Fabrication of Co-Assembly from Berberine and Tannic Acid for Multidrug-Resistant Bacteria Infection Treatment.

Long-term antibiotic use induces drug resistance in bacteria. This has given rise to the challenge of refractory infections, which have become a global health threat. Berberine (BBR) and tannic acid (TA) from plants exhibit promising antibacterial activities and may overcome antibiotic resistance. However, poor solubility and/or low penetration capability have limited their application. Carrier-free co-assembled nanocomposites composed entirely of BBR and TA exhibit improved or new properties and produce improved efficacy. Herein, we demonstrated that an ordered nanostructure could be spontaneously co-assembled by the solvent evaporation method using the two natural products. These co-assembled berberine-tannic acid nanoparticles (BBR-TA NPs) exhibited the best antibacterial effect compared with the corresponding physical mixture, pristine BBR, and some first-line antibiotics (benzylpenicillin potassium-BP and ciprofloxacin-Cip) against Staphylococcus aureus (S. aureus) and multidrug-resistant Staphylococcus aureus (MRSA). Even if the concentration of BBR-TA NPs was as low as 15.63 µg/mL, the antibacterial rate against S. aureus and MRSA was more than 80%. In addition to the synergistic effect of the two compounds, the antibacterial mechanism underlying the nanostructures was that they strongly adhered to the surface of the bacterial cell wall, thereby inducing cell membrane damage and intracellular ATP leakage. Furthermore, the in vivo wound healing effect of BBR-TA NPs was verified using an MRSA wound infection mouse model. The BBR-TA NPs achieved the best efficacy compared with BP and Cip. Moreover, cytotoxic and histopathological evaluations of mice revealed that the nanodrug had good biological safety. This facile and green co-assembly strategy for preparing nanoparticles provides a feasible reference for the clinical treatment of bacterial infection.

Effect and Mechanism of Pharmaceutical Excipients on Berberine to Alleviate Ulcerative Colitis via Regulating Gut Microbiota.

BACKGROUND: Various potential effect of drugs on alleviating diseases by regulating intestinal microbiome as well as the pharmaceutical excipients on gut microbiota has been revealed. However, the interaction between them is rarely investigated. METHODS: Histological analysis, immunohistochemistry analysis, enzyme-linked immunosorbent assay (ELISA) analysis, RT-qPCR, and 16S rRNA analysis were utilized to explore the effect mechanism of the five excipients including hydroxypropyl methylcellulose (HPMC) F4M, Eudragit (EU) S100, chitosan (CT), pectin (PT), and rheum officinale polysaccharide (DHP) on berberine (BBR) to cure UC. RESULTS: The combined BBR with PT and DHP group exhibited better therapeutic efficacy of UC with significantly increased colon length, and decreased hematoxylin-eosin (H&E) scores than other groups. Furthermore, the expression of tight junction ZO-1 and occludin in colon tissue were upregulated, and claudin-2 was downregulated. Ultimately, the serum content of tumor necrosis (TNF)-α, interleukin (IL)-1ß, and IL-6 was decreased. Moreover, the combined BBR with PT significantly promoted the restoration of gut microbiota. The relative abundance of Firmicutes and Lactobacillus was significantly increased by the supplement of PT and DHP, and the relative abundance of Proteobacteria was downregulated. CONCLUSIONS: Our study may provide a new perspective that the selection of pharmaceutical excipients could be a crucial factor affecting the drugs' therapeutic efficiency outcome.

Atractylon Treatment Attenuates Pulmonary Fibrosis via Regulation of the mmu_circ_0000981/miR-211-5p/TGFBR2 Axis in an Ovalbumin-Induced Asthma Mouse Model.

Asthma-induced pulmonary fibrosis (PF) is an important public health concern that has few treatment options given its poorly understood etiology; however, the epithelial to mesenchymal transition (EMT) of pulmonary epithelial cells has been implicated to play an important role in inducing PF. Although previous studies have found atractylon (Atr) to have anti-inflammatory effects, whether Atr has anti-PF abilities remains unknown. The purpose of the current study was to validate the protective efficiency of Atr in both an animal model of ovalbumin (OVA)-induced asthma and an EMT model induced by transforming growth factor-ß1 (TGF-ß1) using TC-1 cells. The results of this study revealed that Atr treatment suppressed OVA-induced PF via fibrosis-related protein expression. Atr treatment suppressed OVA-induced circRNA-0000981 and TGFBR2 expression but promoted miR-211-5p expression. In vivo studies revealed that Atr suppressed TGF-ß1-induced EMT and fibrosis-related protein expression via suppressing circRNA-0000981 and TGFBR2 expression. The results also suggested that the downregulation of circRNA-0000981 expression suppressed TGFBR2 by sponging miR-211-5p, which was validated by a luciferase reporter assay. Collectively, the findings of the present study suggest that Atr treatment attenuates PF by regulating the mmu_circ_0000981/miR-211-5p/TGFBR2 axis in an OVA-induced asthma mouse model.

Prussian Blue Modified PLA Microcapsules Containing R6G for Ultrasonic/Fluorescent Bimodal Imaging Guided Photothermal Tumor Therapy.

A theranostic agent has been successfully constructed for fluorescence/ultrasound dual-modal imaging guided photothermal therapy by loading the fluorescent dye R6G into polylactide microcapsules (PLA MCs) followed by deposition of Prussian blue nanoparticles (PB NPs) into the surface of PLA MCs. It was proved that the obtained microcapsules of R6G@PLA/PB MCs could serve as an efficient probe to simultaneously enhance fluorescence imaging and ultrasound imaging greatly in vivo. R6G@PLA/PB MCs exhibited significant photothermal cytotoxicity. Cancer cells could be killed efficiently through photothermal effects of R6G@PLA/PB MCs due to the strong absorption of PB NPs in the near infrared region under laser irradiation. In a word, R6G@PLA/PB MCs integrate multiple capabilities for effective tumor imaging and therapy. Such a single agent provides us a possibility to interpret accurately the obtained images, identify the size and location of the tumor, as well as guide and monitor the photothermal therapy.

Graphene Oxide and Gadolinium-Chelate Functionalized Poly(lactic acid) Nanocapsules Encapsulating Perfluorooctylbromide for Ultrasound/Magnetic Resonance Bimodal Imaging Guided Photothermal Ablation of Cancer.

This paper successfully fabricated a novel multifunctional theranostic agent (PFOB@PLA/GO/Gd-DTPA NCs) by loading perfluorooctylbromide (PFOB) into poly(lactic acid) (PLA) nanocapsules (NCs) followed by surface functionalization with graphene oxide (GO) and gadolinium-chelate (Gd-DTPA). It was found that the resulting nanoagent could serve as a contrast agent simultaneously to enhance ultrasound (US) and magnetic resonance imaging (MRI). Benefiting from the strong absorption in the near infrared (NIR) region, the nanocapsules could efficiently kill cancer cells under NIR laser irradiation. Thus, such a single theranostic agent with the combination of realtime US imaging and high-resolution MR imaging could achieve great therapeutic effectiveness without systemic damage to the body. In addition, the cytotoxicity assay on HUVEC cells revealed a good biocompatibility of PFOB@PLA/GO/Gd-DTPA NCs, showing that the versatile nanocapsule system may hold great potential as an effective nanoplatform for contrast enhanced imaging guided photothermal therapy.

Gold nanoshelled liquid perfluorocarbon nanocapsules for combined dual modal ultrasound/CT imaging and photothermal therapy of cancer.

The integration of multimodal contrast-enhanced diagnostic imaging and therapeutic capabilities could utilize imaging guided therapy to plan the treatment strategy based on the diagnostic results and to guide/monitor the therapeutic procedures. Herein, gold nanoshelled perfluorooctylbromide (PFOB) nanocapsules with PEGylation (PGsP NCs) are constructed by oil-in-water emulsion method to form polymeric PFOB nanocapsules, followed by the formation of PEGylated gold nanoshell on the surface. PGsP NCs could not only provide excellent contrast enhancement for dual modal ultrasound and CT imaging in vitro and in vivo, but also serve as efficient photoabsorbers for photothermal ablation of tumors on xenografted nude mouse model. To our best knowledge, this is the first report of gold nanoshell serving as both CT contrast agents and photoabsorbers for photothermal therapy. The novel multifunctional nanomedicine would be of great value to offer more comprehensive diagnostic information to guide more accurate and effective cancer therapy.

Contrast ultrasound-guided photothermal therapy using gold nanoshelled microcapsules in breast cancer.

OBJECTIVES: The purpose of this study was to test whether dual functional gold nano-shelled microcapsules (GNS-MCs) can be used as an ultrasound imaging enhancer and as an optical absorber for photothermal therapy (PTT) in a rodent model of breast cancer. METHODS: GNS-MCs were fabricated with an inner air and outer gold nanoshell spherical structure. Photothermal cytotoxicity of GNS-MCs was tested with BT474 cancer cells in vitro and non-obese diabetes-SCID (NOD/SCID) mice with breast cancer. GNS-MCs were injected into the tumor under ultrasound guidance and treated with near-infrared (NIR) laser irradiation. The photothermal ablative effectiveness of GNS-MCs was evaluated by measuring the surface and internal temperature of the tumor as well as the size of the tumor using histological confirmation. RESULTS: NIR laser irradiation resulted in significant tumor cell death in GNS-MCs-treated BT474 cells in vitro. GNS-MCs were able to serve as an ultrasound enhancer to guide the intratumoral injection of GNS-MCs and ensure their uniform distribution. In vivo studies revealed that NIR laser irradiation increased the intratumoral temperature to nearly 70°C for 8 min in GNS-MCs-treated mice. Tumor volumes decreased gradually and tumors were completely ablated in 6 out of 7 mice treated with GNS-MCs and laser irradiation by 17 days after treatment. CONCLUSION: This study demonstrates that ultrasound-guided PTT with theranostic GNS-MCs is a promising technique for in situ treatment of breast cancer.

Engineering of perfluorooctylbromide polypyrrole nano-/microcapsules for simultaneous contrast enhanced ultrasound imaging and photothermal treatment of cancer.

A versatile oil-in-water emulsion method has been explored for constructing water-dispersible polypyrrole (PPy) nano-/microcapsules with a soluble PPy complex as multifunctional photothermal agents for tumor ablation. In this work, both PPy nanocapsules (280.4 ± 79.0 nm) and microcapsules (1.31 ± 0.45 µm) with liquid perfluorooctylbromide (PFOB) core could be obtained by simply tuning the process energy for emulsion formation from ultrasonication to homogenization. Owing to the encapsulated liquid PFOB and strong near-infrared (NIR) absorption of PPy shell, the resulted PPy capsules showed great promise in ultrasound imaging guided photothermal ablation of tumor cells without inducing any significant side effect. Thus, it is anticipated that fine-tuning of the other encapsulated drugs or functional materials in PPy capsules would foster avenues for the development of multifunctional platforms for cancer treatments.

Polypyrrole hollow microspheres as echogenic photothermal agent for ultrasound imaging guided tumor ablation.

Ultrasound (US) imaging provides a valuable opportunity to administer photothermal therapy (PTT) of cancer with real-time guidance to ensure proper targeting, but only a few theranostic agents were developed by physically grafting near infrared (NIR)-absorbing inorganic nanomaterials to ready-made ultrasound contrast agents (UCAs) for US imaging guided PTT. In this paper, NIR absorbing hollow microspheres were generated from polypyrrole merely using a facile one-step microemulsion method. It was found that the obtained polypyrrole hollow microspheres (PPyHMs) can act as an efficient theranostic agent not only to enhance US imaging greatly, but also exhibit excellent photohyperthermic effects. The contrast consistently sustained the echo signals for no less than 5 min and the NIR laser light ablated the tumor completely within two weeks in the presence of PPyHMs. More importantly, no use of additional NIR absorber substantially minimizes an onetime dose of the theranostic agent.

Graphene oxide modified PLA microcapsules containing gold nanoparticles for ultrasonic/CT bimodal imaging guided photothermal tumor therapy.

Theranostic microcapsules were successfully fabricated by introducing gold nanoparticles into poly(lactic acid) microcapsules through a double-microemulsion method, followed by depositing graphene oxide onto the microcapsule surface via electrostatic layer-by-layer self-assembly technique. It was proved that the obtained microcapsules could serve as a contrast agent to simultaneously enhance US imaging and X-ray CT imaging greatly both in vitro and in vivo. In addition, the in vivo therapeutic examinations showed that the microcapsule was an effective agent for photothermal therapy of cancer. The near-infrared laser light ablated the tumor completely within 9 days in the presence of the microcapsules and the tumor growth inhibition was 83.8%. The combination of real-time ultrasound with 3-D computed tomography through a single microcapsule agent is very helpful for accurately interpreting the obtained images, identifying the size and location of the tumor, as well as guiding and monitoring the photothermal therapy. Simultaneously, the effectiveness of photothermal therapy could be evaluated by the combined US and CT imaging enhanced by the microcapsule agent. Such a versatile microcapsule system might bring opportunities to the next generation of multimodal imaging guided cancer therapy.

Targeted delivery of CuS nanoparticles through ultrasound image-guided microbubble destruction for efficient photothermal therapy.

Novel "soft" microbubbles have been fabricated to show outstanding ultrasound imaging capability, and triggered CuS nanoparticles delivery through ultrasound-targeted microbubble destruction for efficient photothermal ablation of cancer cells.