No abstract

Sonodynamic therapy eliminates cancer cells with reactive oxygen species (ROS) triggered by ultrasound whose energy is spatiotemporally controllable, is safe to human tissues and organs, and penetrates deeply through tissues. Its application, however, is hindered by the scarcity of sonodynamic sensitizers. We herein demonstrate piezoelectric materials as a new source of sonodynamic sensitizers, using few-layer black phosphorus (BP) nanosheet as a model. BP nanosheet exhibited ultrasound-excited cytotoxicity to cancer cells via ROS generation, thereby suppressing tumor growth and metastasis without causing off-target toxicity in tumor-bearing mouse models. The ultrasonic wave introduces mechanical strain to the BP nanosheet, leading to piezoelectric polarization which shifts the conduction band of BP more negative than O2/·O2 – while its valence band more positive than H2O/·OH, thereby accelerating the ROS production. This work identifies a new mechanism for discovering sonodynamic sensitizers and suggests BP nanosheet as an excellent sensitizer for tumor sonodynamic therapy.

Staphylococcus aureus bacteremia is one of the most serious bacterial infections worldwide. Most complications of S. aureus bacteremia arise because the pathogen can survive inside host phagocytes, especially macrophages, which makes elimination of intracellular S. aureus key to clinical success. Unfortunately, most antibiotics have poor cellular penetration capacity, which necessitates intracellular delivery of antibiotics. We herein use nanoparticle coated with membrane of extracellular vesicle secreted by S. aureus (i.e., NP@EV) as active-targeting antibiotic carrier, with counterparts coated with PEGylated lipid bilayer (i.e., NP@Lipo; PEG = poly(ethylene glycol)) or with membrane of outer membrane vesicle secreted by Escherichia coli (i.e., NP@OMV) included as controls. NP@EV is internalized at higher efficiency by S. aureus-infected macrophage than by nai ̈ve counterpart, whereas NP@Lipo and NP@OMV are not; instead, NP@OMV, but neither NP@EV nor NP@Lipo, is internalized at higher efficiency by E. coli-infected macrophage than by nai ̈ve counterpart. Moreover, when injected intravenously into mouse models, NP@EV, but neither NP@OMV nor NP@Lipo, exhibits significantly higher accumulations within four major organs (kidney, lung, spleen, and heart) bearing metastatic S. aureus infections than within healthy counterparts. These observations suggest that EV membrane coating of NP@EV endows the particle with active targeting capacity both in vitro and in vivo. As a result, when preloaded with antibiotics and intravenously administered to alleviate metastatic infection in S. aureus bacteremia-bearing mouse model, NP@EV confers its cargoes with strikingly improved efficacy; in doing so, NP@EV is significantly more efficient than both NP@Lipo and NP@OMV in kidney and lungwhich bear the highest metastatic bacterial burden and represent most common sites for S. aureus infection, respectively. Such an active-targeting delivery platform may have implications in promoting clinical success on intracellular pathogen-associated complications.

No abstract

Recently, micelles, which are self-assembled by amphiphilic copolymers, have attracted tremendous attention as promising drug delivery systems for cancer treatment. Thus, the hydrophobic core of the micelles, which could efficiently encapsulate small molecular drug, will play a significant role for the anticancer efficiency. Unfortunately, the effect of hydrophobicity of micellar core on its anticancer efficiency was rarely reported. Herein, the amphiphilic diblock polymers of poly(ethylene glycol) and polyphosphoester with different side groups (butyl, hexyl, octyl) were synthesized to tune the hydrophobicity of the micellar core. We found that the in vitro cytotoxicity of the DOX-loaded micelles decreased with the increasing hydrophobicity of micellar core due to the drug release rate. However, following systemic delivery, the DOX-loaded micelles with the most hydrophobic core exhibited the most significant inhibition of tumor growth in a MDA-MB-231 tumor model, indicating the importance of hydrophobicity of core on the antitumor efficacy of drug delivery systems.

Membrane-disruptive, drug-free macromolecular therapeutics may help overcome cancer drug-resistance. Their inability to distinguish cancerous from normal cells, however, results in significant off-target toxicity. Note that the tumor has a slightly acidic microenvironment (pH 6.5–6.8) in contrast to the alkaline microenvironment in normal tissues (pH 7.4) and that host-defense peptides (HDPs) and their synthetic mimetics need to be net cationic to be membrane-disruptive. We herein endow polymer mimetics of HDPs with acid-triggered cationicity, to make them membrane-disruptive at only tumor pH. For these polymer mimetics, there exists a maximal threshold of chain length that determines whether the micelle of a mimetic inherits its pH-sensitive activity. Using the most and least active micelles as representatives, we find that their distinct potency in disrupting membranes arises because of their striking tendency to dissociate upon exposure to tumor pH. As expected, these micelles exhibit in vitro cytotoxicity profiles that correlate with their membrane-disruptive activity profiles. When administered intravenously, these micellesirrespective of their distinct activity profilesunanimously exhibit long systemic circulation as do PEGylated micelle nanoparticles, despite of their lacking stealth materials, owing to the zwitterionic nature of their surfaces at blood pH. Nevertheless, the pH-sensitive micelle achieves significantly higher tumor uptake and strikingly better therapeutic efficacy than its completely inactive analogue. More important, the pH-sensitive micelle exhibits undetectable off-target toxicity, owing to its pH-sensitivity. Clearly, making HDPs and their mimetics sensitive to tumor-characteristic cues (e.g., acidic pH) is efficient in minimizing their off-target toxicity, thereby offering membrane-disruptive, drug-free macromolecular therapeutics for fighting against cancer drug-resistance.

The antioxidant potential of jujube honey, one of the most widely consumed honeys in China, has never been determined fully. In this study, jujube honey from six geographical origins in China was analyzed for individual phenolic acid, total phenolic content, and the antioxidant effect in chronic alcohol-related hepatic disease in mice. The results showed that jujube honey from Linxian of Shanxi province contained higher phenol levels, exhibited DPPH antioxidant activity, ferric ion reducing antioxidant power (FRAP) and protective effects against DNA damage. Treatment with jujube honey (Shanxi Linxian) for 12 weeks significantly inhibited serum lipoprotein oxidation, reduced the impact of alcoholism on aspartate aminotransferase (AST) and alanine aminotransferase (ALT). It also inhibited the generation of 8-hydroxy-2-deoxyguanosine (8-OHdG), lowered the levels of malondialdehyde (MDA) and increased the activity of hepatic glutathione peroxidase (GSH-Px). The study indicates that jujube honey exerts potent antioxidant activity and significant protection in hepatic disorders associated with chronic alcoholism. The protective effect is attributed to its antioxidant mechanisms and inhibition of oxidative degradation of lipids.

Nanoparticle elasticity is crucial in nanoparticles’ physiological fate, but how this occurs is largely unknown. Using core-shell nanoparticles with a same PEGylated lipid bilayer shell yet cores differing in elasticity (45 kPa – 760 MPa) as models, we isolate the effects of nanoparticle elasticity from those of other physiochemical parameters and, using mouse models, observe a non-monotonic relationship of systemic circulation lifetime versus nanoparticle elasticity. Incubating our nanoparticles in mouse plasma provides protein coronas varying non-monotonically in composition depending on nanoparticle elasticity. Particularly, apolipoprotein A-I (ApoA1) is the only protein whose relative abundance in corona strongly correlates with our nanoparticles’ blood clearance lifetime. Notably, similar results are observed when above nanoparticles’ PEGylated lipid bilayer shell is changed to be non-PEGylated. This work unveils the mechanisms by which nanoparticle elasticity affects nanoparticles’ physiological fate and suggests nanoparticle elasticity as a readily tunable parameter in future rational exploiting of protein corona.