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Featured researches published by Jinning Lou.


Journal of Controlled Release | 2010

Dual-targeting daunorubicin liposomes improve the therapeutic efficacy of brain glioma in animals

Xue Ying; He Wen; Wan-Liang Lu; Ju Du; Jia Guo; Wei Tian; Ying Men; Yan Zhang; Ruo-Jing Li; Ting-Yuan Yang; De-Wei Shang; Jinning Lou; Liang-Ren Zhang; Qiang Zhang

Chemotherapy for brain glioma has been of limited value due to the inability of transport of drug across the blood-brain barrier (BBB) and poor penetration of drug into the tumor. For overcoming these hurdles, the dual-targeting daunorubicin liposomes were developed by conjugating with p-aminophenyl-alpha-D-manno-pyranoside (MAN) and transferrin (TF) for transporting drug across the BBB and then targeting brain glioma. The dual-targeting effects were evaluated on the BBB model in vitro, C6 glioma cells in vitro, avascular C6 glioma tumor spheroids in vitro, and C6 glioma-bearing rats in vivo, respectively. After applying dual-targeting daunorubicin liposomes, the transport ratio across the BBB model was significantly increased up to 24.9%. The most significant uptake by C6 glioma was evidenced by flow cytometry and confocal microscope. The C6 glioma spheroid volume ratio was significantly lowered to 54.7%. The inhibitory rate to C6 glioma cells after crossing the BBB was significantly enhanced up to 64.0%. The median survival time of tumor bearing rats after administering dual-targeting daunorubicin liposomes (22 days) was significantly longer than that after giving free daunorubicin (17 days, P=0.001) or other controls. In conclusion, the dual-targeting daunorubicin liposomes are able to improve the therapeutic efficacy of brain glioma in vitro and in animals.


Biomaterials | 2009

Gene delivery targeted to the brain using an Angiopep-conjugated polyethyleneglycol-modified polyamidoamine dendrimer

Weilun Ke; Kun Shao; Rongqin Huang; Liang Han; Yang Liu; Jianfeng Li; Yuyang Kuang; Liya Ye; Jinning Lou; Chen Jiang

Angiopep targeting to the low-density lipoprotein receptor-related protein-1 (LRP1) was identified to exhibit high transcytosis capacity and parenchymal accumulation. In this study, it was exploited as a ligand for effective brain-targeting gene delivery. Polyamidoamine dendrimers (PAMAM) were modified with angiopep through bifunctional PEG, then complexed with DNA, yielding PAMAM-PEG-Angiopep/DNA nanoparticles (NPs). The angiopep-modified NPs were observed to be internalized by brain capillary endothelial cells (BCECs) through a clathrin- and caveolae-mediated energy-depending endocytosis, also partly through marcopinocytosis. Also, the cellular uptake of the angiopep-modified NPs were competed by angiopep-2, receptor-associated protein (RAP) and lactoferrin, indicating that LRP1-mediated endocytosis may be the main mechanism of cellular internalization of angiopep-modified NPs. And the angiopep-modified NPs showed higher efficiency in crossing blood-brain barrier (BBB) than unmodified NPs in an in vitro BBB model, and accumulated in brain more in vivo. The angiopep-modified NPs also showed higher efficiency in gene expressing in brain than the unmodified NPs. In conclusion, PAMAM-PEG-Angiopep showed great potential to be applied in designing brain-targeting drug delivery system.


Biomaterials | 2012

A dual-targeting nanocarrier based on poly(amidoamine) dendrimers conjugated with transferrin and tamoxifen for treating brain gliomas

Yan Li; Hai He; Xinru Jia; Wan-Liang Lu; Jinning Lou; Yen Wei

A pH-sensitive dual-targeting drug carrier (G4-DOX-PEG-Tf-TAM) was synthesized with transferrin (Tf) conjugated on the exterior and Tamoxifen (TAM) in the interior of the fourth generation PAMAM dendrimers for enhancing the blood-brain barrier (BBB) transportation and improving the drug accumulation in the glioma cells. It was found that, on average, 7 doxorubicine (DOX) molecules, over 30 PEG(1000) and PEG(2000) chains and one Tf group were bonded on the periphery of each G4 PAMAM dendrimer, while 29 TAM molecules were encapsulated into the interior of per dendrimer. The pH-triggered DOX release was 32% at pH 4.5 and 6% at pH 7.4, indicating a comparatively fast drug release at weak acidic condition and stable state of the carrier at physiological environment. The in vitro assay of the drug transport across the BBB model showed that G4-DOX-PEG-Tf-TAM exhibited higher BBB transportation ability with the transporting ratio of 6.06% in 3 h. The carrier was internalized into C6 glioma cells upon crossing the BBB model by the coactions of TfR-mediated endocytosis and the inhibition effect of TAM to the drug efflux transports. Moreover, it also displayed the in vitro accumulation of DOX in the avascular C6 glioma spheroids made the tumor volume effectively reduced.


Biomaterials | 2009

Brain-targeting gene delivery and cellular internalization mechanisms for modified rabies virus glycoprotein RVG29 nanoparticles

Yang Liu; Rongqin Huang; Liang Han; Weilun Ke; Kun Shao; Liya Ye; Jinning Lou; Chen Jiang

A 29 amino-acid peptide derived from the rabies virus glycoprotein (RVG29) was exploited as a ligand for efficient brain-targeting gene delivery. RVG29 was modified on polyamidoamine dendrimers (PAMAM) through bifunctional PEG, then complexed with DNA, yielding PAMAM-PEG-RVG29/DNA nanoparticles (NPs). The NPs were observed to be uptaken by brain capillary endothelial cells (BCECs) through a clathrin and caveolae mediated energy-depending endocytosis. The specific cellular uptake can be inhibited by free RVG29 and GABA but not by nicotinic acetylcholine receptor (nAchR) agonists/antagonists, indicating RVG29 probably relates to the GABA(B) receptor besides nAchR reported previously. PAMAM-PEG-RVG29/DNA NPs showed higher blood-brain barrier (BBB)-crossing efficiency than PAMAM/DNA NPs in an in vitro BBB model. In vivo imaging showed that the NPs were preferably accumulated in brain. The report gene expression of the PAMAM-PEG-RVG29/DNA NPs was observed in brain, and significantly higher than unmodified NPs. Thus, PAMAM-PEG-RVG29 provides a safe and noninvasive approach for the gene delivery across the BBB.


Biomaterials | 2011

PEGylated Poly(amidoamine) dendrimer-based dual-targeting carrier for treating brain tumors

Hai He; Yan Li; Xinru Jia; Ju Du; Xue Ying; Wan-Liang Lu; Jinning Lou; Yan Wei

A dual-targeting drug carrier (PAMAM-PEG-WGA-Tf) based on the PEGylated fourth generation (G = 4.0) PAMAM dendrimer with transferrin (Tf) and wheat germ agglutinin (WGA) on the periphery and doxorubicin (DOX) loaded in the interior was synthesized and its BBB penetration and tumor targeting properties were explored. DLS and TEM measurements revealed the size of PAMAM-PEG-WGA-Tf was in the range of 14-20 nm. It reduced the cytotoxicity of DOX to the normal cells greatly, while efficiently inhibited the growth rate of the C6 glioma cells. The assay of transport across the BBB showed that PAMAM-PEG-WGA-Tf delivered 13.5% of DOX in a period of 2 h, demonstrating an enhanced transport ratio as compared to the ratio of 8% for PAMAM-PEG-WGA, 7% for PAMAM-PEG-Tf and 5% for free DOX in the same period of time. The accumulation of DOX in the tumor site was increased due to the targeting effects of both Tf and WGA, leading to the complete breakage of the avascular C6 glioma spheroids in vitro.


Journal of Controlled Release | 2010

Angiopep-2 modified PE-PEG based polymeric micelles for amphotericin B delivery targeted to the brain.

Kun Shao; Rongqin Huang; Jianfeng Li; Liang Han; Liya Ye; Jinning Lou; Chen Jiang

Amphotericin B (AmB) is a poorly water soluble antibiotic and is used to treat fungal infections of the central nervous system (CNS). However, AmB shows poor penetration into the CNS. Angiopep-2, the ligand of low-density lipoprotein receptor-related protein (LRP) present on the BBB, exhibits higher transcytosis capacity and parenchymal accumulation, which allowed us to consider the selectivity of it for receptor-mediated drug targeting to the brain. With this in mind, we prepared angiopep-2 modified PE-PEG based micellar drug delivery system loaded with the antifungal drug AmB to evaluate the efficiency of AmB accumulating into the brain. PE-PEG based micelles as nano-scaled drug carriers were investigated by incorporating AmB with high drug entrapping efficiency, improving solubilization of AmB and reducing its toxicity to mammalian cells. The AmB-incorporated angiopep-2 modified micelles showed highest efficiency in penetrating across the blood-brain barrier (BBB) than unmodified micelles and Fungizone (deoxycholate amphotericin B) in vitro and in vivo. Meanwhile, contrary to the free Rho 123, the enhancement of Rho 123-incorporated angiopep-2 modified micelles across the BBB can be explained by angiopep-2 modified polymeric micelles that have a potential to overcome the activity of efflux proteins expressed on the BBB such as P-glycoprotein. In conclusion, angiopep-2 modified polymeric micelles could be developed as a novel drug delivery system for brain targeting.


Biomaterials | 2010

A leptin derived 30-amino-acid peptide modified pegylated poly-L-lysine dendrigraft for brain targeted gene delivery.

Yang Liu; Jianfeng Li; Kun Shao; Rongqin Huang; Liya Ye; Jinning Lou; Chen Jiang

The blood-brain barrier is the major obstacle that prevents diagnostic and therapeutic drugs being delivered to the central nervous systems in order to exert their effects. Specific ligand-receptor binding mediated endocytosis is one of the possible strategies to cross this barrier. A 30-amino-acid peptide (leptin30) derived from an endogenic hormone-leptin is exploited as brain-targeting ligand as it is reported to possess the same brain accumulation efficiency after intravenous injection. Dendrigraft poly-L-lysine (DGL) is used as non-viral gene vector in this study. DGL-PEG-Leptin30 was complexed with plasmid DNA yielding nanoparticles (NPs). The cellular uptake characteristic and mechanism were explored in brain capillary endothelial cells (BCECs) which express leptin receptors. Furthermore, brain parenchyma microglia cells such as BV-2 cells expressing leptin receptors could promote ligand-receptor mediated endocytosis leading to enhanced gene transfection ability of DGL-PEG-Leptin30/DNA NPs. The targeted NPs were proved to be transported across in vitro BBB model effectively and accumulate more in brains after i.v. resulting in a relatively high gene transfection efficiency both in vitro and in vivo. Besides, the NPs showed low cytotoxicity after in vitro transfection. Thus, DGL-PEG-Leptin30 provides a safe and noninvasive approach for the delivery of gene across the blood-brain barrier.


Journal of Cerebral Blood Flow and Metabolism | 2009

Brain-targeting mechanisms of lactoferrin-modified DNA-loaded nanoparticles

Rongqin Huang; Weilun Ke; Liang Han; Yang Liu; Kun Shao; Liya Ye; Jinning Lou; Chen Jiang; Yuanying Pei

Ligand-mediated brain-targeting drug delivery is one of the focuses at present. Elucidation of exact targeting mechanisms serves to efficiently design these drug delivery systems. In our previous studies, lactoferrin (Lf) was successfully exploited as a brain-targeting ligand to modify cationic dendrimer-based nanoparticles (NPs). The mechanisms of Lf-modified NPs to the brain were systematically investigated in this study for the first time. The uptake of Lf-modified vectors and NPs by brain capillary endothelial cells (BCECs) was related to clathrin-dependent endocytosis, caveolae-mediated endocytosis, and macropinocytosis. The intracellular trafficking results showed that Lf-modified NPs could rapidly enter the acidic endolysosomal compartments within 5 mins and then partly escape within 30 mins. Both Lf-modified vectors and NPs showed higher blood–brain barrier-crossing efficiency than unmodified counterparts. All the results suggest that both receptor- and adsorptive-mediated mechanisms contribute to the cellular uptake of Lf-modified vectors and NPs. Enhanced brain-targeting delivery could be achieved through the synergistic effect of the macromolecular polymers and the ligand.


Biomaterials | 2015

Enhanced blood-brain barrier penetration and glioma therapy mediated by a new peptide modified gene delivery system.

Hui Yao; Kaiyuan Wang; Yi Wang; Shanshan Wang; Jianfeng Li; Jinning Lou; Liya Ye; Xueying Yan; Weiyue Lu; Rongqin Huang

Successful glioma gene therapy lays on two important factors, the therapeutic genes and efficient delivery vehicles to cross the blood-brain barrier (BBB) and reach gliomas. In this work, a new gene vector was constructed based on dendrigraft poly-l-lysines (DGL) and polyethyleneglycol (PEG), conjugated with a cell-penetrating peptide, the nucleolar translocation signal (NoLS) sequence of the LIM Kinase 2 (LIMK2) protein (LIMK2 NoLS peptide, LNP), yielding DGL-PEG-LNP. Plasmid DNA encoding inhibitor of growth 4 (ING4) was applied as the therapeutic gene. DGL-PEG-LNP/DNA nanoparticles (NPs) were monodispersed, with a mean diameter of 90.6 ± 8.9 nm. The conjugation of LNP significantly enhanced the BBB-crossing efficiency, cellular uptake and gene expression within tumor cells. Mechanism studies suggested the involvement of energy, caveolae-mediated endocytosis and macropinocytosis in cellular uptake of LNP-modified NPs. MTT results showed that no apparent cytotoxicity was observed when cells were treated with synthesized vectors. Furthermore, LNP-modified NPs mediated strongest and most intensive apoptosis on the tumor site, and the longest median survival time of glioma-bearing mice. All the results demonstrated that LNP is a kind of efficient CPPs especially for BBB-crossing application, and DGL-PEG-LNP/DNA is a potential non-viral platform for glioma gene therapy via intravenous administration.


European Journal of Pharmaceutical Sciences | 2010

Enhanced efficacy of functionalized epirubicin liposomes in treating brain glioma-bearing rats.

Wei Tian; Xue Ying; Ju Du; Jia Guo; Ying Men; Yan Zhang; Ruo-Jing Li; Hong-Juan Yao; Jinning Lou; Liang-Ren Zhang; Wan-Liang Lu

PURPOSE The restriction of drug transporting across the blood-brain barrier (BBB) and the limit of drug penetrating into the tumor tissue remain the major obstacles for brain tumor chemotherapy. In the present study, we developed a functionalized liposomal nanoconstruct, epirubicin liposomes modified with tamoxifen (TAM) and transferrin (TF), for transporting drug across the BBB and afterwards targeting the brain glioma. METHODS Evaluations were performed on the murine C6 glioma cells, the C6 glioma spheroids, the BBB model in vitro and the brain glioma-bearing rats. RESULTS When compared with controls, epirubicin liposomes modified with TAM and TF showed the strongest inhibitory effect to C6 glioma cells or glioma spheroids in vitro, significant transport ability across the BBB model in vitro, an evident effect of targeting the brain tumor cells in vitro, and an extended median survival time in the brain glioma-bearing rats. CONCLUSION Epirubicin liposomes modified with TAM and TF significantly improve the therapeutic efficacy of brain glioma in vitro and in animals, hence providing a new strategy for brain tumor chemotherapy.

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Liya Ye

China-Japan Friendship Hospital

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Yang Liu

Université Paris-Saclay

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