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Choroidal neovascularization (CNV) is the major cause of vision loss in wet age-related macular degeneration (AMD). Current therapies require repeated intravitreal injections, which are painful and can cause infection, bleeding, and retinal detachment. Here we develop nanoparticles (NP-[CPP]) that can be administered intravenously and allow local drug delivery to the diseased choroid via light-triggered targeting. NP-[CPP] is formed by PEG-PLA chains modified with a cell penetrating peptide (CPP). Attachment of a DEACM photocleavable group to the CPP inhibits cellular uptake of NP-[CPP]. Irradiation with blue light cleaves DEACM from the CPP, allowing the CPP to migrate from the NP core to the surface, rendering it active. In mice with laser-induced CNV, intravenous injection of NP-[CPP] coupled to irradiation of the eye allows NP accumulation in the neovascular lesions. When loaded with doxorubicin, irradiated NP-[CPP] significantly reduces neovascular lesion size. We propose a strategy for non-invasive treatment of CNV and enhanced drug accumulation specifically in diseased areas of the eye.

Echovirus 18 (E18), a serotype of Enterovirus B (EV-B) species, is an important pathogen in aseptic meningitis. E18 had rarely been detected in mainland China, but became the predominant pathogen associated with viral encephalitis (VE) and meningitis in Hebei province for the first time in 2015. To investigate the molecular epidemiology and genetic characteristics of E18 in mainland China, sixteen E18 strains from patient throat swabs with hand, foot, and mouth disease (HFMD) in six provinces in China collected between 2015 and 2016, and four E18 strains isolated from 18 patient cerebrospinal fluid specimens with VE in Hebei Province in 2015 were obtained and sequenced. Combined with the sequences from the GenBank database, we performed an extensive genetic analysis. Phylogenetic analysis of VP1 gene sequences revealed that all E18 strains from mainland China after 2015 belonged to subgenotype C2. There were no obvious specific differences in phylogenetic and variation analyses of E18 genome sequences between HFMD and VE/meningitis strains. Potential multiple recombination may have occurred in the 5'-untranslated region and in the P2 and P3 nonstructural protein-encoding regions of E18 strains from China. The current E18 strains were potential multiple-recombinant viruses. Overall, these findings supported that E18 caused HFMD, VE, and meningitis, although there were no significant associations between clinical features and viral genomic characteristics.

Externally triggerable drug delivery systems have promising potential in providing flexible control of the timing, duration, and intensity of treatment according to patient's needs, while reducing side effects and increasing therapeutic efficacy. However, a limitation to translating such systems into clinical practice is the difficulty to predict the tissue depth at which such systems could be safely used in vivo (e.g. activatable at the target site with a clinically-safe energy dosage). An effective method is needed to evaluate the clinical potential of externally triggerable drug delivery systems. Here we have a method and approach to predicting the tissue depth at which a drug delivery system can be safely triggered in vivo by an external energy source. We used in vitro and ex vivo experiments combined with a mathematical model to develop a method to predict activated drug release at different tissue depths, which was then validated in vivo. We constructed these models for liposomal drug delivery systems triggered by two of the most commonly studied external stimuli: ultrasound and near infrared light. We developed the approach in two prevalent tissue types: muscle and fat. Our method identified two important parameters in the activation of drug delivery systems in tissue: 1) the ability of the activating energy to penetrate tissue, 2) the sensitivity of the system to the activation source. The method was validated by correlation with triggered sciatic nerve block in the rat in vivo, demonstrating that this approach provided an accurate estimate of activated release at different tissue depths., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Chemotherapy-based treatment for cancer has made great progress in the past decades. However, there is still a big challenge for the treatment of lung cancer. Herein, a multifunctional nanocarrier was developed through electrostatic interaction between the fluorescent gold nanocluster-conjugated chitosan and the nucleolin targeting AS1411 aptamer. Then methotrexate was loaded into the multifunctional nanocarrier through hydrophobic interaction to obtain the nanodrug carrier systems. The prepared nanodrug carrier systems have an average nanoparticle size of 200 nm with 13.8% drug loading efficiency. The drug release is pH-dependent. The in vitro results demonstrated that the nanodrug carrier systems were selectively taken up by cancer cells in a time-dependent manner and exhibited significantly enhanced anticancer activity in a model of lung cancer A549 cells. The in vivo results showed that intravenous administration of nanodrug carrier systems into BALB/c mice led to accumulation of methotrexate at the tumor site and significantly inhibited the tumor growth but without overt toxicity. The present study suggests that the prepared multifunctional nanocarrier can be used as an effective drug delivery system for anticancer drugs and exhibits great potential in clinical applications., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

We report sub-100 nm metal-shell (Au) dielectric-core (BaTiO 3 ) nanoparticles with bimodal imaging abilities and enhanced photothermal effects. The nanoparticles efficiently absorb light in the near infrared range of the spectrum and convert it to heat to ablate tumors. Their BaTiO 3 core, a highly ordered non-centrosymmetric material, can be imaged by second harmonic generation, and their Au shell generates two-photon luminescence. The intrinsic dual imaging capability allows investigating the distribution of the nanoparticles in relation to the tumor vasculature morphology during photothermal ablation. Our design enabled in vivo real-time tracking of the BT-Au-NPs and observation of their thermally-induced effect on tumor vessels., Statement of Significance: Photothermal therapy induced by plasmonic nanoparticles has emerged as a promising approach to treating cancer. However, the study of the role of intratumoral nanoparticle distribution in mediating tumoricidal activity has been hampered by the lack of suitable imaging techniques. This work describes metal-shell (Au) dielectric-core (BaTiO 3 ) nanoparticles (abbreviated as BT-Au-NP) for photothermal therapy and bimodal imaging. We demonstrated that sub-100 nm BT-Au-NP can efficiently absorb near infrared light and convert it to heat to ablate tumors. The intrinsic dual imaging capability allowed us to investigate the distribution of the nanoparticles in relation to the tumor vasculature morphology during photothermal ablation, enabling in vivo real-time tracking of the BT-Au-NPs and observation of their thermally-induced effect on tumor vessels., (Copyright © 2018 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.)

The efficacy of tetrodotoxin (TTX), a very potent local anesthetic, is limited by its poor penetration through barriers to axonal surfaces. To address this issue, we encapsulated TTX in hollow silica nanoparticles (TTX-HSN) and injected them at the sciatic nerve in rats. TTX-HSN achieved an increased frequency of successful blocks, prolonged the duration of the block, and decreased the toxicity compared to free TTX. In animals injected with fluorescently labeled HSN, the imaging of frozen sections of nerve demonstrated that HSN could penetrate into nerve and that the penetrating ability of silica nanoparticles was highly size-dependent. These results demonstrated that HSN could deliver TTX into the nerve, enhancing efficacy while improving safety.

In this study, the epidemiology of Hand-foot-mouth disease(HFMD)composition of enterovirus (EV) pathogen and VP1 coding gene of Enterovirus A71(EV-A71)were analyzed in Chongqing from 2014 to 2015,to provide a scientific basis for strategies of prevention and control of HFMD in Chongqing. It is reported that there were a total of 100,176 cases of HFMD, of which 284 cases of severe,37 cases of death in Chongqing.39counties(autonomous counties)of Chongqing have reported cases, and the urbans reported incidence rate(298.83/100,000)was significantly higher than the suburbs(103.37/100,000),children 3and under 3years old accounted for 83.21%%,and 5and under 5years old accounted for 95.64%of reported cases, the big peak of epidemics of HFMD was from April to July and the small peak took shape from October to November. Severe cases(96.83%)and deaths(100%)were concentrated in the age group of 5years old and below. The severe cases were mainly in the three districts, WanZhou District, Liangping County and FuLing District, accounting for 74.65% of reported cases, and death cases were widely distributed, scattered in 17 counties.7503nucleic acid of clinical specimens of HFMD were detected, suggested that EV-A71,CV-A16,non-EV-A71/CV-A16 of other EV accounted for 23.54%,33.21%,43.25% respectively,Non-EV-A71/ CV-A16 of other EV became the dominant pathogen of HFMD in Chongqing, but EV-A71 was still the dominant pathogen in severe and death cases. The results showed that 54 strains belonged to C4a and one strain belonged to B5 in the analyses of the VP1 sequences of 55 strains during2014-2015 in Chongqing. This study provides important epidemiological and etiological data for HFMD prevention and control strategies and reduction of severe and death caused by EV-A71 in Chongqing.

To understand the epidemiological etiology characteristics of hand, foot and mouth disease(HFMD)in Guangdong province, and to explore the risk change trend of the whole province. By using the descriptive epidemiological methods, the whole province’s incidence trend, population distribution and pathogenic form of HFMD were analyzed with the HFMD surveillance data,population data and geographic information of Guangdong province from 2008 to 2015.The analysis results show: A total of 2,133,722 cases of HFMD, including 5,066 severe cases and 259 death cases were reported in Guangdong province from 2008 to 2015.All the cities of Guangdong had HFMD cases, especially the Pearl River Delta Regions, which were on high-risk areas. There were two peaks every year, with the main peak of incidence occurred in spring and summer, and the sub peak occurred in autumn.Most cases were children aged<5years old, the proportion of this group in overall infections, the severe and death cases were 90.58%,95.93%and 97.30%,respectively,while the proportion for the children less than 3years old were 77.32% and 81.85%,respectively. The incidence of this disease among men was higher than that of women. Dynamic changes were presented between different years and seasons:CV-A16 was more popular in 2009,and enterovirus that none EV-A71 and none CV-A16 were predominant strains in 2013 and 2015.Especially in 2015,the proportion of other EV ranged as high as 71.97%.Besides,EV-A71 was the absolute predominance pathogen within death cases and was important pathogen in severe cases. This study suggests that HFMD epidemiology and laboratory monitoring in Guangdong Province should be strengthened, and provides scientific data support for further improvement of HFMD prevention and control strategies in Guangdong Province.

Immunogenic cell death (ICD) occurs when apoptotic tumor cell elicits a specific immune response, which may trigger an anti-tumor effect, via the release of immunostimulatory damage-associated molecular patterns (DAMPs). Hypothesizing that nanomedicines may impact ICD due to their proven advantages in delivery of chemotherapeutics, we encapsulated oxaliplatin (OXA) or gemcitabine (GEM), an ICD and a non-ICD inducer respectively, into the amphiphilic diblock copolymer nanoparticles. Neither GEM nor nanoparticle-encapsulated GEM (NP-GEM) induced ICD, while both OXA and nanoparticle-encapsulated OXA (NP-OXA) induced ICD. Interestingly, NP-OXA treated tumor cells released more DAMPs and induced stronger immune responses of dendritic cells and T lymphocytes than OXA treatment in vitro. Furthermore, OXA and NP-OXA exhibited stronger therapeutic effects in immunocompetent mice than in immunodeficient mice, and the enhancement of therapeutic efficacy was significantly higher in the NP-OXA group than the OXA group. Moreover, NP-OXA treatment induced a higher proportion of tumor infiltrating activated cytotoxic T-lymphocytes than OXA treatment. This general trend of enhanced ICD by nanoparticle delivery was corroborated in evaluating another pair of ICD inducer and non-ICD inducer, doxorubicin and 5-fluorouracil. In conclusion, although nanoparticle encapsulation did not endow a non-ICD inducer with ICD-mediated anti-tumor capacity, treatment with a nanoparticle-encapsulated ICD inducer led to significantly enhanced ICD and consequently improved anti-tumor effects than the free ICD inducer. The proposed nanomedicine approach may impact cancer immunotherapy via the novel cell death mechanism of ICD., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

We analyzed the genetic characteristics of coxsackievirus A4 (CV-A4) based on the entire VP1 coding region. Samples were isolated from patients with acute flaccid paralysis (AFP) in Shaanxi, China from 2006 to 2010. We wished to ascertain the predominant genotype and the relationship between CV-A4 infection and AFP. Sixty-eight non-polio enteroviruses were inoculated onto RD cells (to increase the virus titer) and molecular typing was undertaken. The entire VP1 coding region was amplified. Percentage of CV-A4 was 10.3% (7/68). Analyses of genetic identify and creation of phylogenetic trees revealed that CV-A4 could be classified into A, B and C genotypes. Seven CV-A4 strains from Shaanxi and other CV-A4 strains from China formed an independent evolution lineage located in group 4 and belonged to the C2 sub-genotype. These data suggested that CV-A4 strains of sub-genotype C2 were the predominant genotypes in China. These strains co-evolved and co-circulated with those from other provinces in China, so continued monitoring of CV-A4 (by clinical and genetic surveillance) should be enhanced.

We wished to understand the genetic characteristics of enteric cytopathic human orphan (ECHO) virus type 6 (ECHO6) circulating in China. First, the partial VP1 coding region of six strains of the ECH-O6 virus isolated from cases of hand, foot and mouth diseases during routine surveillance in Hunan Province (China) from 2009 to 2014 were sequenced. Those sequences were analyzed along with 138 sequences of ECHO viruses covering five provinces of China and countries outside China retrieved from the GenBank database. A phylogenetic tree based on partial VPI was constructed, and it indicated that Chinese strains of the ECHO virus could form two distinct evolutionary branches: branch 1 and branch 2. All isolates of the ECHO virus from Hunan Province belonged to the 2c subranch, which revealed that they may share a common evolutionary origin. ECHO strains in branch 2 may be the predominant strains in China due to their wide geographic distribution and long period of circulation. We used nucleotide differences of >30%o as the basis of cluster division. ECHO, viruses could be divided into four clusters (A-D). Cluster D could be divided further into ten subclusters on the basis of nucleotide differences of 15%-30%. All ECHO6 isolates from Hunan Province belonged to the D7 subcluster. These data showed that the ECHO6 strains that circulated in Hunan Province in 2009-2014 were closely related to each other, and probably shared a common evolutionary origin. In addition, at least four distinct lineages of ECHO viruses have circulated in China.