Nanomedicine: Nanotechnology, Biology and Medicine最新文献

Colorectal and ovarian cancers frequently develop peritoneal metastases with few treatment options. Intraperitoneal chemotherapy has shown promising therapeutic effects, but is limited by rapid drug clearance and systemic toxicity. We therefore encapsulated the cabazitaxel taxane in poly(alkyl cyanoacrylate) (PACA) nanoparticles (NPs), designed to improve intraperitoneal delivery. Toxicity of free and encapsulated cabazitaxel was investigated in rats by monitoring clinical signs, organ weight and blood hematological and biochemical parameters. Pharmacokinetics, biodistribution and treatment response were evaluated in mice. Biodistribution was investigated by measuring both cabazitaxel and the 2-ethylbutanol NP degradation product. Drug encapsulation was shown to increase intraperitoneal drug retention, leading to prolonged intraperitoneal drug residence time and higher drug concentrations in peritoneal tumors. As a result, encapsulation of cabazitaxel improved the treatment response in two in vivo models bearing intraperitoneal tumors. Together, these observations indicate a strong therapeutic potential of NP-based cabazitaxel encapsulation as a novel treatment for peritoneal metastases.

Detection of cancer in its early stage is a challenging task for oncologists. Inflammatory breast cancer has symptoms that are similar to mastitis and can be mistaken for microbial infection. Currently, the differential diagnosis between mastitis and Inflammatory breast cancer via nipple aspirate fluid (NAF) is difficult. Here, we report a label-free and amplification-free detection platform using an engineered nanopore of the phi29 DNA-packaging motor with biomarker Galectin3 (GAL3), Thomsen-Friedenreich (TF) binding peptide as the probe fused at its C-terminus. The binding of the biomarker in NAF samples from breast cancer patients to the probe results in the connector's conformational change with a current blockage of 32 %. Utilization of dwell time, blockage ratio, and peak signature enable us to detect basal levels of biomarkers from patient NAF samples at the single-molecule level. This platform will allow for breast cancers to be resolved at an early stage with accuracy and thoroughness.

The interplay of liposome-protein corona hinders the clinical application of liposomes due to active macrophage sequestration and rapid plasma clearance. Here we showed that, CXCL10 as a therapeutic protein was coronated the thermosensitive liposomes to form stealth-like nanocarriers (CXCL10/TSLs). Decoration of the corona layer of CXCL10/TSLs by hyaluronic acid conjugated oridonin (ORD/CXCL10/TSLs), overcame the “fluid barrier” built by biological proteins, drastically reduced capture by leukocytes in whole blood, allowed the specific targeting of tumor sites. Multifunctional medicine ORD/CXCL10/TSLs with hyperthermia drove the sustained cytokine-CXCL10 inflammatory loop to switch macrophage phenotype to M1-like, expand tumor-infiltrating natural killer cells and induce intratumoral levels of interferon-γ. Oridonin synergized with CXCL10 during ORD/CXCL10/TSLs treatment, downregulated PI3K/AKT and Raf/MEK signaling for M1-like polarization and migration inhibition. Furthermore, ORD/CXCL10/TSLs potently synergized with anti-PD-L1 antibody in mice bearing metastatic melanoma, induced sustained immunological memory and controlled metastatic spread.

We investigated the potential effects and mechanisms of vascular endothelial growth factor (VEGF)-nanofiber membranes (NFMs) treatment in a rat model of chronic cerebral hypoperfusion (CCH). VEGF-NFMs treatment promoted angiogenesis in surgical temporal cortex and hippocampus, alleviating decreased CBF in these two cerebral regions. VEGF-NFMs application improved reduced NAA/Cr ratio, preventing neuronal loss. VEGF-NFMs sticking decreased the number of TUNEL-positive cells in surgical temporal cortex, ameliorated impaired synaptic plasticity, and inhibited the release of pro-inflammatory cytokines and the activation of microglia and astrocytes in surgical temporal cortex and hippocampus. Furthermore, BDNF-TrkB/PI3K/AKT, BDNF-TrkB/ERK and HIF-1a/VEGF/ERK pathways were involved in the treatment of VEGF-NFMs against CCH-induced neuronal injury. These results showed the neuroprotective effects of VEGF-NFMs sticking may initiate from neurovascular repairing followed by inhibition of neuronal apoptosis and neuronal and synaptic damage, eventually leading to the suppression of cognitive dysfunction, which provided theoretical foundation for further clinical transformation of VEGF-NFMs.

Urinary extracellular vesicles (uEVs) are promising biomarkers for various diseases. However, many tools measuring uEVs rely on time-consuming uEV isolation methods, which could induce sample bias. This study demonstrates the detection of single uEVs without isolation using imaging flow cytometry (IFCM). Unstained urine samples contained auto-fluorescent (A-F) particles when characterized with IFCM. Centrifugation successfully removed A-F particles from the unprocessed urine. Based on the disappearance of A-F particles, a gate was defined to distinguish uEVs from A-F particles. The final readouts of IFCM were verified as single EVs based on detergent treatment and serial dilutions. When developing this protocol to measure urine samples with abnormally high protein levels, 25 mg/mL dithiothreitol (DTT) showed improved uEV recovery over 200 mg/mL DTT. This study provides an isolation-free protocol using IFCM to quantify and phenotype single uEVs, eliminating the hindrance and influence of A-F particles, protein aggregates, and coincidence events.

Autoimmune diseases (AIDs) are caused by the loss of self-tolerance and destruction of tissues by the host's immune system. Several antigen-specific immunotherapies, focused on arresting the autoimmune attack, have been tested in clinical trials with discouraging results. Therefore, there is a need for innovative strategies to restore self-tolerance safely and definitively in AIDs. We previously demonstrated the therapeutic efficacy of phosphatidylserine (PS)-liposomes encapsulating autoantigens in experimental type 1 diabetes and multiple sclerosis. Here, we show that PS-liposomes can be adapted to other autoimmune diseases by simply replacing the encapsulated autoantigen. After administration, they are distributed to target organs, captured by phagocytes and interact with several immune cells, thus exerting a tolerogenic and immunoregulatory effect. Specific PS-liposomes demonstrate great preventive and therapeutic efficacy in rheumatoid arthritis and myasthenia gravis. Thus, this work highlights the therapeutic potential of a platform for several autoimmunity settings, which is specific, safe, and with long-term effects.

Bile acid-modified nanomedicine is a promising strategy to improve oral bioavailability. However, the efficiencies of different bile acids have not been clarified. To clarify this issue, deoxycholic acid (DCA) and cholic acid (CA) and glycocholic acid (GCA) were conjugated to carboxylated polystyrene nanoparticle (CPN). The endocytosis, intracellular and transcellular transport among the NPs were compared in Caco-2 cells, and their oral pharmacokinetics profiles were studied in C57BL/6 J mice. It was found that DCPN demonstrated higher uptake and transcytosis rate. With modification by different bile acids, the transport pathways of the NPs were altered. In mice, GCPN showed the highest absorption speed and oral bioavailability. It was found that the synergic effect of hydrophobicity and ASBT affinity might lead to the difference between in vitro and in vivo transport. This study will build a basis for the rational design of bile acid-modified nanomedicines.

Carbon-based nanomaterials have a high specific surface area, biocompatibility, and controlled mesopore structures. These characteristics make carbon nanospheres excellent carriers for drugs, biological dyes, photosensitizers, etc. Nevertheless, little is known about the impact of topological features on the surface of carbon nanomaterials on their in vivo immunoreactivity. In this study, we fabricated mesoporous carbon nanoparticles (MCNs) and solvent-processable carbon vesicles (CVs) by high-temperature calcination. The hematoxylin and eosin (H&E) staining suggested CVs' relatively poor dispersion capacity compared to MCNs and carbon precursors (CPs), leading to more severe muscle inflammation and necrosis. Immunostaining and Fluorescence Activated Cell Sorter (FACS) analysis further showed that both MCNs and CVs triggered a transient immune response in transplanted muscle and muscle-draining lymph nodes, but did not alter muscle resistance to exogenous viruses. In conclusion, this study provides insights into how carbon nanoparticles modulate the activation of immune responses in vivo.

The complex stroke pathophysiology, like oxidative stress and inflammatory reactions, causes substantially challenged in stroke treatment. Thymoquinone (TQ) is attributed to pharmacological actions like antioxidant and anti-inflammation. Thymoquinone is chemically hydrophobic, which causes poor solubility and bioavailability. To overcome this challenge Thymoquinone niosome was applied in this in-vivo study. The results demonstrated a significant reduction in rats treated with Thymoquinone niosome compared to free Thymoquinone and control groups (SOD), (TAC), and (GPX) activities were increased in the TQN group compared to the MCAO control group. The decrease in (MDA) level was seen in the Thymoquinone niosome group compared to the MCAO control group. The inflammation factors expression rates of IL-IB, IL-6, TNFα in I/R Thymoquinone niosome group were decreased. This study indicated that Thymoquinone niosome might be utilized as a promising novel carrier to improve Thymoquinone bioavailability and therapeutic effect in treating cerebral I/R injury.

Porous polymer microspheres are employed in biotherapeutics, tissue engineering, and regenerative medicine. Porosity dictates cargo carriage and release that are aligned with the polymer physicochemical properties. These include material tuning, biodegradation, and cargo encapsulation. How uniformity of pore size affects therapeutic delivery remains an area of active investigation. Herein, we characterize six branched aliphatic hydrocarbon-based porogen(s) produced to create pores in single and multilayered microspheres. The porogens are composed of biocompatible polycaprolactone, poly(lactic-co-glycolic acid), and polylactic acid polymers within porous multilayered microspheres. These serve as controlled effective drug and vaccine delivery platforms.