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Zhang B.C.,Wuhan General Hospital of Guangzhou Command | Gao J.,Wuhan General Hospital of Guangzhou Command | Wang J.,General Hospital of Jinan Command | Rao Z.G.,Wuhan General Hospital of Guangzhou Command | And 2 more authors.
Medical Oncology | Year: 2011

Tumor-associated macrophages (TAMs) have been implicated in promoting tumor progression. Nowadays, adenocarcinoma has surpassed squamous cell carcinoma as the most frequent type of lung cancer, but in lung adenocarcinoma, the correlation of TAMs with lymphangiogenesis patients remains unclear. The aim of this study was to examine the relationship between TAMs and lymphangiogenesis and the lung adenocarcinoma patients' prognosis. Tumor specimens from 65 patients with lung adenocarcinoma were determined for TAMs count and lymphatic microvessel density (LMVD) by immunohistochemistry. A positive correlation existed between TAMs count and D2-40-positive peritumoral LMVD (r = 0.069, P < 0.001). TAMs infiltration was significantly associated with P-TNM staging (P = 0.042) and lymph node metastasis (P = 0.037), and peritumoral LMVD was correlated with lymph node metastasis (P = 0.003). A significant difference in overall survival was detected not only between tumors with a high TAMs count and a low TAMs count (P = 0.009) but also between tumors with a high peritumoral LMVD and a low peritumoral LMVD (P = 0.005). Both TAMs count and peritumoral LMVD were independent prognostic factors for overall survival. Our results indicate that TAMs infiltration correlates with tumor lymphangiogenesis and poor survival in lung adenocarcinoma. © 2010 Springer Science+Business Media, LLC.


Sheng S.,Liaoning Medical University | Kong F.,General Hospital of jiNan Command
Pharmaceutical Biology | Year: 2012

Context: Affinity chromatography is an efficient antibody, antigen and protein separation method based on the interaction between specific immobilized ligands and target antibody, antigen, and so on. Populations of available ligands can be used to separate antibodies or their Fab fragments. Similarly, antigens can be isolated by immunoaffinity chromatography (IAC) on immobilized antibodies of low affinity. Objective: This review describes the advantages, the applications, as well as the drawbacks, of IAC in the separation and purification of antibodies and antigens. Methods: The present review discussed all types of purification and isolation of antibodies and antigens by IAC, including purification of antibodies using immobilized and synthetic mimic proteins A, G and L; isolation of Fab fragments of antibodies; separation of antibodies against different antigen forms; isolation of antigens by immobilized antibodies and so on. These methods come from over 60 references compiled from all major databases. Results: Purification of antigens with antibodies should choose low-affinity antibodies to avoid denaturation of most proteins. Concern for cost and safety, prompted research activities focused on novel synthetic ligands with improved properties such as lower cost, avoidance of the risk of contamination associated with natural ligands of human or animal origin to isolate antibodies and antigens. Conclusion: It is anticipated that the improvements of IAC will have impact not only on large-scale production of antibodies but also on the generation of new affinity-based methods for the increasing number of proteins and antibody derivatives available by protein engineering and the proteomics revolution. © 2012 Informa Healthcare USA, Inc.


Wang W.,General Hospital of Jinan Command | Zhou F.,General Hospital of Jinan Command | Ge L.,General Hospital of Jinan Command | Liu X.,General Hospital of Jinan Command | Kong F.,General Hospital of Jinan Command
International Journal of Nanomedicine | Year: 2012

Background: The main barriers to non-viral gene delivery include cellular and nuclear membranes. As such, the aim of this study was to develop a type of vector that can target cells through receptor-mediated pathways and by using nuclear localization signal (NLS) to increase the nuclear uptake of genetic materials. Methods: A dexamethasone (Dexa)-conjugated lipid was synthesized as the material of the solid lipid nanoparticles (SLNs), and transferrin (Tf) was linked onto polyethylene glycolphosphatidylethanolamine (PEG-PE) to obtain Tf-PEG-PE ligands for the surface modification of the carriers. The in vitro transfection efficiency of the novel modified vectors was evaluated in human hepatoma carcinoma cell lines, and in vivo effects were observed in an animal model. Results: Tf-PEG-PE modified SLNs/enhanced green fluorescence protein plasmid (pEGFP) had a particle size of 222 nm and a gene loading quantity of 90%. Tf-PEG-PE-modified SLNs/ pEGFP (Tf-SLNs/pEGFP) displayed remarkably higher transfection efficiency than non-modified SLNs/pEGFP and the vectors not containing Dexa, both in vitro and in vivo. Conclusion: It can be concluded that Tf and Dexa could function as an excellent active targeting ligand to improve the cell targeting and nuclear targeting ability of the carriers, and the resulting nanomedicine could be a promising active targeting drug/gene delivery system. © 2012 Zeng et al, publisher and licensee Dove Medical Press Ltd.


Jiang Z.,General Hospital of Jinan Command | Sun C.,General Hospital of Jinan Command | Yin Z.,General Hospital of Jinan Command | Zhou F.,General Hospital of Jinan Command | And 3 more authors.
International Journal of Nanomedicine | Year: 2012

Background: The applications of ligand-polyethylene glycol (PEG)-modified nanocarriers have now emerged, as well as recognized strategies to provide the vectors with active targeting properties. In this research, premodification and postmodification were compared using the same ligand, ie, a novel conjugated mannan-containing PEG and L-α-phosphatidylethanolamine (PE). Methods: Premodified and postmodified solid lipid nanoparticles were prepared and the characteristics of the two kinds of vehicles were evaluated. The modified vectors were then administered intravenously to rats and the in vivo targeting behavior of the complexes was investigated in liver macrophages. Results: By carefully formulating the carriers with an optimal ratio of mannan-containing PEG-PE, postmodified vehicles displayed more efficient gene expression in rat Kupffer cells both in vitro and in vivo. Conclusion: Postmodified gene carriers are superior to premodified gene vectors, although the latter is also promising for targeted gene delivery. This discovery could guide our future research. © 2012 Jiang et al, publisher and licensee Dove Medical Press Ltd.


Wu G.,Shandong Provincial Crops Hospital | Zhou F.,General Hospital of Jinan Command | Ge L.,General Hospital of Jinan Command | Liu X.,General Hospital of Jinan Command | Kong F.,General Hospital of Jinan Command
Journal of Nanomaterials | Year: 2012

Purpose. Biodegradable polymeric nanoparticles have been used frequently as gene delivery vehicles. The aim of this study is to modify bioadhesive PLGA nanoparticles with novel synthetic mannan-PEG-PE (MN-PEG-PE) to obtain active targeted gene delivery system. Methods. Mannan-PEG-PE ligands were synthesized and modified onto the NPs/pEGFP complexes. The modification rate was optimized, and the characteristics of the vehicle were evaluated. Then, the modified vectors were intravenous delivered to rats, and in vivo targeting behavior of MN-PEG-PE modified PLGA nanoparticles/pEGFP complexes (MN-PEG-PE-NPs/pEGFP) in liver macrophages was investigated. Results. MN-PEG-PE-NPs/pEGFP displayed remarkably higher transfection efficiencies than nonmodified NPs/pEGFP both in vitro and in vivo. Conclusions. Mannan containing targeting ligands could significantly improve the transfection efficiency of the carriers. MN-PEG-PE modified vectors very useful in targeted gene delivery. Copyright © 2012 Guicun Wu et al.


Wang W.,Integrated Traditional Chinese Medicine and Western Medicine | Zhou F.,General Hospital of jiNan Command | Ge L.,General Hospital of jiNan Command | Liu X.,General Hospital of jiNan Command | Kong F.,General Hospital of jiNan Command
Pharmaceutical Biology | Year: 2014

Context: Non-viral gene delivery could deliver drugs/genes through cellular membranes and nuclear membranes by some modification of materials. Objective: This study develops a kind of vector to target the cells through receptor-mediated pathways. Nuclear localization signal (NLS) was also used to increase the nuclear uptake of genetic materials. Materials and methods: A lipid containing dexamethasone (Dexa) was synthesized as the material of the preparation of solid lipid nanoparticles (SLNs) and folate (Fa)-conjugated PEG-PE (Fa-PEG-PE) ligands were used to modify the SLNs. The in vitro cytotoxicity of the carriers at various concentrations (10, 20, 50, 100, and 200μg/ml) were evaluated in KB human carcinoma cells (KB cells). In vivo transfection efficiency of the novel modified vectors was evaluated in disseminated peritoneal tumors on mice bearing KB cells. Results: Fa-PEG-PE modified SLNs/enhanced green fluorescence protein plasmid (pEGFP) has a particle size of 258nm, and the gene loading quantity of the vector was 90%. The in vitro cytotoxicity of Fa-PEG-PE-modified SLNs/pEGFP (Fa-SLNs/pEGFP) was low (cell viabilities were between 80% and 100% compared with controls). Fa-SLNs/pEGFP displayed remarkably higher transfection efficiency (40%) than non-modified SLNs/pEGFP (24%) and the vectors not containing Dexa (30%) in vivo. Conclusion: The results demonstrate that Fa and Dexa could function as excellent active targeting ligands to improve the cell targeting and nuclear targeting ability of the carriers and the resulting vectors could be promising active targeting drug/gene delivery systems. © 2014 Informa Healthcare USA, Inc.


Zhou F.,General Hospital of jiNan Command | Kong F.,General Hospital of jiNan Command | Ge L.,General Hospital of jiNan Command | Liu X.,General Hospital of jiNan Command | Huang N.,General Hospital of jiNan Command
International Journal of Photoenergy | Year: 2012

The studies of targeted gene delivery nanocarriers have gained increasing attention during the past decades. In this study, mannan modified DNA loaded bioadhesive PLGA nanoparticles (MAN-DNA-NPs) were investigated for targeted gene delivery to the Kupffer cells (KCs). Bioadhesive PLGA nanoparticles were prepared and subsequently bound with pEGFP. Following the coupling of the mannan-based PE-grafted ligands (MAN-PE) with the DNA-NPs, the MAN-DNA-NPs were delivered intravenously to rats. The transfection efficiency was determined from the isolated KCs and flow cytometry was applied for the quantitation of gene expression after 48h post transfection. The size of the MAN-DNA-NPs was found to be around 190nm and the Zeta potential was determined to be 15.46mV. The pEGFP binding capacity of MAN-DNA-NPs was (88.9±5.8)% and the in vitro release profiles of the MAN-DNA-NPs follow the Higuchi model. When compared with non-modified DNA-NPs and Lipofectamine 2000-DNA, MAN-DNA-NPs produced the highest gene expressions, especially in vivo. The in vivo data from flow cytometry analysis showed that MAN-DNA-NPs displayed a remarkably higher transfection efficiency (39%) than non-modified DNA-NPs (25%) and Lipofectamine 2000-DNA (23%) in KCs. The results illustrate that MAN-DNA-NPs have the ability to target liver KCs and could function as promising active targeting drug delivery vectors.


PubMed | General Hospital of Jinan Command, Jinan Infectious Disease Hospital and Shandong University
Type: | Journal: International journal of nanomedicine | Year: 2014

Nanostructured lipid carriers (NLC), composed of solid and liquid lipids, and surfactants are potentially good colloidal drug carriers. The aim of this study was to develop surface-modified NLC as multifunctional nanomedicine for codelivery of enhanced green fluorescence protein plasmid (pEGFP) and doxorubicin (DOX).TWO DIFFERENT NANOCARRIERS: pEGFP- and DOX-loaded NLC, and solid lipid nanoparticles (SLN) were prepared. Transferrin-containing ligands were used for the surface coating of the vectors. Their average size, zeta potential, and drug encapsulation capacity were evaluated. In vitro transfection efficiency of the modified vectors was evaluated in human alveolar adenocarcinoma cell line (A549 cells), and in vivo transfection efficiency of the modified vectors was evaluated in a mouse bearing A549 cells model.Transferrin-modified DOX and pEGFP coencapsulated NLC (T-NLC) has a particle size of 198 nm and a +19 mV surface charge. The in vitro cell viabilities of the T-NLC formulations were over 80% compared with the control. T-NLC displayed remarkably greater gene transfection efficiency and enhanced antitumor activity than DOX- and pEGFP-coencapsulated SLN in vivo.The results demonstrate that T-NLC noticeably enhanced antitumor activity through the combination of gene therapy with chemotherapy. Also coating of active transferrin improved the lung cancer cell-targeting of the carriers. In summary, the novel gene and drug delivery system offers a promising strategy for the treatment of lung cancer.


PubMed | General Hospital of Jinan Command and Jinan Infectious Disease Hospital
Type: Journal Article | Journal: Pharmaceutical development and technology | Year: 2016

Nanostructured lipid carriers (NLC) are potentially good colloidal drug carriers for gene delivery. They are advised to be the second lifetime of lipid nanocarriers.The aim of this study is to develop novel modified NLC as nanomedicine for delivery of plasmid-containing enhanced green fluorescence protein (pEGFP). This system could target the lung cancer cells through receptor-mediated pathways to increase the nuclear uptake of genetic materials.In the present study, pEGFP-loaded NLC (NLC/pEGFP) were prepared. Transferrin (Tf) containing ligands were used for the surface coating of the vectors. In vitro transfection efficiency of the modified vectors was evaluated in human alveolar adenocarcinoma cell line (A549 cells) and in vivo transfection efficiency of the modified vectors was evaluated on mice bearing A549 cells model.Tf-modified NLC/pEGFP (Tf-NLC/pEGFP) has a particle size of 157 nm, and 82% of gene loading quantity. Tf-NLC/pEGFP displayed remarkably higher transfection efficiency than non-modified NLC/pEGFP both in vitro and in vivo.The results demonstrate that the novel NLC gene delivery system offers an effective strategy for lung cancer gene therapy.


PubMed | The Fourth Peoples Hospital of Jinan, General Hospital of Jinan Command and Chinese People's Liberation Army
Type: | Journal: International journal of nanomedicine | Year: 2015

Combination anticancer therapy is promising to generate synergistic anticancer effects to maximize the treatment effect and overcome multidrug resistance. The aim of the study reported here was to develop multifunctional, dual-ligand, modified, self-assembled nanoparticles (NPs) for the combination delivery of baicalein (BCL) and paclitaxel (PTX) prodrugs.Prodrug of PTX and prodrug of BCL, containing dual-targeted ligands of folate (FA) and hyaluronic acid (HA), were synthesized. Multifunctional self-assembled NPs for combination delivery of PTX prodrug and BCL prodrug (PTX-BCL) were prepared and the synergistic antitumor effect was evaluated in vitro and in vivo. The in vitro transfection efficiency of the novel modified vectors was evaluated in human lung cancer A549 cells and drug-resistant lung cancer A549/PTX cells. The in vivo antitumor efficiency and systemic toxicity of different formulations were further investigated in mice bearing A549/PTX drug-resistant human lung cancer xenografts.The size of the PTX-BCL NPs was approximately 90 nm, with a positive zeta potential of +3.3. The PTX-BCL NPs displayed remarkably better antitumor activity over a wide range of drug concentrations, and showed an obvious synergism effect with CI50 values of 0.707 and 0.513, indicating that double-ligand modification and the co-delivery of PTX and BCL prodrugs with self-assembled NPs had remarkable superiority over other formulations.The prepared PTX-BCL NP drug-delivery system was proven efficient by its targeting of drug-resistant human lung cancer cells and delivering of BCL and PTX prodrugs. Enhanced synergistic anticancer effects were achieved by PTX-BCL NPs, and multidrug resistance of PTX was overcome by this promising targeted nanomedicine.

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