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Huile G.,Fudan University | Huile G.,Key Laboratory of Smart Drug Delivery | Shuaiqi P.,Fudan University | Shuaiqi P.,Key Laboratory of Smart Drug Delivery | And 14 more authors.

Targeted drug delivery to selected brain cell types is a crucial step in enhancing therapeutic effects while limiting side effects in non-target cells. Here we report on the development and evaluation of a new cascade targeting delivery system that employs PEG-PCL nanoparticles modified with both an angiopep-2 peptide and a EGFP-EGF1 protein for precise targeting of brain neuroglial cells. Angiopep-2 penetrates the blood-brain barrier and EGFP-EGF1 binds neuroglial cells, providing the system with two stages of targeting. In vitro studies demonstrated that both bEnd.3 cells and neuroglial cells had a higher uptake of angiopep-2 and EGFP-EGF1 conjugated nanoparticles (AENP) as compared to unmodified nanoparticles. Ex vivo imaging showed that AENP had higher accumulation in the brain over unmodified nanoparticles and EGFP-EGF1 modified nanoparticles. Fluorescent in situ hybridization of brain slides demonstrated that AENP co-localized with neuroglial cells. Transmission electron microscopy further showed that AENP could target and enter neuroglial cells. This newly developed cascade targeting delivery system that precisely targets neuroglial cells has great potential in the diagnosis and treatment of neuroglial related diseases. Replacing EGFP-EGF1 and angiopep-2 with other ligands may extend the utility of the system to diagnose and treat organ diseases beyond brain. © 2011 Elsevier Ltd. Source

Ruan X.-L.,Huazhong University of Science and Technology | Ruan X.-L.,Targeted Biotherapy Key Laboratory of Ministry of Education | Li S.,Hubei University | Zeng X.-T.,Hubei University of Medicine | And 4 more authors.
Chinese Medical Journal

Background Many studies indicated the human cytochrome P450 2D6 (CYP2D6) gene polymorphism was associated with acute leukemia (AL) susceptibility, however, the results were inconsistent. So we performed this meta-analysis to evaluate the relationship between CYP2D6*3 or CYP2D6*4 polymorphism and AL susceptibility. Methods We searched PubMed database up to February 20, 2013, and finally yielded 9 case-control studies including 1343 cases and 1843 controls which tested the association between CYP2D6*3 or *4 polymorphism and AL. After data extraction, we conducted a meta-analysis using the Comprehensive Meta Analysis software. Results Overall, no significant association between CYP2D6*3 or *4 polymorphism and AL risk was found in this meta-analysis (+ vs. -: OR=1.13, 95% CI=0.79-1.63; +/+ vs. -/-: OR=1.73, 95% CI=0.99-3.02; -/+ vs. -/-: OR=1.03, 95% CI=0.68-1.56; (-/+ and +/+) vs. -/-: OR=1.08, 95% CI=0.72-1.63; +/+ vs. (-/+ and -/-): OR=1.76, 95% CI=0.98-3.17). Similar results were also been found in stratified subgroup analysis. There was no publication bias. Conclusion CYP2D6*3 or *4 polymorphism might not be associated with AL susceptibility. However, the results need to be further confirmed by well-designed and high quality randomized controlled trials with larger sample sizes. Source

Ming Z.,Blood Research Institute | Ming Z.,Huazhong University of Science and Technology | Hu Y.,Huazhong University of Science and Technology | Hu Y.,Targeted Biotherapy Key Laboratory of Ministry of Education | And 6 more authors.

Inhibition of platelet responsiveness is important to control pathologic thrombus formation. Platelet-endothelial cell adhesion molecule-1 (PECAM-1) and the Src family kinase Lyn inhibit platelet activation by the glycoprotein VI (GPVI) collagen receptor; however, it is not known whether PECAM-1 and Lyn function in the same or different inhibitory pathways. In these studies, we found that, relative to wild-type platelets, platelets derived from PECAM-1-deficient, Lyn-deficient, or PECAM-1/Lyn double-deficient mice were equally hyperresponsive to stimulation with a GPVI-specific agonist, indicating that PECAM-1 and Lyn participate in the same inhibitory pathway. Lyn was required for PECAM-1 tyrosine phosphorylation and subsequent binding of the Src homology 2 domain-containing phosphatase-2, SHP-2. These results support a model in which PECAM-1/SHP-2 complexes, formed in a Lyn-dependent manner, suppress GPVI signaling. © 2011 by The American Society of Hematology. Source

Mei H.,Huazhong University of Science and Technology | Mei H.,Targeted Biotherapy Key Laboratory of Ministry of Education | Shi W.,Huazhong University of Science and Technology | Shi W.,Targeted Biotherapy Key Laboratory of Ministry of Education | And 11 more authors.

In a strategy for anti-thrombotic therapy, we have expressed EGFP-EGF1 fusion protein, in which EGF1 can bind with tissue factor (TF). EGFP has previously been widely used as a fluorescent protein marker. EGFP-EGF1 protein was thiolated and conjugated to the malemide covering on the pegylated nanoparticles (NP) to form the EGFP-EGF1-NP. The EGFP-EGF1-NP was characterized in terms of morphology, size and zeta potential. In vitro cell viability experiment confirmed that the biodegradable EGFP-EGF1-NP was safe. To evaluate the delivering ability of EGFP-EGF1-NP, a fluorochrome dye, Dir, was incorporated into the nanoparticle, and the loading capacity and release property of the particle were examined. In vitro results showed that the binding ability of EGFP-EGF1-NP with TF-expressing cells was significantly stronger than that of non-conjugated NP. In vivo multispectral fluorescent imaging demonstrated that EGFP-EGF1-NP had high specificity and sensitivity in targeting thrombi. Our study demonstrated that EGFP-EGF1-NP is a promising TF-targeting drug delivery system for thrombolytic treatment. © 2010 Elsevier Ltd. Source

Tang L.,Huazhong University of Science and Technology | Tang L.,Targeted Biotherapy Key Laboratory of Ministry of Education | Jian X.-R.,Huazhong University of Science and Technology | Jian X.-R.,Targeted Biotherapy Key Laboratory of Ministry of Education | And 11 more authors.
American Journal of Hematology

Protein S (ProS) is a physiological inhibitor of coagulation with an important function in the down-regulation of thrombin generation. ProS deficiency is a major risk factor for venous thrombosis. This study enrolled 40 ProS-deficient probands to investigate the molecular basis of hereditary ProS deficiency in Chinese patients. A mutation analysis was performed by resequencing the PROS1 gene. Large deletions were identified by multiplex ligation-dependent probe amplification (MLPA) analysis. A total of 20 different mutations, including 15 novel mutations, were identified in 21 of the 40 index probands. Small mutations were detected in 18 (45.0%) probands, and large deletions were found in 3 (7.5%) probands, leaving 19 (47.5%) patients without causative variants. To evaluate the functional consequences of 2 novel missense variants, ex vivo thrombin-generation assays, bioinformatics tools, and in vitro expression studies were employed. The p.Asn365Lys ProS variant was found to have moderately impaired secretion and reduced activated protein C cofactor activity. In contrast, the p.Pro410His mutant appeared to have severely impaired secretion but full anticoagulant activity. This study is the largest investigation of ProS deficiency in China and the first investigation of the influence of Type I ProS missense mutations on the global level of coagulation function. The p.K196E mutation, which is common in the neighboring Japanese population, was not found in our Chinese population, and null mutations were common in our Chinese population but not common in Japan. Further genetic analysis is warranted to understand the causes of ProS deficiency in patients without a genetic explanation. Am. J. Hematol. 88:899-905, 2013. © 2013 Wiley Periodicals, Inc. Source

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