Dual-responsive nanoparticles with transformable shape and reversible charge for amplified chemo-photodynamic therapy of breast cancer.

Herein, we designed a dual-response shape transformation and charge reversal strategy with chemo-photodynamic therapy to improve the blood circulation time, tumor penetration and retention, which finally enhanced the anti-tumor effect. In the system, hydrophobic photosensitizer chlorin e6 (Ce6), hydrophilic chemotherapeutic drug berberrubine (BBR) and matrix metalloproteinase-2 (MMP-2) response peptide (PLGVRKLVFF) were coupled by linkers to form a linear triblock molecule BBR-PLGVRKLVFF-Ce6 (BPC), which can self-assemble into nanoparticles. Then, positively charged BPC and polyethylene glycol-histidine (PEG-His) were mixed to form PEG-His@BPC with negative surface charge and long blood circulation time. Due to the acidic tumor microenvironment, the PEG shell was detached from PEG-His@BPC attributing to protonation of the histidine, which achieved charge reversal, size reduction and enhanced tumor penetration. At the same time, enzyme cutting site was exposed, and the spherical nanoparticles could transform into nanofibers following the enzymolysis by MMP-2, while BBR was released to kill tumors by inducing apoptosis. Compared with original nanoparticles, the nanofibers with photosensitizer Ce6 retained within tumor site for a longer time. Collectively, we provided a good example to fully use the intrinsic properties of different drugs and linkers to construct tumor microenvironment-responsive charge reversal and shape transformable nanoparticles with synergistic antitumor effect.

Replicase 1a gene plays a critical role in pathogenesis of avian coronavirus infectious bronchitis virus.

Avian coronavirus infectious bronchitis virus (IBV) is an important pathogen threatening poultry production worldwide. Here, two recombinant IBVs (rYN-1a-aYN and rYN-1b-aYN) were generated in which ORF1a or ORF1b of the virulent YN genome were replaced by the corresponding regions from the attenuated strain aYN. The pathogenicity and virulence of rIBVs were evaluated in ovo and in vivo. The results revealed that mutations in the ORF1a gene during passage in embryonated eggs caused the decreased pathogenicity of virulent IBV YN strain, proven by determination of virus replication in ECEs and CEK cells, the observation of clinical signs, gross lesions, microscopic lesions, tracheal ciliary activity and virus distribution in chickens following exposure to rIBVs. However, mutations in ORF1b had no obvious effect on virus replication in both ECEs and CEK cells, or pathogenicity in chickens. Our findings demonstrate that the replicase 1a gene of avian coronavirus IBV is a determinant of pathogenicity.

Macrophage-mimic shape changeable nanomedicine retained in tumor for multimodal therapy of breast cancer.

The current nanomedicines for cancer therapy based on the enhance permeability and retention (EPR) effect remain insufficient to satisfy the clinical need, and the challenges hindering nanomedicines delivery should be conquered for strong therapeutic efficacy. To address these problems, a membrane-coated laser-responsive shape changeable nanomedicine, I-P@NPs@M, is reported. The covering macrophage membrane promotes the circulation and tumor targeting of nanomedicines. Then the chlorin e6 (Ce6) in I-P@NPs@M can convert 650 nm laser into reactive oxygen species (ROS) to trigger the spherical micelles changing into nanofibers for strong retention in tumor region, consequently the linear nanofibers long locate and sustainably release drugs. On the other hand, the ROS not only directly kills tumor cells by photodynamic therapy but stimulates the dimeric paclitaxel (PTX) generating monomeric PTX. The combinational chemo- photodynamic therapy heavily suppresses tumor growth and inducing immunogenic cell death, which is synergistic with Indoximod (IND) inhibiting the IDO pathway to activate immune response for immunotherapy. By chemotherapy, photodynamic therapy and immunotherapy gathering, the treatment of I-P@NPs@M + laser shows the best antitumor effect, resulting in 85.27 ± 12.80% suppression of breast cancer in mice model, and also remarkably inhibits lung metastasis.

NP protein and F protein of pigeon paramyxovirus type 1 are associated with its low pathogenicity in chickens.

In this study, we investigated which structural proteins of pigeon paramyxovirus type 1 (PPMV-1) are responsible for its low pathogenicity in chickens. The results revealed that the pathogenicity of the virus is determined by multiple genes. The NP protein and F protein were found to have the strongest individual effect on virulence, and this effect further enhanced when the two proteins were expressed in combination. Our study highlights the influence of the NP and F proteins on the pathogenicity of PPMV-1 in chickens.

Photothermal therapy of cancer cells using novel hollow gold nanoflowers.

This article presents a new strategy for fabricating large gold nanoflowers (AuNFs) that exhibit high biological safety under visible light and very strong photothermal cytotoxicity to HeLa cells under irradiation with near-infrared (NIR) light. This particular type of AuNF was constructed using vesicles produced from a multiamine head surfactant as a template followed by depositing gold nanoparticles (AuNPs) and growing their crystallites on the surface of vesicles. The localized surface plasmon-resonance spectrum of this type of AuNF can be easily modulated to the NIR region by controlling the size of the AuNFs. When the size of the AuNFs increased, biosafety under visible light improved and cytotoxicity increased under NIR irradiation. Experiments in vitro with HeLa cells and in vivo with small mice have been carried out, with promising results. The mechanism for this phenomenon is based on the hypothesis that it is difficult for larger AuNFs to enter the cell without NIR irradiation, but they enter the cell easily at the higher temperatures caused by NIR irradiation. We believe that these effects will exist in other types of noble metallic NPs and cancer cells. In addition, the affinity between AuNPs and functional biomolecules, such as aptamers and biomarkers, will make this type of AuNF a good recognition device in cancer diagnosis and therapy.