Sharpmcguire6162

Some compounds showed significant cytotoxicities, anti-inflammatory or antioxidant activities. The attractive dual PKSs gene clusters for azaphilones biosynthesis were mined by bioinformatic analysis and overexpression of a pathway specific transcription factor. Our work therefor provides an efficient approach to mine the chemical diversity of endophytic fungi.Tumor microenvironment has been widely utilized for advanced drug delivery in recent years, among which hypoxia-responsive drug delivery systems have become the research hotspot. Although hypoxia-responsive micelles or polymersomes have been successfully developed, a type of hypoxia-degradable nanogel has rarely been reported and the advantages of hypoxia-degradable nanogel over other kinds of degradable nanogels in tumor drug delivery remain unclear. Deferoxamine clinical trial Herein, we reported the synthesis of a novel hypoxia-responsive crosslinker and the fabrication of a hypoxia-degradable zwitterionic poly(phosphorylcholine)-based (HPMPC) nanogel for tumor drug delivery. The obtained HPMPC nanogel showed ultra-long blood circulation and desirable immune compatibility, which leads to high and long-lasting accumulation in tumor tissue. Furthermore, HPMPC nanogel could rapidly degrade into oligomers of low molecule weight owing to the degradation of azo bond in hypoxic environment, which leads to the effective release of the loaded drug. Impressively, HPMPC nanogel showed superior tumor inhibition effect both in vitro and in vivo compared to the reduction-responsive phosphorylcholine-based nanogel, owing to the more complete drug release. Overall, the drug-loaded HPMPC nanogel exhibits a pronounced tumor inhibition effect in a humanized subcutaneous liver cancer model with negligible side effects, which showed great potential as nanocarrier for advanced tumor drug delivery.Multi-modal therapeutics are emerging for simultaneous diagnosis and treatment of cancer. Polymeric carriers are often employed for loading multiple drugs due to their versatility and controlled release of these drugs in response to a tumor specific microenvironment. A theranostic nanomedicine was designed and prepared by complexing a small gadolinium chelate, conjugating a chemotherapeutic drug PTX through a cathepsin B-responsive linker and covalently bonding a fluorescent probe pheophorbide a (Ppa) with a branched glycopolymer. The branched prodrug-based nanosystem was degradable in the tumor microenvironment with overexpressed cathepsin B, and PTX was simultaneously released to exert its therapeutic effect. The theranostic nanomedicine, branched glycopolymer-PTX-DOTA-Gd, had an extended circulation time, enhanced accumulation in tumors, and excellent biocompatibility with significantly reduced gadolinium ion (Gd3+) retention after 96 h post-injection. Enhanced imaging contrast up to 24 h post-injection and excellent antitumor efficacy with a tumor inhibition rate more than 90% were achieved from glycopolymer-PTX-DOTA-Gd without obvious systematic toxicity. This branched polymeric prodrug-based nanomedicine is very promising for safe and effective diagnosis and treatment of cancer.Developing tumor-specific drug delivery systems with minimized off-target cargo leakage remains an enduring challenge. In this study, inspired from the natural cryptobiosis explored by certain organisms and stimuli-responsive polyphenol‒metal coordination chemistry, doxorubicin (DOX)-conjugated gelatin nanoparticles with protective shells formed by complex of tannic acid and FeIII (DG@TA-FeIII NPs) were successfully developed as an "AND" logic gate platform for tumor-targeted DOX delivery. Moreover, benefiting from the well-reported photothermal conversion ability of TA-FeIII complex, a synergistic tumor inhibition effect was confirmed by treating 4T1 tumor-bearing mice with DG@TA-FeIII NPs and localized near-infrared (NIR) laser irradiation. As a proof of concept study, this work present a simple strategy for developing "AND" logic gate platforms by coating enzyme-degradable drug conjugates with detachable polyphenol‒metal shells.Chemotherapy has been a major option in clinic treatment of malignant tumors. However, single chemotherapy faces some drawbacks, such as multidrug resistance, severe side effects, which hinder its clinic application in tumor treatment. Multifunctional nanoparticles loading with chemotherapeutic agent and photosensitizer could be a promising way to efficiently conduct tumor combination therapy. In the current study, a novel pH-sensitive and bubble-generating mesoporous silica-based drug delivery system (denoted as M(a)D@PI-PEG-RGD) was constructed. Ammonium bicarbonate (NH4HCO3; abc) and chemotherapeutic agent doxorubicin (DOX) were loaded into the pores of mesoporous silica. Indocyanine green (ICG) as a photothermal and photodynamic agent was loaded onto the polydopamine (PDA) layer surface. The synthesized nanoparticles displayed a narrow polydispersity (PDI) and small particle size as characterized through dynamic light scattering-autosizer analysis. The nanoparticles also showed high targeting efficacy through RGD modification as indicated by cellular uptake and animal studies. DOX release analysis confirmed that the nanoparticles were pH-dependent and that NH4HCO3 accelerated drug release. At the same time, the nanoparticles had obvious photothermal and photodynamic effects performed by ICG which restrained tumor growth remarkably. In summary, the multifunctional nanoparticles presented a promising system for combination therapy.Psoriatic arthritis (PsA) is a complicated psoriasis comorbidity with manifestations of psoriatic skin and arthritic joints, and tailoring specific treatment strategies for simultaneously delivering different drugs to different action sites in PsA remains challenging. We developed a need-based layered dissolving microneedle (MN) system loading immunosuppressant tacrolimus (TAC) and anti-inflammatory diclofenac (DIC) in different layers of MNs, i.e., TD-MN, which aims to specifically deliver TAC and DIC to skin and articular cavity, achieving simultaneous alleviation of psoriatic skin and arthritic joint lesions in PsA. In vitro and in vivo skin permeation demonstrated that the inter-layer retained TAC within the skin of ∼100 μm, while the tip-layer delivered DIC up to ∼300 μm into the articular cavity. TD-MN not only efficiently decreased the psoriasis area and severity index scores and recovered the thickened epidermis of imiquimod-induced psoriasis but also alleviated carrageenan/kaolin-induced arthritis even better than DIC injection through reducing joint swelling, muscle atrophy, and cartilage destruction.