Qizhi Zhang

Fudan University, Shanghai, Shanghai Shi, China

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Publications (43)209.7 Total impact

  • Chi Zhang · Qingfeng Liu · Xiayan Shao · Yong Qian · Qizhi Zhang
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    ABSTRACT: Drug distribution to the brain is one of the most difficult challenges in the treatment of the central nervous system (CNS) diseases due to the presence of the blood-brain barrier (BBB). To enhance brain-specific drug delivery, a cyclic peptide CRTIGPSVC selectively interacting with apo-transferrin (apo-Tf), was modified to the surface of poly (ethyleneglycol)–poly (lactide acid) (PEG-PLA) nanoparticles to yield a novel delivery system (Pep-NP). The in vitro cytotoxicity of the delivery system was low. The cellular uptake of Pep-NP was significantly higher than that of NP. Following intravenous administration, much more notable fluorescence was found in the mice brains with Pep-NP than NP. The results indicated the cyclic peptide modified nanoparticles system had great potential in drug delivery across the BBB, thus providing a safe approach for brain targeting.
    No preview · Article · Mar 2016
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    ABSTRACT: Inability of nanomedicine to efficiently home to tumor site still poses great challenge in tumor drug delivery. Inspired by the amplified formation of fibrin in clotting cascade, a self-amplified drug delivery system was developed for tumor photothermal therapy (CMWNTs-PEG) using multi-walled carbon nanotubes (MWNTs) with favorable photothermal effect as the vector, polyethylene glycol as the shelter, CREKA peptide with special affinity for fibrin as the targeting moiety and NIR illumination as the external power. The self-amplified targeting property was carefully characterized. The in vivo temperature monitoring experiment demonstrated that CMWNTs-PEG could significantly elevate the temperature in the tumor region than its counterpart 24 h post an initial NIR illumination. The in vivo imaging and biodistribution experiment showed IR783-labeled CMWNTs-PEG with illumination could accumulate in tumors tissues about 6.4-fold higher than control group, much stronger than other treatment groups. In vivo distribution experiments revealed Cy3-labeled CMWNTs-PEG could deposit on the wall of tumor vessels, intravascular and extravascular spaces, far more extensive than its counterpart in tumor slices. The pharmacodynamics experiment revealed that after four times of illumination, the CMWNTs-PEG almost totally eradiated the tumor xenografts. Altogether, the self-amplified targeting system CMWNTs-PEG showed strong tumor targeting capacity and powerful photothermal therapeutic efficacy.
    No preview · Article · Dec 2015 · Biomaterials
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    ABSTRACT: Poor aqueous solubility is a serious problem for most chemotherapeutics. Docetaxel (DTX), an inhibitor of microtubule depolymerization, is frequently used to treat many malignancies. However, the surfactant used in its commercial preparation (Taxotere®) has proven problematic in clinical use because it has been associated with several side effects. By utilizing the high DTX-loading property of albumin, a new formulation, DTX-incorporated albumin-lipid nanoparticles (DNPs), was prepared and evaluated. DTX was bound to albumin in vitro and dispersed by egg yolk lecithin. The DNP particle size was 110.1 nm, while the average DNP zeta potential was –2.95 mV. The median lethal dose of DNPs was 180.6 mg/kg, which was 75.3% higher than that of Taxotere®. DNPs could effectively inhibit the proliferation of several cell lines and induce cell apoptosis. In vivo imaging suggested that DNPs localize to and accumulate at the glioma site, which is likely due to the enhanced permeation and retention effects of DNPs. These pharmacological experiments further confirmed that DNPs can inhibit tumor growth, prolong the median survival time of mice with gliomas and induce higher levels of apoptosis. In conclusion, this novel formulation of DTX (DNPs) displayed lower toxicity and a superior anti-glioma effect relative to standard DTX preparations.
    Full-text · Article · Dec 2015 · Journal of Biomedical Nanotechnology
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    ABSTRACT: Lapatinib, a selective small-molecule dual-tyrosine kinase inhibitor of HER2 and EGFR, is effective in HER2-positive patients with advanced metastatic breast cancer. However, its low and variable oral absorption, large required daily dose and serious gastrointestinal side effects all limit its clinical use. Intravenous administration offers a good option to overcome these disadvantages. However, the poor solubility of lapatinib in water and organic solvents causes lapatinib to fail in a common injectable preparation. Considering lapatinib's high albumin binding ability (>99%), in this study, we developed human serum albumin nanoparticles loaded with lapatinib (LHNPs) by Nab technology for intravenous administration and investigated its efficacy against HER2-positive breast cancer. Raman shift, X-ray diffraction and X-ray photoelectron spectroscopy studies demonstrated that lapatinib was successfully incorporated into nanoparticles, and LHNPs exhibited good stability and sustained-release effect in vitro. LHNPs could be effectively taken up by SKBr3 cells in a concentration- and time-dependent manner, and the uptake was mediated by energy-dependent endocytosis, which involved clathrin-dependent pinocytosis. Furthermore, in vitro and in vivo data indicated that LHNPs presented the strong ability to induce apoptosis and superior anti-tumor efficacy in tumor-bearing mice to the commercial tablet Tykerb through the inhibition of HER2 phosphorylation. Subchronic toxicity assays indicated that LHNPs had no hepatic or kidney toxicity. With mature technology for industrial production and enhanced therapeutic effects, LHNPs are likely to have great potential as a safe therapeutic candidate against HER2-positive breast cancer in the clinic.
    No preview · Article · Oct 2015 · Colloids and surfaces B: Biointerfaces
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    ABSTRACT: H102, a novel β-sheet breaker peptide, was encapsulated into liposomes to reduce its degradation and increase its brain penetration through intranasal administration for the treatment of Alzheimer's disease (AD). The H102 liposomes were prepared using a modified thin film hydration method, and their transport characteristics were tested on Calu-3 cell monolayers. The pharmacokinetics in rats' blood and brains were also investigated. Behavioral experiments were performed to evaluate the improvements on AD rats' spatial memory impairment. The neuroprotective effects were tested by detecting acetylcholinesterase (AchE), choline acetyltransferase (ChAT) and insulin degrading enzyme (IDE) activity and conducting histological assays. The safety was evaluated on rats' nasal mucosa and cilia. The liposomes prepared could penetrate Calu-3 cell monolayers consistently. After intranasal administration, H102 could be effectively delivered to the brain, and the AUC of H102 liposomes in the hippocampus was 2.92-fold larger than that of solution group. H102 liposomes could excellently ameliorate spatial memory impairment of AD model rats, increase the activities of ChAT and IDE and inhibit plaque deposition, even in a lower dosage compared with H102 intranasal solution. H102 nasal formulations showed no toxicity on nasal mucosa. The H102-loaded liposome prepared in this study for nasal administration is stable, effective and safe, which has great potential for AD treatment.
    No preview · Article · Jun 2015 · Pharmaceutical Research
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    ABSTRACT: As one of the most serious infectious respiratory diseases, influenza A (H1N1) is a great threat to human health, and it has created an urgent demand for effective vaccines. Nasal immunization can induce both systemic and mucosal immune responses against viruses, and it can serve as an ideal route for vaccination. However, the low immunogenicity of antigens on nasal mucosa is a high barrier for the development of nasal vaccines. In this study, we covalently conjugated an influenza A (H1N1) antigen to the surface of N-trimethylaminoethylmethacrylate chitosan (TMC) nanoparticles (H1N1-TMC/NP) through thioester bonds to increase the immunogenicity of the antigen after nasal administration. SDS-PAGE revealed that most of the antigen was conjugated on TMC nanoparticles, and an in vitro biological activity assay confirmed the stability of the antigen after conjugation. After three nasal immunizations, the H1N1-TMC/NP induced significantly higher levels of serum IgG and mucosal sIgA compared with free antigen. A hemagglutination inhibition assay showed that H1N1-TMC/NP induced much more protective antibodies than antigen-encapsulated nanoparticles or alum-precipitated antigen (I.M.). In the mechanistic study, H1N1-TMC/NP was shown to stimulate macrophages to produce IL-1β and IL-6 and to stimulate spleen lymphocytes to produce IL-2 and IFN-γ. These results indicated that H1N1-TMC/NP may be an effective vaccine against influenza A (H1N1) viruses for use in nasal immunization. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.
    No preview · Article · May 2015 · Journal of Medical Virology
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    ABSTRACT: Glioblastoma multiforme (GBM) is the most aggressive central nervous system (CNS) tumor because of its fast development, poor prognosis, difficult control and terrible mortality. Poor penetration and retention in the glioblastoma parenchyma were crucial challenges in GBM nanomedicine therapy. Nanoparticle diameter can significantly influence the delivery efficiency in tumor tissue. Decreasing nanoparticle size can improve the nanoparticle penetration in tumor tissue but decrease the nanoparticle retention effect. Therefore, small nanoparticles with high retention effect in tumor are urgently needed for effective GBM drug delivery. In present study, a small nanoparticle drug delivery system was developed by conjugating fibrin-binding peptide CREKA to Polyamidoamine (PAMAM) dendrimer, where PEGylated PAMAM is used as drug carrier due to its small size and good penetration in tumor and CREKA is used to target the abundant fibrin in GBM for enhanced retention in tumor. In vitro binding ability tests demonstrated that CREKA can significantly enhanced nanoparticle binding with fibrin. In vivo fluorescence imaging of GBM bearing nude mice, ex vivo brain imaging and frozen slices fluorescence imaging further revealed that the CREKA-modified PAMAM achieved higher accumulation and deeper penetration in GBM tissue than unmodified one. These results indicated that the CREKA-modified PAMAM could penetrate the GBM tissue deeply and enhance the retention effect, which was a promising strategy for brain tumor therapy. Copyright © 2015 Elsevier Inc. All rights reserved.
    No preview · Article · Mar 2015 · Journal of Colloid and Interface Science
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    ABSTRACT: Triple-negative breast cancer (TNBC) is an aggressive cancer with limited treatment options. However, the shared feature of epidermal growth factor receptor (EGFR) expression in TNBC offers the opportunity for targeted molecular therapy for this breast cancer subtype. Previous studies have indicated that lapatinib, a selective small-molecular dual-tyrosine kinase inhibitor of HER2 and EGFR, is effective in reducing cancer progression and metastasis, indicating that it might be a candidate for TNBC treatment. However, its poor water solubility, low and variable oral absorption, and large daily dose all limit the clinical use of lapatinib. In this study, we developed human serum albumin (HSA) nanoparticles loaded with lapatinib for intravenous administration to overcome these disadvantages and enhance its efficacy against TNBC. 4T1 cells (a murine TNBC cells) were selected as the cell model because their growth and metastatic spread are very close to those of human breast cancer cells. Lapatinib-loaded HSA nanoparticles (LHNPs) were prepared by Nab technology. LHNPs displayed cytotoxicity similar to the free drug but exhibited superior capacity to induce early apoptosis in 4T1 monolayer cells. Importantly, LHNPs showed improved penetration and inhibition effects in tumor spheroids compared to lapatinib solution (LS). Pharmacokinetic investigations revealed that HSA nanoparticles (i.v.) effectively increased the accumulation of lapatinib in tumor tissue at 2.38 and 16.6 times the level of LS (i.v.) and Tykerb (p.o.), respectively. Consequently, it had markedly better suppression effects both on primary breast cancer and lung metastasis in tumor-bearing mice compared to the commercial drug Tykerb. The improved anti-tumor efficacy of LHNPs may be partly attributed to its close binding to SPARC, which is widely present in the extracellular matrix of tumor tissue. These results demonstrated that LHNPs might be a promising anti-tumor agent for TNBC.
    No preview · Article · Feb 2015 · International Journal of Pharmaceutics
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    ABSTRACT: Now it is well evidenced that tumor growth is a comprehensive result of multiple pathways, and glioma parenchyma cells and stroma cells are closely associated and mutually compensatory. Therefore, drug delivery strategies targeting both of them simultaneously might obtain more promising therapeutic benefits. In the present study, we developed a multi-targeting drug delivery system modified with uPA-activated cell-penetrating peptide (ACPP) for the treatment of brain glioma (ANP). In vitro experiments demonstrated nanoparticles (NP) decorated with cell-penetrating peptide (CPP) or ACPP could significantly improve nanoparticles uptake by C6 glioma cells and nanoparticles penetration into glioma spheroids as compared with traditional NP and thus enhanced the therapeutic effects of its payload when paclitaxel (PTX) was loaded. In vivo imaging experiment revealed that ANP accumulated more specifically in brain glioma site than NP decorated with or without CPP. Brain slides further showed that ACPP contributed to more nanoparticles accumulation in glioma site, and ANP could co-localize not only with glioma parenchyma cells, but also with stroma cells including neo-vascular cells and tumor-associated macrophages. The pharmacodynamics results demonstrated ACPP could significantly improve the therapeutic benefits of nanoparticles by significantly prolonging the survival time of glioma-bearing mice. In conclusion, the results suggested that nanoparticles modified with uPA-sensitive ACPP could reach multiple types of cells in glioma tissues and provide a novel strategy for glioma targeted therapy.
    No preview · Article · Jan 2015 · Biomaterials
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    ABSTRACT: Lapatinib (LPT) could sensitize human epidermal growth factor receptor-2 (HER-2) positive breast cancer to paclitaxel (PTX) and induce synergetic action with PTX in preclinical test and phase II/III trial. In this study, LPT-conjugated poly (ethylene glycol) (PEG) and poly (lactic acid) (PLA) (LPT-PEG-PLA) was first synthesized and confirmed with (1) H Nuclear Magnetic Resonance and Matrix-Assisted Laser Desorption/ Ionization Time of Flight Mass Spectrometry, which was used for the preparation of a novel PEG-PLA combined micelles of LPT and PTX (PPM-LP). The obtained PPM-LP exhibited uniform, spherical shape with a size of 25.80 ± 0.47 nm and zeta potential of -3.17 ± 0.15 mv. PTX existed in molecular or amorphous forms in the micelles and superficial LPT could better delay PTX release. The cytotoxicity of PPM-LP with LPT conjugation against SKBr-3 cells (HER-2 positive) was found to be significantly increasing as compared with PPM-PTX, whereas there was no significant difference against MDA-MB-231 cells (HER-2 negative). PPM-LP could escape from endosomes and be distributed into cytoplasm and led to cell arrest in G2/M and G1/S phases simultaneously. Results of nucleus staining and flow cytometry confirmed that LPT could remarkably increase antineoplastic effect of PTX against SKBr-3 cells. All these results demonstrated that PPM-LP may be a promising drug delivery system for HER-2 positive breast cancer. © 2014 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci. © 2014 Wiley Periodicals, Inc. and the American Pharmacists Association.
    No preview · Article · Jan 2015 · Journal of Pharmaceutical Sciences
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    ABSTRACT: Alzheimer's disease (AD) is a complex neurodegenerative disease with few effective treatments. The non-targeted distribution of drugs decreases drug efficiency and cause side effects. The cascade targeting strategy has been suggested for precise drug delivery. We developed a dual-functional nanoparticle drug delivery system loaded with β-sheet breaker peptide H102 (TQNP/H102). Two targeting peptides, TGN and QSH, were conjugated to the surface of the nanoparticles for blood-brain barrier transport and Aβ42 targeting, respectively. The prepared nanoparticles were spherical and uniform. The brain distribution study of H102 was conducted with the HPLC-Mass method to evaluate whether this nano-carrier could achieve increased AD-lesion delivery. The highest uptake of H102 was observed in the hippocampi of the TQNP/H102 group mice 1h after administration, which was 2.62 and 1.86 times the level of non-modified nanoparticles (NP/H102) and TGN modified nanoparticles (TNP/H102), respectively. The neuroprotective effects of H102 preparations were evaluated using Morris water maze experiment, biochemical indexes assay and tissue histology. The spatial learning and memory of the AD model mice in the TQNP/H102 group were significantly improved compared with the AD control group, and were also better than other preparations at the same dosage, even the TNP/H102 group. These results were consistent with the values of biochemical indexes in mice hippocampi as well as the histological observations. The results demonstrate that TQNP is a promising carrier for peptide or protein drugs, such as H102, for entry into the central nervous system (CNS) and subsequent location of brain AD lesions, thus offering a highly-specific method for AD therapy.
    No preview · Article · Aug 2014 · Journal of Controlled Release
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    ABSTRACT: Purpose: Antigens were conjugated on the surface of N-trimethylaminoethylmethacrylate chitosan (TMC) nanoparticles to induce systemic and mucosal immune responses after nasal immunization. Methods: TMC was synthesized by free radical polymerization and blank nanoparticles were prepared by ionic crosslinking of TMC and sodium tripolyphosphate. The model antigen (ovalbumin) was conjugated on the surface of blank nanoparticles (OVA-NP) through thioester bond formation. The cellular uptake of OVA-NP was investigated in Raw 264.7 macrophages and biodistribution of antigens was studied by the radioiodine labeling method. The immunological effects were evaluated by nasal administration of OVA-NP to Balb/C mice. The transport mechanism and nasal toxicity of OVA-NP were studied in rats. Results: The cellular uptake of OVA-NP was significantly higher than that of ovalbumin-encapsulated nanoparticles (NPe) after 30 min. Nasally administered OVA-NP showed higher transport of antigens to cervical lymph nodes with higher targeting efficiency than all other groups. Compared with NPe, OVA-NP induced much higher levels of systemic and mucosal immune responses in Balb/C mice after three nasal immunizations. Ex vivo culturing of nasopharynx-associated lymphoid tissue (NALT) confirmed its participation in nasal immunization. The transport mechanism study revealed that OVA-NP can be transported across the nasal epithelium through glands and may be taken up in NALT through M cells. OVA-NP did not induce obvious toxicity to nasal mucosa or hemolysis in animals. Conclusion: The present study demonstrated that the conjugation of TMC nanoparticles with antigens is an effective strategy for nasal vaccination.
    No preview · Article · Jun 2014 · Pharmaceutical Research
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    ABSTRACT: The frequent outbreak of respiratory infectious diseases such as influenza and pulmonary tuberculosis calls for new immunization strategies with high effectiveness. Nasal immunization is one of the most potential methods to prevent the diseases infected through the respiratory tract. In this study, we designed a water-soluble system based on antigen/N-trimethylaminoethylmethacrylate chitosan conjugates for nasal immunization. N-trimethylaminoethylmethacrylate chitosan (TMC) was synthesized by free radical polymerization of chitosan and N-trimethylaminoethylmethacrylate chloride and identified by (1)H NMR and FT-IR. Thiolated ovalbumin (OVA) was covalently conjugated to maleimide modified TMC with high conjugation efficiency. OVA conjugated TMC (OVA-TMC) significantly increased uptake of OVA by Raw 264.7 cells, which was 2.38 times higher than that of OVA/TMC physical mixture (OVA+TMC) at 4h. After nasal administration, OVA-TMC showed higher transport efficiency to superficial and deep cervical lymph nodes than OVA+TMC or OVA alone. Balb/C mice were intranasally given with OVA-TMC three times at 2-week internals to evaluate the immunological effect. The serum IgG, IgG1 and IgG2a levels of the OVA-TMC group were 17.9-87.9 times higher than that of the OVA+TMC group and comparable to that of the intramuscular group. The secretory IgA levels in nasal wash and saliva of the OVA-TMC group were 5.2-7.1 times higher than that of the OVA+TMC group while the secretory IgA levels of the intramuscular alum-precipitated OVA group were not increased. After immunofluorescence staining of nasal cavity, IgA antibody secreting cells were mainly observed in the lamina propria regions and glands of nasal mucosa. OVA-TMC showed little toxicity to the nasal epithelia or cilia of rats after nasal administration for three consecutive days. These results demonstrated that antigen conjugated TMC can induce both systemic and mucosal immune responses after nasal administration and may serve as a convenient, safe and effective vaccine for preventing respiratory infectious diseases.
    No preview · Article · Mar 2014 · Vaccine
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    ABSTRACT: To improve the solubility, bioavailability and anti-tumor effect of lapatinib, lapatinib-incorporated lipid nanoparticles (LTNPs) were prepared and characterized. The particle size of LTNPs was 88.6 nm with a zeta potential of 20 mV. Laptinib was loaded into LTNPs with a non-crystal structure as determined by FT-IR. In vitro, LTNPs could be effectively uptaken into C6 glioma cells at a concentration-dependent manner. In vivo, LTNPs showed a relative higher AUC, which was 5.27- and 3.21-fold as that of Tykerb and lapatinib suspension (LTS) group. LTNPs also showed highest glioma concentration, which may benefit from the enhanced permeability and retention effect and active targeting ability. In toxicity studies, LTNPs displayed a half lethal dose over 250 mg/kg. Repeating administering 30 mg/kg of LTNPs could led to toxicity to hematology which might owe to the bovine serum albumin, a foreign protein to mice. However, there was no organic change observed through HE staining. In conclusion, LTNPs could target to glioma with high concentration and low side effect.
    Full-text · Article · Jan 2014 · Current pharmaceutical biotechnology
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    ABSTRACT: Disabilities caused by neurodegeneration have become one of the main causes of mortality in elderly population, with drug distribution to the brain remaining one of the most difficult challenges in the treatment of the central nervous system (CNS) diseases due to the existence of blood-brain barrier. Lectins modified polyethylene glycol-polylactide-polyglycolide (PEG-PLGA) nanoparticles could enhance the drug delivery to the brain following intranasal administration. In this study, basic fibroblast growth factor (bFGF) was entrapped in nanoparticles conjugated with solanum tuberosum lectin (STL), which selectively binds to N-acetylglucosamine on the nasal epithelial membrane for its brain delivery. The resulting nanoparticles had uniform particle size and negative zeta potential. The brain distribution of the formulations following intranasal administration was assessed using radioisotopic tracing method. The areas under the concentration-time curve of (125)I-bFGF in the olfactory bulb, cerebrum, and cerebellum of rats following nasal application of STL modified nanoparticles (STL-bFGF-NP) were 1.79∼5.17 folds of that of rats with intravenous administration, and 0.61∼2.21 and 0.19∼1.07 folds higher compared with intranasal solution and unmodified nanoparticles, respectively. Neuroprotective effect was evaluated using Mirror water maze task in rats with intracerebroventricular injection of β-Amyloid25-35 and ibotenic acid. The spatial learning and memory of Alzheimer's disease (AD) rats in STL-bFGF-NP group were significantly improved compared with AD model group, and were also better than other preparations. The results were consistent with the value of choline acetyltransferase activity of rat hippocampus as well as the histological observations of rat hippocampal region. The histopathology assays also confirmed the in vivo safety of STL-bFGF-NP. These results clearly indicated that STL-NP was a promising drug delivery system for peptide and protein drugs such as bFGF to enter the CNS and play the therapeutic role.
    No preview · Article · Nov 2013 · International Journal of Pharmaceutics
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    ABSTRACT: Alzheimer's disease (AD) is a common neurodegenerative disorder with few treatments. The limitations imposed by the blood-brain barrier (BBB) and the non-selective distribution of drugs in the brain have hindered the effective treatment of AD and may result in severe side effects on the normal brains. We developed a dual-functional nanoparticle drug delivery system based on a PEGylated poly (lactic acid) (PLA) polymer. Two targeting peptides that were screened by phage display, TGN and QSH, were conjugated to the surface of the nanoparticles. TGN specifically targets ligands at the BBB, while QSH has good affinity with Aβ1-42, which is the main component of amyloid plaque. Tests probing the bEnd.3 cell uptake and in vivo imaging were conducted to determine the best density of TGN on the nanoparticles' surfaces. The optimal amount of QSH was studied using a Thioflavin T (ThT) binding assay and surface plasmon resonance (SPR) experiments. The optimal maleimide/peptide molar ratio was 3 for both TGN and QSH on the surface of the nanoparticles (T3Q3-NP), and these nanoparticles achieved enhanced and precise targeted delivery to amyloid plaque in the brains of AD model mice. A MTT assay also validated the safety of this dual-targeted delivery system; little cytotoxicity was demonstrated with both bEnd.3 and PC 12 cells. In conclusion, the T3Q3-NP might be a valuable targeting system for AD diagnosis and therapy.
    No preview · Article · Oct 2013 · Biomaterials
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    ABSTRACT: Chemotherapy for brain glioma has been of limited benefit due to the inability of drugs to penetrate the blood-brain barrier (BBB) and non-selective drug accumulation in the entire brain. To obviate these limitations, dual-targeting paclitaxel-loaded nanoparticles were developed by decoration with peptide-22 (PNP-PTX), a peptide with special affinity for low-density lipoprotein receptor (LDLR), to transport the drug across the BBB, and then target brain tumour cells. Enzyme-linked immune sorbent assay (ELISA) revealed that LDLR was over-expressed in C6 cells and brain capillary endothelial cells (BCECs), but low LDLR expression was observed in H92c(2-1) cells. Nanoparticle uptake demonstrated that peptide-22-decorated nanoparticles significantly increased the cellular uptake of nanoparticles by C6 cells and BCECs but not by H92c(2-1) cells, and excess free peptide-22 significantly inhibited the cellular uptake of PNP by C6 cells and BCECs. Cellular uptake mechanism experiments showed that PNP uptake by both BCECs and C6 cells was energy-dependant and caveolae- and clathrin-mediated endocytosis pathway other than macropinocytosis were involved. Dual-targeting effects in an in vitro BBB model showed that peptide-22 decoration on nanoparticles loaded with paclitaxel significantly increased the transport ratio of PTX across the BBB and induced apoptosis of C6 glioma cells below the BBB, and these effects were significantly inhibited by excess free peptide-22. Ex vivo and in vivo fluorescence imaging indicated that PNP labelled with a near-infrared dye could permeate the BBB and accumulate more in the glioma site than unmodified NP. Glioma section observed by fluorescence microscopy further demonstrated PNP distributed more extensively in both glioma bulk and infiltrative region around than unmodified NP. Pharmacodynamics results revealed that the median survival time of glioma-bearing mice administered with dual-targeting PNP-PTX was significantly prolonged compared with that of any other group. TUNEL assay and H&E staining showed that PNP-PTX treatment induced significantly more cell apoptosis and tumour necrosis compared with other treatments. Taken together, these promising results suggested that the dual-targeting drug delivery system might have great potential for glioma therapy in clinical applications.
    No preview · Article · Sep 2013 · Biomaterials
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    ABSTRACT: Abstract Concanavalin A (ConA)-conjugated poly(ethylene glycol)-poly(lactic acid) nanoparticles (ConA-NPs) were prepared for targeted drug delivery to the cervical lymph nodes after intranasal administration. ConA, a lectin specifically binding to α-mannose and α-glucose, was covalently conjugated on NPs without loss of its carbohydrates binding bioactivity. In vitro cellular uptake experiment demonstrated that NPs could be uptaken by Calu-3 cells in a time- and concentration-dependent manner, and conjugation of ConA on NPs could significantly increase the rate and amount of cellular uptake. ConA-NP showed no obvious toxicity to Calu-3 cells in vitro or to the nasal cilia of rats in vivo. Compared with NPs without ConA, ConA-NP is more effective in targeting drugs to the deep cervical lymph nodes, as evidenced by 1.36-2.52 times increase of targeting efficiency, demonstrating that ConA-NP is a potential carrier for targeted drug delivery to the cervical lymph nodes via nasal route.
    No preview · Article · Apr 2013 · Journal of Microencapsulation
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    ABSTRACT: Purpose: A phage-displayed peptide TGN was used as a targeting motif to help the delivery of NAP-loaded nanoparticles across the blood-brain barrier (BBB), which sets an obstacle for brain delivery of NAP in vivo. Methods: Intracerebroventricular injection of Aβ₁₋₄₀ into mice was used to construct in vivo model of Alzheimer's disease. The water maze task was performed to evaluate the effects of the NAP formulations on learning and memory deficits in mice. The neuroprotective effect was tested by detecting acetylcholinesterase (AChE) and choline acetyltransferase (ChAT) activity and conducting histological assays. Results: Intravenous administration of NAP-loaded TGN modified nanoparticles (TGN-NP/NAP) has shown better improvement in spatial learning than NAP solution and NAP-loaded nanoparticles in Morris water maze experiment. The crossing number of the mice with memory deficits recovered after treatment with TGN-NP/NAP in a dose dependent manner. Similar results were also observed in AChE and ChAT activity. No morphological damage and no detectable Aβ plaques were found in mice hippocampus and cortex treated with TGN-NP/NAP. Conclusions: TGN modified nanoparticles could be a promising drug delivery system for peptide and protein drug such as NAP to enter the brain and play the therapeutic role.
    No preview · Article · Apr 2013 · Pharmaceutical Research
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    ABSTRACT: Aim: The poor water solubility of many active compounds is a serious deterrent to their use as commercial drugs. Lapatinib is a dual inhibitor of the EGF receptor and EGF receptor 2 approved by the US FDA to treat advanced breast cancer. This study prepares lapatinib-incorporated lipoprotein-like nanoparticles (LTNPs) to enhance the water solubility and elevate the anti-tumor effect of lapatinib. Materials & methods: Bovine albumin was used to bind with lapatinib, and egg yolk lecithin was used to stabilize the conjugation of bovine albumin and lapatinib. The characteristics of LTNPs were evaluated by several experiments. Cell uptake and toxicity were performed on BT-474 cells. In vivo anti-tumor effect was performed on BT-474 xenograft-bearing mice. Results: LTNPs contained a lipid corona and a core of lapatinib and albumin. LTNPs could be effectively taken up by BT-474 cells and induced apoptosis. An in vivo study demonstrated that LTNPs could passively distribute into a tumor via the enhanced permeability and retention effect and induce anti-tumor activity in breast cancer. Conclusion: The authors present a convenient nanoformulation with improved anti-tumor effect, which is a promising candidate for clinical trials.
    Full-text · Article · Mar 2013 · Nanomedicine