GSH-Responsive Prodrug Nanoassembly as a Carrier-Free Nanoplatform for Tumor-Targeting Delivery and Chemo-Photothermal Therapy.

Photothermal therapy, combined with chemotherapy, holds promising prospects for the therapeutic outcome of malignant tumors. However, the synergistic therapeutic effect suffers from low coloading capacity and inefficient synchronous tumor-targeting delivery of chemodrug and photothermal photosensitizers. Herein, we designed a versatile carrier-free nanoplatform to seek improvement for chemo-photothermal therapy. An NIR photosensitizer IR-808 was used for noninvasive cancer imaging, diagnosis, and imaging-guided photothermal therapy. A reduction-sensitive paclitaxel prodrug (PTX-SS-PEG2k) was rationally synthesized by covalently linking paclitaxel with polyethylene glycol 2000 via a disulfide bond. Then, the carrier-free nanoassemblies were constructed with an inner core of IR-808 and an amphiphilic paclitaxel prodrug shell. PTX-SS-PEG2k served as a stabilizer and chemodrug and could facilitate the self-assembly of IR-808 nanoparticles with high coloading efficiency and reduction-sensitive drug release. The versatile nanoplatform exhibited multiple advantages, including high drug payload, reduction-sensitive drug release, tumor-targeting drug delivery, and potent synergistic antitumor effect. We provide a versatile theranostic nanoplatform, which improves the effectiveness of synergetic chemo-photothermal therapy and reduces the off-target toxicity.

pH/Hyal-Responsive Surface-Charge Switchable Electrostatic Complexation for Efficient Elimination of MRSA Infection.

Methicillin-resistant Staphylococcus aureus (MRSA) has become a great threat to human health worldwide, making new effective antibacterial strategies urgently desired. In this study, a cationic pH-responsive delivery system (pHSM) was developed based on poly(ß-amino esters)-methoxy poly(ethylene glycol), by which linezolid (LZD) could be encapsulated to form pHSM/LZD. The biocompatibility and stability of pHSM/LZD were further enhanced by adding low-molecular-weight hyaluronic acid (LWT HA) on the surface through electrostatic interaction to form pHSM/LZD@HA, of which the positive surface charges were neutralized by LWT HA under physiological conditions. LWT HA can be degraded by hyaluronidase (Hyal) after arriving at the infection site. In vitro, pHSM/LZD@HA could rapidly change to being positively charged on the surface within 0.5 h under acidic conditions, especially when Hyal was present, thus promoting bacterial binding and biofilm penetration of pHSM/LZD@HA. In addition, the pH/Hyal-dependent accelerated drug release behavior was also observed and it is beneficial for the comprehensive treatment of MRSA infection in vitro and in vivo. Our study provides a novel strategy to develop a pH/Hyal-responsive drug delivery system for the treatment of MRSA infection.

Identifying the intervention mechanisms of polydatin in hyperuricemia model rats by using UHPLC-Q-Exactive Orbitrap mass spectroscopy metabonomic approach.

Introduction: Polydatin is a biologically active compound found in mulberries, grapes, and Polygonum cuspidatum, and it has uric acid-lowering effects. However, its urate-lowering effects and the molecular mechanisms underlying its function require further study. Methods: In this study, a hyperuricemic rat model was established to assess the effects of polydatin on uric acid levels. The body weight, serum biochemical indicators, and histopathological parameters of the rats were evaluated. A UHPLC-Q-Exactive Orbitrap mass spectrometry-based metabolomics approach was applied to explore the potential mechanisms of action after polydatin treatment. Results: The results showed a trend of recovery in biochemical indicators after polydatin administration. In addition, polydatin could alleviate damage to the liver and kidneys. Untargeted metabolomics analysis revealed clear differences between hyperuricemic rats and the control group. Fourteen potential biomarkers were identified in the model group using principal component analysis and orthogonal partial least squares discriminant analysis. These differential metabolites are involved in amino acid, lipid, and energy metabolism. Of all the metabolites, the levels of L-phenylalanine, L-leucine, O-butanoylcarnitine, and dihydroxyacetone phosphate decreased, and the levels of L-tyrosine, sphinganine, and phytosphingosine significantly increased in hyperuricemic rats. After the administration of polydatin, the 14 differential metabolites could be inverted to varying degrees by regulating the perturbed metabolic pathway. Conclusion: This study has the potential to enhance our understanding of the mechanisms of hyperuricemia and demonstrate that polydatin is a promising potential adjuvant for lowering uric acid levels and alleviating hyperuricemia-related diseases.