Systemic Delivery of Paclitaxel by Find-Me Nanoparticles Activates Antitumor Immunity and Eliminates Tumors.

Local delivery of immune-activating agents has shown promise in overcoming an immunosuppressive tumor microenvironment (TME) and stimulating antitumor immune responses in tumors. However, systemic therapy is ultimately needed to treat tumors that are not readily locatable or accessible. To enable systemic delivery of immune-activating agents, we employ poly(lactic-co-glycolide) (PLGA) nanoparticles (NPs) with a track record in systemic application. The surface of PLGA NPs is decorated with adenosine triphosphate (ATP), a damage-associated molecular pattern to recruit antigen-presenting cells (APCs). The ATP-conjugated PLGA NPs (NPpD-ATP) are loaded with paclitaxel (PTX), a chemotherapeutic agent inducing immunogenic cell death to generate tumor antigens in situ. We show that the NPpD-ATP retains ATP activity in hostile TME and provides a stable "find-me" signal to recruit APCs. Therefore, the PTX-loaded NPpD-ATP helps populate antitumor immune cells in TME and attenuate the growth of CT26 and B16F10 tumors better than a mixture of PTX-loaded NPpD and ATP. Combined with anti-PD-1 antibody, PTX-loaded NPpD-ATP achieves complete regression of CT26 tumors followed by antitumor immune memory. This study demonstrates the feasibility of systemic immunotherapy using a PLGA NP formulation that delivers ICD-inducing chemotherapy and an immunostimulatory signal.

Synthesis and Sonodynamic Antibacterial Activity Evaluation of Three Novel Fluoroquinolone Compounds.

OBJECTIVE: Three ciprofloxacin derivatives (CPDs) were synthesized. Also, their sonodynamic antibacterial activities and possible mechanism under ultrasound (US) irradiation were preliminarily investigated. METHODS: Staphylococcus aureus and Escherichia coli were selected as the research objects. The sonodynamic antibacterial effects of three CPDs and their structure-effective relationship were explored by the inhibition rate. The reactive oxygen species (ROS) produced under US irradiation were detected by oxidative extraction spectrophotometry and used to analyze the sonodynamic antibacterial mechanism of three CPDs. RESULTS: Research indicated that three CPDs, named compound 1 (C1), compound 2 (C2) and compound 3 (C3), separately all had strong sonodynamic antibacterial activities. In addition, C3 had the strongest effect relative to the other CPDs. The study also found that CPDs' concentration, US irradiation time, US solution temperature and US medium could disturb their sonodynamic antimicrobial effects. Moreover, 1O2 and ·OH were the main types of ROS produced by C1 and C3; the ROS produced by C2 included 1O2, among other types. CONCLUSION: Results showed that all three CPDs could be activated to produce ROS after US irradiation. Among them, C3 displayed the highest ROS production and the utmost activity, which may be related to the introduction of the electron-giving group at the C-3 position of the quinoline backbone.

Binding of fluphenazine with human serum albumin in the presence of rutin and quercetin: An evaluation of food-drug interaction by spectroscopic techniques.

The interactions between human serum albumin (HSA) and fluphenazine (FPZ) in the presence or absence of rutin or quercetin were studied by fluorescence, absorption and circular dichroism (CD) spectroscopy and molecular modeling. The results showed that the fluorescence quenching mechanism was static quenching by the formation of an HSA-FPZ complex. Entropy change (ΔS0 ) and enthalpy change (ΔH0 ) values were 68.42 J/(mol⋅K) and -4.637 kJ/mol, respectively, which indicated that hydrophobic interactions and hydrogen bonds played major roles in the acting forces. The interaction process was spontaneous because the Gibbs free energy change (ΔG0 ) values were negative. The results of competitive experiments demonstrated that FPZ was mainly located within HSA site I (sub-domain IIA). Molecular docking results were in agreement with the experimental conclusions of the thermodynamic parameters and competition experiments. Competitive binding to HSA between flavonoids and FPZ decreased the association constants and increased the binding distances of FPZ binding to HSA. The results of absorption, synchronous fluorescence, three-dimensional fluorescence, and CD spectra showed that the binding of FPZ to HSA caused conformational changes in HSA and simultaneous effects of FPZ and flavonoids induced further HSA conformational changes.