied in cancer photothermal therapy. Finally, we discussed a synopsis of associated challenges and future perspectives for the applications of NIRN-Lips in cancer photothermal therapy.

Stromal Barrier-Dismantled Nanodrill-Like and Cancer Cell-Targeted pH-Responsive Polymeric Micelles for Further Enhancing the Anticancer Efficacy of Doxorubicin.

Cancer-associated fibroblasts (CAFs) were believed to establish a tight physical barrier and a dense scaffold for tumor cells to make them maintain immunosuppression and drug resistance, strongly hindering nanoparticles to penetrate into the core of tumor tissues and limiting the performance of tumor cell-targeted nanoparticles. Here, we fabricated the substrate Z-Gly-Pro of fibroblast activation protein α (FAPα) and folic acid-codecorated pH-responsive polymeric micelles (dual ligand-modified PEOz-PLA polymeric micelles, DL-PP-PMs) that possessed nanodrill and tumor cell-targeted functions based on Z-Gly-pro-conjugated poly(2-ethyl-2-oxazoline)-poly(D,l-lactide) (ZGP-PEOz-PLA), folic acid (FA)-conjugated PEOz-PLA (FA-PEOz-PLA), and PEOz-PLA for cancer therapy. The micelles with about 40 nm particle size and a narrow distribution exhibited favorable pH-activated endo/lysosome escape induced by their pH responsibility. In addition, the enhancement of in vitro cellular uptake and cytotoxicity to folate receptors or FAPα-positive cells for doxorubicin (DOX)/DL-PP-PMs compared with DOX/PP-PMs evidenced the dual target ability of DOX/DL-PP-PMs, which was further supported by in vivo biodistribution results. As expected, in the human oral epidermal carcinoma (KB) cells xenograft nude mice model, the remarkable enhancement of antitumor efficacy for DOX/DL-PP-PMs with low toxicity was observed compared with DOX/FA-PP-PMs and DOX/ZGP-PP-PMs. The possible mechanism was elucidated to be the dismantling of the stromal barrier by nanodrill-like DOX/DL-PP-PMs via the deletion of CAFs evidenced by the downregulation of α-SMA and inhibition of their functions proved by the decrease in the microvascular density labeled with CD31 and the reduction in the extracellular matrix detected by the collagen content, thereby promoting tumor penetration and enhancing their uptake by tumor cells. The present research offered an alternative approach integrating anticancer and antifibrosis effects in one delivery system to enhance the delivery efficiency and therapeutic efficacy of anticancer drugs.

Multi pH-sensitive polymer-drug conjugate mixed micelles for efficient co-delivery of doxorubicin and curcumin to synergistically suppress tumor metastasis.

Combination therapy has been proved to be an effective strategy to inhibit metastasis, however, its efficacy is always compromised by the poor delivery efficiency of drugs. In this study, multi pH-sensitive polymer-drug conjugate mixed micelles were fabricated by the self-assembly of PEOz-PLA-ace-Cur, a conjugate of curcumin (Cur) with poly(2-ethyl-2-oxazoline)-poly(d,l-lactide) (PEOz-PLA) through the linkage of the pH-cleavable acetal bond, and PEOz-PLA-imi-DOX, a conjugate of doxorubicin (DOX) with PEOz-PLA through the linkage of the pH-cleavable benzoic imine bond. The mixed conjugate micelles (PP-Cur/PP-DOX-Mix-PMs) with accurately and conveniently controlled mass ratio of the two drugs were demonstrated to have a small particle size (40-128 nm), high drug loading capacity and pH-dependent drug release behavior. Notably, PP-Cur5/PP-DOX1-Mix-PMs exhibited slower DOX release under physiological conditions compared with PEOz-PLA-imi-DOX micelles, resulting in deeply reduced side effects in vivo. Furthermore, the mixed conjugate micelles showed synergistically enhanced inhibition of MDA-MB-231 cell growth and metastasis evidenced by the results of in vitro anti-invasion, wound healing and anti-migration assessment, and in vivo bioluminescence imaging in nude mice, and significant reduction of the side effects of DOX compared with dual drug physically loaded polymeric micelles. Mechanistic studies demonstrated that the possible inhibitory mechanism of PP-Cur5/PP-DOX1-Mix-PMs on tumor metastasis could be assigned to their inhibition of the invasion, migration, intravasation and extravasation of tumor cells. In conclusion, the multi pH-sensitive polymer-drug conjugate mixed micelles with synergistically enhanced anti-tumor and anti-metastasis activity are potential candidates for safe and effective cancer combination therapy.

Focusing on the premature death of redeployed miners in China: an analysis of cause-of-death information from non-communicable diseases.

BACKGROUND: Reducing premature deaths is an important step towards achieving the World Health Organization's sustainable development goal. Redeployed miners are more prone to disease or premature death due to the special occupational characteristics. Our aims were to describe the deaths of redeployed miners, assess the losses due to premature death and identify their main health problems. All the records of individuals were obtained from Fuxin Mining Area Social Security Administration Center. Year of life lost (YLL) and average year of life lost were used to assess the loss due to premature death. YLL rates per 1000 individuals were considered to compare deaths from different populations. RESULTS: Circulatory system diseases contributed the most years of life lost in the causes of death, followed by neoplasms. But average year of life lost in neoplasms was 6.85, higher than circulatory system diseases, 5.63. Cerebrovascular disease and ischemic heart disease were the main causes of death in circulatory system diseases. And average years of life lost in cerebrovascular disease and ischemic heart disease were 5.85 and 5.62, higher than those in other circulatory system diseases. Lung cancer was the principal cause of death in neoplasms. Average year of life lost in liver cancer was 7.92, the highest in neoplasms. CONCLUSIONS: For redeployed miners, YLL rates per 1000 individuals in cerebrovascular disease, ischemic heart disease and lung cancer were higher than those in other populations, especially in men. It is important to attach importance to the health of redeployed miners, take appropriate measures to reduce premature death and achieve the sustainable development goal. Our findings also contribute to a certain theoretical reference for other countries that face or will face the same problem.

Composite Film of Vanadium Dioxide Nanoparticles and Ionic Liquid-Nickel-Chlorine Complexes with Excellent Visible Thermochromic Performance.

Vanadium dioxide (VO2), as a typical thermochromic material used in smart windows, is always limited by its weaker solar regulation efficiency (ΔTsol) and lower luminous transmittance (Tlum). Except for common approaches such as doping, coating, and special structure, compositing is another effective method. The macroscopic thermochromic (from colorless to blue) ionic liquid-nickel-chlorine (IL-Ni-Cl) complexes are selected in this paper to be combined with VO2 nanoparticles forming a composite film. This novel scheme demonstrates outstanding optical properties: ΔTsol = 26.45% and Tlum,l = 66.44%, Tlum,h = 43.93%. Besides, the addition of the IL-Ni-Cl complexes endows the film with an obvious color change from light brown to dark green as temperature rises. This splendid visible thermochromic performance makes the composite film superior in function exhibiting and application of smart windows.