Chen Jiang

Fudan University, Shanghai, Shanghai Shi, China

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Publications (49)303.32 Total impact

  • Sai An · Dongsheng He · Ernst Wagner · Chen Jiang
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    ABSTRACT: Lipopolymer 49, a solid-phase synthesized T-shaped peptide-like oligoamide containing two central oleic acids, 20 aminoethane, and two terminal cysteine units, is identified as very potent and biocompatible small interfering RNA (siRNA) carrier for gene silencing in glioma cells. This carrier is combined with a novel targeting polymer 727, containing a precise sequence of Angiopep 2 targeting peptide, linked with 28 monomer units of ethylene glycol, 40 aminoethane, and two terminal cysteines in siRNA complex formation. Angiopep-polyethylene glycol (PEG)/siRNA polyplexes exhibit good nanoparticle features, effective glioma-targeting siRNA delivery, and intracellular siRNA release, resulting in an outstanding gene downregulation both in glioma cells and upon intravenous delivery in glioma model nude mice without significant biotoxicity. Therefore, this novel siRNA delivery system is expected to be a promising strategy for targeted and safe glioma therapy. © 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.
    Small 07/2015; DOI:10.1002/smll.201501167 · 8.37 Impact Factor
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    ABSTRACT: Existing limitations of common RNA interference (RNAi) oncotherapy severely compromised their therapeutic effects. In this study, a novel glioma-targeting RNAi system was developed. Single-component RNAi nanospheres were tactfully self-assembled in vitro, combining the carrier and cargo as a whole. An artificially synthesized polycation (pOEI) with redox-sensitive disulfides in structure condensed the RNAi nanospheres into more compacted nanoparticles. Then a novelly designed tumor-homing and penetrating cyclopeptide iNGR was further modified on the surface. iNGR modified RNAi nanoparticles demonstrated significantly enhanced accumulation in glioma site, remaining stable in circulation until the release of naked RNAi nanospheres were triggered off by the paranormal concentration of glutathione within glioma cells. Naked RNAi nanospheres were digested into abudant siRNA afterwards. Remarkable luciferase gene down-regulations have confirmed their outstanding RNAi effects. With specific design of sequences, the iNGR modified RNAi nanoparticles were supposed to be of great potential in safe and efficient glioma therapy in future. Copyright © 2015. Published by Elsevier Ltd.
    Biomaterials 06/2015; 53. DOI:10.1016/j.biomaterials.2015.02.084 · 8.31 Impact Factor
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    ABSTRACT: Encapsulation of small molecule drugs in hydrophobic polymers or amphiphilic copolymers have been extensively used for preparing polymeric nanoparticles (NPs). The loadings and loading efficiencies of a wide range of drugs in polymeric NPs, however, tend to be very low. In this communication, we report a strategy to prepare polymeric NPs with exceptionally high drug loading (> 50%) and quantitative loading efficiency. Specifically, a dimeric-drug conjugate bearing a trigger responsive domain was designed and used as the core-constructing unit of the NPs. Upon co-precipitation of the dimeric drug and methoxypoly(ethylene glycol)-b-polylactide (mPEG-PLA), NPs with dimeric drug core and polymer shell were formed. The high drug-loading NPs showed excellent stability in physiological conditions. No pre-matured drug or prodrug release was observed in PBS solution without triggering while drug was controlled released in its authentic form upon external triggering.
    Journal of the American Chemical Society 03/2015; 137(10). DOI:10.1021/ja513034e · 11.44 Impact Factor
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    ABSTRACT: In clinical therapy, the poor prognosis of hepatocellular carcinoma (HCC) is mainly attributed to the failure of chemotherapeutical agents to accumulate in tumor as well as their serious systemic toxicity. In this work, we developed actively tumor-targeting trilayer micelles with microenvironment-sensitive cross-links as a novel nanocarrier for HCC therapy. These micelles comprised biodegradable PEG-pLys-pPhe polymers, in which pLys could react with a disulfide-containing agent to form redox-responsive cross-links. In vitro drug release and pharmacokinetics studies showed that these cross-links were stable in physiological condition whereas cleaved once internalized into cells due to the high level of glutathione, resulting in facilitated intracellular doxorubicin release. In addition, dehydroascorbic acid (DHAA) was decorated on the surface of micelles for specific recognition of tumor cells via GLUT1, a member of glucose transporter family overexpressed on hepatocarcinoma cells. Moreover, DHAA exhibited a "one-way" continuous accumulation within tumor cells. Cellular uptake and in vivo imaging studies proved that these micelles had remarkable targeting property towards hepatocarcinoma cells and tumor. Enhanced anti-HCC efficacy of the micelles was also confirmed both in vitro and in vivo. Therefore, this micellar system may be a potential platform of chemotherapeutics delivery for HCC therapy.
    ACS Applied Materials & Interfaces 02/2015; 7(9). DOI:10.1021/am5091462 · 6.72 Impact Factor
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    ABSTRACT: A new linear-dendritic copolymer composed of poly(ethylene glycol) (PEG) and all-trans-retinoic acid (ATRA) was synthesized as the anticancer drug delivery platform (PEG-G3-RA8). It can self-assemble into core-shell micelles with a low critical micelle concentration (CMC) at 3.48 mg/L. Paclitaxel (PTX) was encapsulated into PEG-G3-RA8 to form PEG-G3-RA8/PTX micelles for breast cancer treatment. The optimized formulation had high drug loading efficacy (20% w/w of drug copolymer ratio), nanosized diameter (27.6 nm), and narrow distribution (PDI = 0.103). Compared with Taxol, PEG-G3-RA8/PTX remained highly stable in the serum-containing cell medium and exhibited 4-fold higher cellular uptake. Besides, near-infrared fluorescence (NIR) optical imaging results indicated that fluorescent probe loaded micelle had a preferential accumulation in breast tumors. Pharmacokinetics and biodistribution studies (10 mg/kg) showed the area under the plasma concentration-time curve (AUC0-∞) and mean residence time (MRT0-∞) for PEG-G3-RA8/PTX and Taxol were 12.006 ± 0.605 mg/L h, 2.264 ± 0.041 h and 15.966 ± 1.614 mg/L h, 1.726 ± 0.097 h, respectively. The tumor accumulation of PEG-G3-RA8/PTX group was 1.89-fold higher than that of Taxol group 24 h postinjection. With the advantages like efficient cellular uptake and preferential tumor accumulation, PEG-G3-RA8/PTX showed superior therapeutic efficacy on MCF-7 tumor bearing mice compared to Taxol.
    Bioconjugate Chemistry 02/2015; 26(3). DOI:10.1021/acs.bioconjchem.5b00030 · 4.82 Impact Factor
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    Ji-Qin Wu · Kun Shao · Chen Jiang · Li-Ping Zhu
    Antimicrobial Agents and Chemotherapy 02/2015; 59(2):1387. DOI:10.1128/AAC.04774-14 · 4.45 Impact Factor
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    ABSTRACT: Due to complication factors such as blood-brain barrier (BBB), integrating high efficiency of brain target ability with specific cargo releasing into one nanocarrier seems more important. A brain targeting nanoscale system is developed using dehydroascorbic acid (DHA) as targeting moiety. DHA has high affinity with GLUT1 on BBB. More importantly, the GLUT1 transportation of DHA represents a “one-way” accumulative priority from blood into brain. The artificial micelles are fabricated by a disulfide linkage, forming a bio-responsive inner barrier, which can maintain micelles highly stable in circulation and shield the leakage of entrapped drug before reaching the targeting cells. The designed micelles can cross BBB and be further internalized by brain cells. Once within the cells, the drug release can be triggered by high intracellular level of glutathione (GSH). Itraconazole (ITZ) is selected as the model drug because of its poor brain permeability and low stability in blood. It demonstrates that the functionalized nanoscale micelles can achieve highly effective direct drug delivery to targeting site. Based on the markedly increased stability in blood circulation and improved brain delivery efficiency of ITZ, DHA-modified micelles show highly effective in anti-intracranial infection. Therefore, this smart nanodevice shows a promising application for the treatment of brain diseases.
    Advanced Healthcare Materials 08/2014; 4(2). DOI:10.1002/adhm.201400214 · 4.88 Impact Factor
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    ABSTRACT: Achieving effective gene therapy for glioma depends on gene delivery systems. The gene delivery system should be able to cross the blood brain-barrier (BBB) and further target glioma at its early stage. Active brain tumor targeted delivery can be achieved using the "Trojan horse" technology, which involves either endogenous ligands or extraneous substances that can recognize and bind to specific receptors in target sites. This method facilitates receptor-mediated endocytosis to cross the BBB and enter into glioma cells. Dendrigraft poly-L-lysines (DGLs), which are novel nonviral gene vectors, are conjugated to a peptide (sequence: EPRNEEK) derived from Streptococcus pneumonia, a pathogen causing meningitis. This process yields peptide-modified nanoparticles (NPs) after DNA loading. Cellular uptake and in vivo imaging results indicate that EPRNEEK peptide-modified NPs have a better brain tumor targeted effect compared with a pentapeptide derived from endogenous laminin after intravenous injection. The mechanism of this effect is further explored in the present study. Besides, EPRNEEK peptide-modified NPs also exhibited a prolonged median survival time. In conclusion, the EPRNEEK peptide-modified DGL NPs exhibit potential as a nonviral platform for efficient, noninvasive, and safe brain glioma dual-targeted gene delivery.
    Molecular Pharmaceutics 06/2014; 11(10). DOI:10.1021/mp500084s · 4.79 Impact Factor
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    ABSTRACT: Amphotericin B (AMB) has been a mainstay therapy for fungal infections of the central nervous system, but its use has been limited by its poor penetration into the brain, the mechanism of which remains unclear. In this study, we aimed to investigate the role of P-glycoprotein (P-gp) in AMB crossing the blood-brain barrier (BBB). The uptake of AMB by primary brain capillary endothelial cells in vitro was significantly enhanced after inhibition of P-gp by verapamil. The impact of two model P-gp inhibitors, verapamil and itraconazole, on brain/plasma ratios of AMB was examined in both uninfected CD-1 mice and those intracerebrally infected with Cryptococcus neoformans. In uninfected mice, the brain/plasma ratios of AMB were increased 15 min (3.5 versus 2.0; P < 0.05) and 30 min (5.2 versus 2.8; P < 0.05) after administration of verapamil or 45 min (6.0 versus 3.9; P < 0.05) and 60 min (5.4 versus 3.8; P < 0.05) after itraconazole administration. The increases in brain/plasma ratios were also observed in infected mice treated with AMB and P-gp inhibitors. The brain tissue fungal CFU in infected mice were significantly lower in AMB-plus-itraconazole or verapamil groups than in the untreated group (P < 0.005), but none of the treatments protected the mice from succumbing to the infection. In conclusion, we demonstrated that P-gp inhibitors can enhance the uptake of AMB through the BBB, suggesting that AMB is a P-gp substrate.
    Antimicrobial Agents and Chemotherapy 05/2014; 58(8). DOI:10.1128/AAC.02535-14 · 4.45 Impact Factor
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    Liang Han · Mingming Liu · Deyong Ye · Ning Zhang · Ed Lim · Jing Lu · Chen Jiang
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    ABSTRACT: Minimizing the background signal is crucial for developing tumor-imaging techniques with sufficient specificity and sensitivity. Here we use pH difference between healthy tissues and tumor and tumor targeting delivery to achieve this goal. We synthesize fluorophore-dopamine conjugate as pH-dependent electron donor-acceptor fluorescence system. Fluorophores are highly sensitive to electron-transfer processes, which can alter their optical properties. The intrinsic redox properties of dopamine are oxidation of hydroquinone to quinone at basic pH and reduction of quinone to hydroquinone at acidic pH. Quinone can accept electron then quench fluorescence. We design tumor cell membrane-targeting carrier for delivery. We demonstrate quenched fluorophore-quinone can be specially transferred to tumor extracellular environment and tumor-accumulated fluorophore can be activated by acidic pH. These tumor-targeting pH-dependent electron donor-acceptor fluorescence systems may offer new opportunity for developing tumor-imaging techniques.
    Biomaterials 03/2014; 35(9). DOI:10.1016/j.biomaterials.2013.12.020 · 8.31 Impact Factor
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    ABSTRACT: Malignant glioma, a highly aggressive tumor, is one of the deadliest types of cancer associated with dismal outcome despite of optimal chemotherapeutic regimens. One explanation for this is the failure of most chemotherapeutics accumulation into tumors, additionally causing serious side effects in periphery. To solve these problems, we sought to develop a smart therapeutic nano-device with cooperative dual characteristics of high tumor-targeting ability and selectively controlling drug deposition in tumor cells. This nano-device was fabricated with a cross-linker, containing disulfide linkage to form an inner cellular-microenvironment responsive "-S-S-" barrier, which could shield the entrapped drug leaking in blood circulation. In addition, dehydroascorbic acid (DHA), a novel small molecular tumor-specific vector, was decorated on the nano-device for tumor-specific recognization via GLUT1, a glucose transporter highly expressed on tumor cells. The drug-loaded nano-device was supposed to maintain high integrity in the bloodstream and increasingly to specifically bind with tumor cells through the association of DHA with GLUT1. Once within the tumor cells, the drug release was triggered by high level of intracellular glutathione (GSH). Combination of these two features, the smart nano-device could markedly improve the drug tumor-targeting delivery efficiency, meanwhile decreasing systemic toxicity. Herein, this smart nano-device showed the promising potential as a powerful platform for highly effective anti-glioma treatment.
    ACS Nano 01/2014; 8(2). DOI:10.1021/nn406285x · 12.88 Impact Factor
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    Xi He · Jianfeng Li · Sai An · Chen Jiang
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    ABSTRACT: Drug-delivery system responses to stimuli have been well investigated recently. As pH decrease is observed in most solid tumors, drug-delivery systems responsive to the slightly acidic extracellular pH environment of solid tumors have been developed as a general strategy for tumor targeting. Drug vehicles that are sensitive to acidic endosome/lysosome pH have been constructed for efficient drug release in tumor cells. This review explains the mechanisms of acidic pH in the tumor microenvironment and endocytic-related organelles, endosomes and lysosomes. Nanoparticle responses to acidic extracellular pH are discussed, along with approaches for improving tumor-specific therapy. Endosome/lysosome pH-triggered vehicles are reviewed, which achieve rapid drug release in tumor cells and overcome multidrug resistance.
    Therapeutic delivery 12/2013; 4(12):1499-510. DOI:10.4155/tde.13.120
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    ABSTRACT: Targeting therapy of tumors in their early stages is crucial to increase the survival rate of cancer patients. Currently most drug-delivery systems target the neoplasia through the tumor-associated receptors overexpressed on the cancer cell membrane. However, the expression of these receptors on normal cells and tissues is inevitable, which leads to unwanted accumulation and side effects. Characteristics of the tumor microenvironment, such as acidosis, are pervasive in almost all solid tumors and can be easily accessed. It is shown that the different extracellular pH value can be used to activate/inactivate the receptor-mediated endocytosis on tumor/normal cells. This idea is implemented by conjugating a shielding molecule at the terminus of a receptor-specific ligand via a pH-sensitive hydrazone bond. The acid-activated detachment of the shielding molecule and enhanced tumor/background accumulation ratio are demonstrated. These results suggest that acid active receptor-specific peptide ligand-modified tumor-targeting delivery systems have potential use in the treatment of tumors.
    Small 11/2013; 9(21). DOI:10.1002/smll.201300279 · 8.37 Impact Factor
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    Liang Han · Haojun Ma · Yubo Guo · Yuyang Kuang · Xi He · Chen Jiang
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    ABSTRACT: Nanoparticles target tumor cells by pH-controlled means: Nanoparticles carry three synergistic delivery functions: 1) tumor tissue targeting by the EPR effect; 2) tumor cell targeting by pHLIP-mediated membrane-localization; and 3) tumor cell uptake by adsorptive-mediated endocytosis.
    11/2013; 2(11). DOI:10.1002/adhm.201300013
  • Yang Liu · Chen Jiang
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    ABSTRACT: The blood-brain barrier (BBB) exerts its central nervous system (CNS) protective function as it hinders the delivery of diagnostic and therapeutic agents to the brain. With the development of nanotechnology during the last thirty years, the nanocarriers for delivering drugs make it possible to transport drugs across the BBB. The brain-targeted drug delivery system usually consists of two parts: nanocarriers and brain-targeted strategies. In this review, several kinds of nanocarriers are introduced for brain-targeted drug delivery. We focus on several possible strategies for brain-targeting and comment on their advantages and disadvantages in application.
    Yao xue xue bao = Acta pharmaceutica Sinica 10/2013; 48(10):1532-43.
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    ABSTRACT: The activation of caspase-3 is an important hallmark in Parkinson's disease. It could induce neuron death by apoptosis and microglia activation by inflammation. As a result, inhibition the activation of caspase-3 would exert synergistic dual effect in brain in order to prevent the progress of Parkinson's disease. Silencing caspase-3 genes by RNA interference could inhibit the activation of caspase-3. We developed a brain-targeted gene delivery system based on non-viral gene vector, dendrigraft poly-L-lysines. A rabies virus glycoprotein peptide with 29 amino-acid linked to dendrigraft poly-L-lysines could render gene vectors the ability to get across the blood brain barrier by specific receptor mediated transcytosis. The resultant brain-targeted vector was complexed with caspase-3 short hairpin RNA coding plasmid DNA, yielding nanoparticles. In vivo imaging analysis indicated the targeted nanoparticles could accumulate in brain more efficiently than non-targeted ones. A multiple dosing regimen by weekly intravenous administration of the nanoparticles could reduce activated casapse-3 levels, significantly improve locomotor activity and rescue dopaminergic neuronal loss and in Parkinson's disease rats' brain. These results indicated the rabies virus glycoprotein peptide modified brain-targeted nanoparticles were promising gene delivery system for RNA interference to achieve anti-apoptotic and anti-inflammation synergistic therapeutic effects by down-regulation the expression and activation of caspase-3.
    PLoS ONE 09/2013; 8(5):e62905. DOI:10.1371/journal.pone.0062905 · 3.23 Impact Factor
  • Jianfeng Li · Yubo Guo · Yuyang Kuang · Sai An · Haojun Ma · Chen Jiang
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    ABSTRACT: Combination of gene therapy and chemotherapy is a promising approach for glioma therapy. In this study, a co-delivery system of plasmid encoding human tumor necrosis factor-related apoptosis-inducing ligand (pORF-hTRAIL, Trail) and doxorubicin (DOX) has been simply constructed in two steps. Firstly, DOX was intercalated into Trail to form a stable complex. Secondly, DOX-Trail complex was condensed by Dendrigraft poly-l-lysine (DGL) to form a nanoscaled co-delivery system. Choline transporters are both expressed on blood-brain barrier (BBB) and glioma, Herein, a choline derivate with high choline transporter affinity was chosen as BBB and glioma dual targeting ligand. Choline-derivate modified co-delivery system showed higher cellular uptake efficiency and cytotoxicity than unmodified co-delivery system in U87 MG cells. In comparison with single medication or unmodified delivery system, Choline-derivate modified co-delivery system induced more apoptosis both in vitro and in vivo. The therapeutic efficacy on U87 MG bearing xenografts further confirmed the predominance of this dual targeting and co-delivery system.
    Biomaterials 08/2013; 34(36). DOI:10.1016/j.biomaterials.2013.08.030 · 8.31 Impact Factor
  • Sai An · Yuyang Kuang · Teng Shen · Jianfeng Li · Haojun Ma · Yubo Guo · Xi He · Chen Jiang
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    ABSTRACT: Nanoparticles (NPs) with modification of brain-targeting molecules have been extensively exploited for therapeutic gene delivery across the blood-brain barrier (BBB). As one of the effective RNA interference (RNAi) approaches, short hairpin RNA (shRNA) has been proved to be promising in the field of gene therapy. Apoptosis signal-regulating kinase 1 (Ask1) has been reported to be an important target for gene therapy against cerebral ischemia reperfusion injury. In this study, dendrigraft poly-l-lysine (DGL) was decorated by dermorphin (a μ-opiate receptor agonist) through PEG for efficient brain-targeting, then complexed with anti-Ask1 shRNA plasmid DNA, yielding the DGL-PEG-dermorphin/shRNA NPs. The DGL-PEG-dermorphin/shRNA NPs were characterized and estimated the brain-targeting ability. In vitro, increased cellular uptake and transfection efficiency were explored; in vivo, preferable accumulation and gene transfection in brain were showed in images. The DGL-PEG-dermorphin/shRNA NPs also revealed high efficiency of neuroprotection. As a result of RNAi, corresponding mRNA was distinctly degraded, expression of Ask1 protein was obviously suppressed, apoptotic cell death was apparently decreased and cerebral infarct area was significantly reduced. Above all, DGL-PEG-dermorphin/shRNA NPs were proved to be efficient and safe for brain-targeting RNAi neuroprotection against cerebral ischemia reperfusion injury.
    Biomaterials 08/2013; 34(35). DOI:10.1016/j.biomaterials.2013.07.060 · 8.31 Impact Factor
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    ABSTRACT: Among all the malignant brain tumors, glioma is the deadliest and most common form with poor prognosis. Gene therapy is regarded as a promising way to halt the progress of the disease or even cure the tumor and RNA interference (RNAi) stands out. However, the existence of the blood-brain barrier (BBB) and blood tumor barrier (BTB) limits the delivery of these therapeutic genes. In this work, the delivery system targeting to the transferrin (Tf) receptor highly expressed on both BBB and glioma was successfully synthesized and would not compete with endogenous Tf. U87 cells stably express luciferase were employed here to simulate tumor and the RNAi experiments in vitro and in vivo validated that the gene silencing activity was 2.17-fold higher with the targeting ligand modification. The dual-targeting gene delivery system exhibits a series of advantages, such as high efficiency, low toxicity, stability and high transaction efficiency, which may provide new opportunities in RNAi therapeutics and nanomedicine of brain tumors.
    International Journal of Pharmaceutics 07/2013; 454(1). DOI:10.1016/j.ijpharm.2013.07.019 · 3.65 Impact Factor
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    ABSTRACT: PURPOSE: To prepare an angiopep-conjugated dendrigraft poly-L-lysine (DGL)-based gene delivery system and evaluate the neuroprotective effects in the rotenone-induced chronic model of Parkinson's disease (PD). METHODS: Angiopep was applied as a ligand specifically binding to low-density lipoprotein receptor-related protein (LRP) which is overexpressed on blood-brain barrier (BBB), and conjugated to biodegradable DGL via hydrophilic polyethyleneglycol (PEG), yielding DGL-PEG-angiopep (DPA). In vitro characterization was carried out. The neuroprotective effects were evaluated in a chronic parkinsonian model induced by rotenone using a regimen of multiple dosing intravenous administrations. RESULTS: The successful synthesis of DPA was demonstrated via (1)H-NMR. After encapsulating the therapeutic gene encoding human glial cell line-derived neurotrophic factor (hGDNF), DPA/hGDNF NPs showed a sphere-like shape with the size of 119 ± 12 nm and zeta potential of 8.2 ± 0.7 mV. Angiopep-conjugated NPs exhibited higher cellular uptake and gene expression in brain cells compared to unmodified counterpart. The pharmacodynamic results showed that rats in the group with five injections of DPA/hGDNF NPs obtained best improved locomotor activity and apparent recovery of dopaminergic neurons compared to those in other groups. CONCLUSION: This work provides a practical non-viral gene vector for long-term gene therapy of chronic neurodegenerative disorders.
    Pharmaceutical Research 05/2013; 30(10). DOI:10.1007/s11095-013-1005-8 · 3.95 Impact Factor