Integrated proteomics and phosphoproteomics analyses of esophageal cancer cells with different invasive abilities.

AIMS: Esophageal squamous cell carcinoma (ESCC) is one of the aggressive and lethal malignancies with an extremely poor prognosis. It is necessary to explore the molecular mechanisms of ESCC invasion. MAIN METHODS: We utilized high-throughput mass spectrometry to analyze the proteomes and phosphorylation profiles of two ESCC cell lines with differing invasion capacities (HK vs TE10). Differentially expressed proteins and phosphorites were identified, followed by comprehensive bioinformatics analyses encompassing function and pathway enrichment, protein-protein interaction (PPI) network analysis, hub gene identification, co-expression analysis, kinase-substrate prediction, and drug-target network analysis. CCK-8 assay, transwell examination, wound-healing assay, and western blot was used to validate the effects of fostamatinib on ESCC cells proliferation, invasion, migration, and LYN expression. KEY FINDINGS: The Q4 cluster of differentially phosphorylated proteins was primarily associated with functions and pathways relevant to tumor metastasis. Phosphorylated hub proteins including ARHGAP35, CTNNA1, and SHC1 were identified through the analysis of PPI network, and their respective regulated kinases were predicted. Among the predicted kinases, LYN was validated to be associated with lymph node metastasis (N0 vs. N1-3) and prognosis in ESCC patients at mRNA levels using TGGA data and protein levels in ESCC tissues (p < 0.05). Validation experiments confirmed the inhibitory effects of fostamatinib on ESCC cells proliferation, migration, invasion, and LYN expression. SIGNIFICANCE: Our multi-omics analysis offers deeper perspectives on ESCC invasiveness and unveils new phosphorylated hub proteins with their regulatory kinase. This study also suggests that fostamatinib may be a potential agent for treating ESCC.

Cerebral delivery of redox-responsive lenalidomide prodrug plus methotrexate for primary central nerve system lymphoma combination therapy.

Primary central nervous system lymphoma (PCNSL) is an extremely malignant CNS tumor with high incidence and mortality rates. Its chemotherapy in the clinic has been restricted owing to unsatisfactory drug distribution in the cerebral tissues. In this study, a redox-responsive prodrug of disulfide-lenalidomide-methoxy polyethylene glycol (LND-DSDA-mPEG) was successfully developed for the cerebral delivery of lenalidomide (LND), and methotrexate (MTX) via subcutaneous (s.c.) administration at the neck for combined anti-angiogenesis and chemotherapy on PCNSL. Both the subcutaneous xenograft tumor model and orthotopic intracranial tumor model demonstrated that the co-delivery of LND and MTX nanoparticles (MTX@LND NPs) may significantly inhibit the growth of lymphoma and effectively prevent liver metastasis by downregulating CD31 and VEGF expression. Moreover, an orthotopic intracranial tumor model further verified that through s.c. administration at the neck, redox-responsive MTX@LND NPs could bypass the blood-brain barrier (BBB), efficiently distribute into brain tissues, and effectively inhibit lymphoma growth in the brain, as detected by magnetic resonance imaging (MRI). Taken together, this biodegradable, biocompatible, and redox-responsive nano-prodrug with highly effective targeted delivery of LND and MTX in the brain through the lymphatic vasculature may provide a facile and feasible treatment strategy for PCNSL in the clinic.

Redox-responsive self-assembled polymeric nanoprodrug for delivery of gemcitabine in B-cell lymphoma therapy.

Gemcitabine, as a standard and classic strategy for B-cell lymphoma in the clinic, is limited by its poor pharmacodynamics. Although stimuli-responsive polymeric nanodelivery systems have been widely investigated in the past decade, issues such as complicated procedures, low loading capacity, and uncontrollable release kinetics still hinder their clinical translation. In view of the above considerations, we attempt to construct hyperbranched polyprodrug micelles with considerable drug loading via simple procedures and make use of the particularity of the tumor microenvironment to ensure that the micelles are "inactivated" in normal tissues and "activated" in the tumor microenvironment. Hence, in this work, a redox-responsive polymeric gemcitabine-prodrug (GEM-S-S-PEG) was one-pot synthesized via facile esterification and acylation. The self-assembled subsize (< 100 nm) GEM-S-S-PEG (GSP NPs) with considerable loading capacity (≈ 24.6%) exhibited on-demand and accurate control of gemcitabine release under a simulated tumor microenvironment and thus significantly induced the apoptosis of B-cell lymphoma in vitro. Moreover, in the A20 tumor xenograft murine model, GSP NPs efficiently decreased the expansion of tumor tissues with minimal systemic toxicity. In summary, these redox-responsive and self-assembling GSP NPs with a facile one-pot synthesis procedure may hold great potency in clinical translation for enhanced chemotherapy of B-cell lymphoma. STATEMENT OF SIGNIFICANCE: A redox-responsive polymeric gemcitabine-prodrug (GEM-S-S-PEG) was one-pot synthesized via facile esterification and acylation. The self-assembled subsize (< 100 nm) GEM-S-S-PEG (GSP NPs) exhibited significant tumor therapeutic effects in vitro and in vivo. The polyprodrug GEM-S-S-PEG prepared in this study shows the great potential of redox-responsive nanodrugs for antitumor activity, which provides a reference value for the optimization of the design of functional polyprodrugs.

Nanomedicine as a promising strategy for the theranostics of infectious diseases.

Infectious diseases caused by bacteria, viruses, and fungi and their global spread pose a great threat to human health. The 2019 World Health Organization report predicted that infection-related mortality will be similar to cancer mortality by 2050. Particularly, the global cumulative numbers of the recent outbreak of coronavirus disease (COVID-19) have reached 110.7 million cases and over 2.4 million deaths as of February 23, 2021. Moreover, the crisis of these infectious diseases exposes the many problems of traditional diagnosis, treatment, and prevention, such as time-consuming and unselective detection methods, the emergence of drug-resistant bacteria, serious side effects, and poor drug delivery. There is an urgent need for rapid and sensitive diagnosis as well as high efficacy and low toxicity treatments. The emergence of nanomedicine has provided a promising strategy to greatly enhance detection methods and drug treatment efficacy. Owing to their unique optical, magnetic, and electrical properties, nanoparticles (NPs) have great potential for the fast and selective detection of bacteria, viruses, and fungi. NPs exhibit remarkable antibacterial activity by releasing reactive oxygen species and metal ions, exerting photothermal effects, and causing destruction of the cell membrane. Nano-based delivery systems can further improve drug permeability, reduce the side effects of drugs, and prolong systemic circulation time and drug half-life. Moreover, effective drugs against COVID-19 are still lacking. Recently, nanomedicine has shown great potential to accelerate the development of safe and novel anti-COVID-19 drugs. This article reviews the fundamental mechanisms and the latest developments in the treatment and diagnosis of bacteria, viruses, and fungi and discusses the challenges and perspectives in the application of nanomedicine.

Recent applications and strategies in nanotechnology for lung diseases.

Lung diseases, including COVID-19 and lung cancers, is a huge threat to human health. However, for the treatment and diagnosis of various lung diseases, such as pneumonia, asthma, cancer, and pulmonary tuberculosis, are becoming increasingly challenging. Currently, several types of treatments and/or diagnostic methods are used to treat lung diseases; however, the occurrence of adverse reactions to chemotherapy, drug-resistant bacteria, side effects that can be significantly toxic, and poor drug delivery necessitates the development of more promising treatments. Nanotechnology, as an emerging technology, has been extensively studied in medicine. Several studies have shown that nano-delivery systems can significantly enhance the targeting of drug delivery. When compared to traditional delivery methods, several nanoparticle delivery strategies are used to improve the detection methods and drug treatment efficacy. Transporting nanoparticles to the lungs, loading appropriate therapeutic drugs, and the incorporation of intelligent functions to overcome various lung barriers have broad prospects as they can aid in locating target tissues and can enhance the therapeutic effect while minimizing systemic side effects. In addition, as a new and highly contagious respiratory infection disease, COVID-19 is spreading worldwide. However, there is no specific drug for COVID-19. Clinical trials are being conducted in several countries to develop antiviral drugs or vaccines. In recent years, nanotechnology has provided a feasible platform for improving the diagnosis and treatment of diseases, nanotechnology-based strategies may have broad prospects in the diagnosis and treatment of COVID-19. This article reviews the latest developments in nanotechnology drug delivery strategies in the lungs in recent years and studies the clinical application value of nanomedicine in the drug delivery strategy pertaining to the lung.

Advancements in nanotechnology for the diagnosis and treatment of multiple myeloma.

Multiple myeloma (MM), known as a tumor of plasma cells, is not only refractory but also has a high relapse rate, and is the second-most common hematologic tumor after lymphoma. It is often accompanied by multiple osteolytic damage, hypercalcemia, anemia, and renal insufficiency. In terms of diagnosis, conventional detection methods have many limitations, such as it is invasive and time-consuming and has low accuracy. Measures to change these limitations are urgently needed. At the therapeutic level, although the survival of MM continues to prolong with the advent of new drugs, MM remains incurable and has a high recurrence rate. With the development of nanotechnology, nanomedicine has become a powerful way to improve the current diagnosis and treatment of MM. In this review, the research progress and breakthroughs of nanomedicine in MM will be presented. Meanwhile, both superiorities and challenges of nanomedicine were discussed. As a new idea for the diagnosis and treatments of MM, nanomedicine will play a very important role in the research field of MM.