Hua Zhang

Peking University, Peping, Beijing, China

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Publications (76)452.73 Total impact

  • [Show abstract] [Hide abstract]
    ABSTRACT: Doxorubicin (DOX) is a potent anticancer drug for the treatment of tumors, but the poor specificity and multi-drug resistance (MDR) on tumor cells have restricted its application. Here, a pH and reduction-responsive peptide-drug conjugate (PDC), pHLIP-SS-DOX, was synthesized to overcome these drawbacks. pH low insertion peptide (pHLIP) is a cell penetrating peptide (CPP) with pH-dependent transmembrane ability. And because of the unique cell membrane insertion pattern, it might reverse the MDR. The cellular uptake study showed that on both drug-sensitive MCF-7 and drug-resistant MCF-7/Adr cells, pHLIP-SS-DOX obviously facilitated the uptake of DOX at pH 6.0 and the uptake level on MCF-7/Adr cells was similar with that on MCF-7 cells, indicating that pHLIP-SS-DOX had the ability to target acidic tumor cells and reverse MDR. In vitro cytotoxicity study mediated by GSH-OEt demonstrated that the cytotoxic effect of pHLIP-SS-DOX was reduction responsive, with obvious cytotoxicity at pH 6.0; while it had poor cytotoxicity at pH 7.4, no matter with or without GSH-OEt pretreatment. This illustrated that pHLIP could deliver DOX into tumor cells with acidic microenvironment specifically and could not deliver drugs into normal cells with neutral microenvironment. In summary, pHLIP-SS-DOX is a promising strategy to target drugs to tumors and provides a possibility to overcome MDR.
    Drug Delivery 04/2015; DOI:10.3109/10717544.2015.1028601 · 2.20 Impact Factor
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    ABSTRACT: Although transferrin receptor (TfR) is widely accepted as a target for cancer therapy, few studies have elaborated on delivery efficiency of TfR upon interactions with TfR-targeted nanomedicine. Here, a micellar system employing TfR-specific 7peptide (Histidine-Alanine-Isoleucine-Tyrosine- Proline-Arginine-Histidine, HAIYPRH, 7pep) as the targeting moiety was constructed; and its endocytosis, intracellular trafficking as well as influence on TfR expression and in vivo tumor targeting were explored in the MCF-7 tumor model. In contrast to unmodified micelles, 7pep modification enhanced the cellular uptake of micelles without altering endocytic pathways, and slowed down the trafficking of micelles to lysosomes without changing the final intracellular co-localization. Interestingly, cellular TfR level was increased by 7pep-modified micelles. Furthermore, receptor saturation and recovery was observed in vivo. In conclusion, this study comprehensively investigated the bio-nano interaction between TfR positive tumors and 7pep-modified micelles, and provided scientific information for cancer therapy with receptor-mediated nanomedicines.
    Molecular Pharmaceutics 03/2015; DOI:10.1021/mp500796d · 4.79 Impact Factor
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    ABSTRACT: Alpha7 nicotinic acetylcholine receptor (α7 nAChR), a ligand-gated ion channel, is increasingly emerging as a new tumor target owing to its expression specificity and significancy for cancer. In an attempt to increase the targeted drug delivery to the α7 nAChR-overexpressing tumors, herein, α-conotoxin ImI, a disulfide-rich toxin with highly affinity for α7 nAChR, was modified on the PEG-DSPE micelles (ImI-PMs) for the first time. The DLS, TEM and HPLC detections showed the spherical nanoparticle morphology about 20 nm with negative charge and high drug encapsulation. The ligand modification did not induce significant differences. The immunofluorescence assay confirmed the expression level of α7 nAChR in MCF-7 cells. In vitro and in vivo experiments demonstrated that the α7 nAChR-targeted nanomedicines could deliver more specifically and faster into α7 nAChR-overexpressing MCF-7 cells. Furthermore, fluo-3/AM fluorescence imaging technique indicated that the increased specificity was attributed to the ligand-receptor interaction, and the inducitivity for intracellular Ca(2+) transient by ImI was still remained after modification. Moreover, paclitaxel, a clinical frequently-used anti-tumor drug for breast cancer, was loaded in ImI-modified nanomedicines to evaluate the targeting efficacy. Besides of exhibiting greater cytotoxicity and inducing more cell apoptosis in vitro, paclitaxel-loaded ImI-PMs displayed stronger anti-tumor efficacy in MCF-7 tumor-bearing nu/nu mice. Finally, the active targeting system showed low systemic toxicity and myelosuppression evidenced by less changes in body weight, white blood cells, neutrophilic granulocyte and platelet counts. In conclusion, α7 nAChR is also a promising target for anti-tumor drug delivery and in this case, α-conotoxin ImI-modified nanocarrier is a potential delivery system for targeting α7 nAChR-overexpressing tumors. Copyright © 2014 Elsevier Ltd. All rights reserved.
    Biomaterials 02/2015; 42C:52-65. DOI:10.1016/j.biomaterials.2014.11.044 · 8.31 Impact Factor
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    ABSTRACT: The biomimetic delivery system (BDS) based on special type of endogenous cells like macrophages and T cells, has been emerging as a novel strategy for cancer therapy, due to its tumor homing property and biocompatibility. However, its development is impeded by complicated construction, low drug loading or negative effect on the cell bioactivity. The present report constructed a BDS by loading doxorubicin (DOX) into a mouse macrophage-like cell line (RAW264.7). It was found that therapeutically meaningful amount of DOX could be loaded into the RAW264.7 cells by simply incubation, without significantly affecting the viability of the cells. Drug could release from the BDS and maintain its activity. RAW264.7 cells exhibited obvious tumor-tropic capacity towards 4T1 mouse breast cancer cells both in vitro and in vivo, and drug loading did not alter this tendency. Importantly, the DOX loaded macrophage system showed promising anti-cancer efficacy in terms of tumor suppression, life span prolongation and metastasis inhibition, with reduced toxicity. In conclusion, it is demonstrated that the BDS developed here seems overcome some of the main issues related to a BDS. The DOX loaded macrophages might be a potential BDS for targeted cancer therapy. Copyright © 2015. Published by Elsevier B.V.
    Journal of Controlled Release 01/2015; 204. DOI:10.1016/j.jconrel.2015.01.039 · 7.26 Impact Factor
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    ABSTRACT: Cyclosporine A (CyA) is a poorly soluble peptide and the available preparation is the surfactant based Sandimmum Neoral(®). In this study, we developed a novel pH-sensitive nanomatrix system of CyA with medical-grade nanoporous silica and Eudragit(®) to enhance the oral absorption of CyA as well as to improve the potential nephrotoxicity caused by the pronounced initial plasma peak of Neoral(®). The nanomatrixs were prepared by an absolutely simple conventional process. The scanning electron microscopy (SEM), X-ray powder diffraction analysis (XRD), differential thermal analysis (DSC) and specific surface area and pore size analysis were used to analyze the physicochemical characterization of the nanomatrix. The nanomatrix, consisted of CyA, Eudragit(®) S100 and Sylysia 350 (1/5/5, w/w/w %), not only increased the dissolution of CyA in vitro but also exhibited excellent enteric behavior. The characterization of CyA nanomatrix showed the CyA was highly dispersed in the nanomatrix in a molecular or amorphous state and partly filled into the nanopores of Sylysia 350. The results of comparative pharmacokinetic study showed that the optimized nanomatrix had a relative bioavailability of 90.8% with Neoral(®) but a lower Cmax than that of Neoral(®). In conclusion, the novel nanomatrix of CyA, composed of pharmaceutical excipients of biological safety and easily prepared, is expected to become a promising marketed product for the oral delivery of CyA. Copyright © 2014. Published by Elsevier B.V.
    International Journal of Pharmaceutics 11/2014; DOI:10.1016/j.ijpharm.2014.11.030 · 3.79 Impact Factor
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    ABSTRACT: Lanreotide is an octapeptide analog of endogenous somatostatin, specifically binding with tumors over-express somatostatin receptor 2 (SSTR2). In this study, we conjugated lanreotide to 1, 2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[methoxy (poly-(ethylene glycol))-2000] (PEG-DSPE), constructed active targeted micelles (lanreotide-PM), characterized their in vitro and in vivo targeting effect, and explored the receptor mediated transportion. The uptake of lanreotide-PM was found to be related to the expression level of SSTR2 in different cell lines and the competitive inhibition phenomenon indicated that the cellular uptake of lanreotide-PM was via a receptor meditated mechanism. In vivo, more lanreotide-PM accumulated in SSTR2 high expression tumor xenografts, endocytosed by the tumor cells, induced more apoptosis of tumor cells, and suppressed tumor growth efficiently. In conclusion, lanreotide–modified micelles containing antitumor drugs provide a promising strategy for the treatment of SSTR-expressing tumors.
    Journal of Drug Targeting 11/2014; DOI:10.3109/1061186X.2014.954118 · 2.72 Impact Factor
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    ABSTRACT: To address the obstacles of cancer chemotherapeutics, including toxicity, side effects, water insolubility, and lack of tumor selectivity, a novel stimuli-responsive drug-delivery system was developed based on paclitaxel-loaded poly(ethylene glycol)-disulfide-paclitaxel conjugate nanoparticles (PEG-SS-PTX/PTX NPs). The formulation emphasizes several benefits, including polymer-drug conjugates/prodrugs, self-assembled NPs, a high drug content, redox-responsibility, and programed drug release. The PTX-loaded, self-assembled NPs, with a uniform size of 103 nm, characterized by DLS, TEM, XRD, DSC and 1H-NMR, exhibited excellent drug-loading capacity (15.7%) and entrapment efficiency (93.3%). PEG-SS-PTX/PTX NPs were relatively stable under normal conditions but disassembled quickly under reductive conditions, indicated by the triggered-aggregation phenomena and drug-release profile in the presence of dithiothreitol (DTT), a reducing agent. What's more, by taking advantages of difference in drug releasing rates between physical-loaded and chemical-conjugated drugs, the "programmed drug release" phenomenon was observed, which attributed to higher concentration and longer action-time of drugs. The influence of PEG-SS-PTX/PTX NPs on in vitro cytotoxicity, the cell cycle, and cellular apoptosis was determined in MCF-7 cell lines, and the NPs demonstrated a superior anti-proliferation activity associated with PTX-induced cell arrest in the G2/M phase and apoptosis over their nonresponsive counterparts. Moreover, the redox-responsive NPs were more efficacious than both free PTX and the non-redox-responsive formulation at equivalent doses of PTX in the breast cancer xenograft mouse model. This redox-responsive PTX drug delivery system is promising and can be explored in effective intracellular drug delivery.
    Molecular Pharmaceutics 09/2014; 11(10). DOI:10.1021/mp500399j · 4.79 Impact Factor
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    ABSTRACT: Tramadol is a synthetic non-opiate analgesic drug and effective for many kinds of chronic and acute pain. This study compared the bioavailability of tramadol after different administration routes in rats (oral, buccal and nasal). A simple HPLC analytical approach was used to determine the concentration of tramadol in plasma. The pharmacokinetic behavior and bioavailability of tramadol after administration via different routes in rats were investigated. Nasal and buccal administration of tramadol resulted in a fast increase followed by a rapid decrease in plasma tramadol concentration. The Cmax values following buccal and nasal administration were 6 times and 20 times higher than that of oral administration, respectively (6827.85 ± 7970.87 ng/ml, 22191.84 ± 5364.86 ng/ml, vs 1127.03 ± 778.34 ng/ml). The relative bioavailabilities of the nasal- and buccal-administered drug when compared to the oral route were 504.8% and 183.4%, respectively, which is much higher than that of oral administration. Nasal and buccal administration increased the bioavailability of tramadol, which may allow for a reduction in the dose of tramadol and a subsequent decrease in both side effects and toxicity. Therefore, this approach provides an effective choice for the delivery of tramadol, an analgesic drug. This article is protected by copyright. All rights reserved.
    Biopharmaceutics & Drug Disposition 09/2014; 35(9). DOI:10.1002/bdd.1916 · 2.18 Impact Factor
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    ABSTRACT: A novel therapeutic strategy combining mTOR inhibitor rapamycin (RAPA) and doxorubicin (DOX)-loaded cyclic octapeptide liposomes for targeting integrin α3 was expected to combat the triple-negative breast cancer (TNBC). RAPA was loaded into PEG–PCL polymer micelles (M-RAPA) to realize solubilization. Flow cytometry analysis and laser confocal microscopy were used to evaluate the in vitro cellular uptake. The in vivo tumor targeting and bio-distribution were investigated by living fluorescence imaging. As the results, LXY modification significantly enhanced the cellular uptake of liposomal DOX in integrin α3 overexpressed TNBC cells (MDA-MB-231) in vitro and accordingly improved the tumor accumulation of liposomes in vivo. When used alone or in combination with LXY-LS-DOX, M-RAPA could greatly inhibit the expression of HIF-1α protein, which is always highly expressed in malignant cancers and involved in tumor angiogenesis, proliferation, therapeutic resistance and poor prognosis. Meanwhile, the improved efficacy of combined targeted therapy with LXY-LS-DOX and M-RAPA was demonstrated by the in vitro cytotoxicity against model TNBC cells and in vivo anti-tumor activity against mouse bearing TNBC model. These results suggested that the targeted combinational therapy based on LXY-LS-DOX and M-RAPA systems may provide a rational strategy to improve therapeutic outcomes of TNBC.
    Biomaterials 07/2014; 35(20):5347–5358. DOI:10.1016/j.biomaterials.2014.03.036 · 8.31 Impact Factor
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    ABSTRACT: Currently, it is unknown whether a receptor-associated protein will be affected when a ligand modified delivery system interacts with its receptor. Besides, chlorotoxin (ClTx)-modified liposomes can target to glioma cells, but the target molecule is not clear: MMP-2, ClC-3 or both? Here a comparative study of ClTx-conjugated liposomes was conducted on two types of tumor cells: U87, a human glioma cell line with high expression of both MMP-2 and ClC-3, and A549, a human lung cancer cell line with expression of only MMP-2. ClTx-modified liposomes behaved similarly in these two cancer cells in terms of in vitro cell uptake, endocytosis pathway, intracellular trafficking and in vivo targeting efficacy, though the two tested cell lines were very different in ClC-3 expression. These results revealed that the targeted delivery of ClTx modified liposomes to U87 tumor was MMP-2-mediated and not correlated with the chloride channel ClC-3. On the other hand, ClTx modified on the liposomes did activate the receptor-associated protein ClC-3 via the binding with MMP-2, leading to the inhibition on cell migration and chloride currents. This is significant because cell migration is a key step in tumor metastasis. Interestingly, higher in vitro cellular uptake and lower in vivo tumor accumulation of liposomal systems was found in U87 compared to the A549 model, possibly due to the biological differences between in vitro and in vivo models. In general, ClTx-modified delivery systems may potentially target to tumors other than glioma that express a high level of MMP-2, and its effect on ClC-3 may help prevent tumor metastasis.
    Biomaterials 07/2014; 35(22):5908–5920. DOI:10.1016/j.biomaterials.2014.03.077 · 8.31 Impact Factor
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    ABSTRACT: The aimed of this study was to prepare stabilized thiomers to overcome the poor stability character of traditional thiomers. Poly(acrylic acid)-cysteine (PAA-Cys) was synthesized by conjugating cysteine with poly(acrylic acid) and poly(acrylic acid)-cysteine-6-mercaptonicotinic acid (PAA-Cys-6MNA, stabilized thiomers) was synthesized by grafting a protecting group 6-mercaptonicotinic acid (6MNA) with PAA-Cys. The free thiol of PAA-Cys was determined by Ellmann's reagent method and the ratio of 6MNA coupled was determined by glutathione reduction method. The study of permeation enhancement and stabilized function was conducted by using Franz diffusion cell method, with fluorescein isothiocyanate dextran (FD4) used as model drug. The influence of polymers on tight junctions of Caco-2 cell monolayer was detected with laser scanning confocal fluorescence microscope. The results indicated that both PAA-Cys and PAA-Cys-6MNA could promote the permeation of FD4 across excised rat intestine, and the permeation function of PAA-Cys-6MNA was not influence by the pH of the storage environment and the oxidation of air after the protecting group 6MNA was grafted. The distribution of tight junction protein of Caco-2 cell monolayer F-actin was influenced after incubation with PAA-Cys and PAA-Cys-6MNA. In conclusion, stabilized thiomers (PAA-Cys-6MNA) maintained the permeation function compared with the traditional thiomers (PAA-Cys) and its stability was improved. The mechanism of the permeation enhancement function of the polymers might be related to their influence on tight junction relating proteins of cells.
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    ABSTRACT: Since they were first reported in 1980, site-specific drug delivery nanocarriers have progressed greatly with the development of nanotechnology and biotechnology, especially in the anti-tumor field. Currently, some of the ligand peptides like RGD have become hot targeting molecules with extensive academic studies and some receptor-medicated nanocarriers are now in clinical trials. Homing peptides have been the preferred ligands thus far due to their low molecular weight, low antigenicity, high modification ratios and low interference in vivo. The major benefit of receptor-medicated nanocarriers over passive ones may be their accumulation within tumors for longer period of time due to their binding to and/or their uptake by cancer cells, preventing them from fast redistribution into systemic circulation. The studies on receptor-mediated nanocarries are very dynamic currently, advancing gradually from these against non-therapeutic targets to these against therapeutic targets. And recently, more studies were focused on these systems against multiple receptors and the combination therapies with receptor-mediated nanocarriers. However, we still face great challenges, especially in the understanding of receptors, the key issue for receptor-mediated delivery. This review presents the past and ongoing studies on various types of drug delivery systems based on receptor mediation, discusses the prospective and challenges, and introduces the possible trend of study in the future.
    Journal of Controlled Release 05/2014; DOI:10.1016/j.jconrel.2014.05.028 · 7.26 Impact Factor
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    ABSTRACT: Previously, PEGylated paclitaxel (PEG-PTX) was found not favorable as a polymer prodrug because of its poor antitumor efficiency. But surprisingly, it was found in our study that PEG-PTX could form a novel nanoparticle system with free PTX. To address how this system works, we compared PTX loaded PEG-PTX nanoparticles (PEG-PTX/PTX) with PTX loaded PEG-PLA micelles (PEG-PLA/PTX) or PTX injection available (Taxol(®)) in vitro and in vivo. Firstly, it was found that PEG-PTX/PTX was more stable in aqueous solution than PEG-PLA/PTX in terms of PTX crystal formation and drug release. Then it was demonstrated that coumarin loaded PEG-PTX nanoparticles had a much higher uptake in MCF-7 cells compared to coumarin loaded PEG-PLA micelles. The in vivo imaging study revealed that DIR or DID (near infrared fluorescent substances) loaded PEG-PTX nanoparticles distributed more in tumors in MCF-7 tumor bearing mice than DIR or DID loaded PEG-PLA micelles and solvent system of Taxol(®). In the efficacy study with MCF-7 tumor bearing mice, PEG-PTX/PTX showed significantly higher antitumor activity than PEG-PLA/PTX at the same PTX dosage. At the dose of 10mg free PTX per kg, PEG-PTX/PTX displayed similar efficacy as Taxol(®) but less toxicity evaluated by the loss of body weight. With the increase of free PTX to 15mg/kg, PEG-PTX/PTX showed significantly better efficacy than Taxol(®). In conclusion, with favorable characteristics in stability, cellular uptake, cytotoxicity, biodistribution, safety and efficacy, PEG-PTX/PTX seems highly potential as a nanocarrier for PTX delivery.
    International Journal of Pharmaceutics 05/2014; 471(1-2). DOI:10.1016/j.ijpharm.2014.05.032 · 3.79 Impact Factor
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    ABSTRACT: Receptor change induced by ligand binding is a new issue to face in the field of targeted delivery. Receptor clustering, the main pattern of receptor changes, decreases the affinity between ligand and receptor due to the redistribution of receptor position. In an attempt to respond to such challenge, we designed and constructed three RGD-modified nanocarriers with different ligand intervals: stealth liposomes modified with the monomeric RGD (moRGD-LP), dimeric RGD (diRGD-LP) and a special dimeric RGD with a linker between two cyclic RGD motifs (P-diRGD-LP). The αvβ3-positive and -negative tumor cells (Melanoma B16 and MCF-7) were used as the cell models. As a result, P-diRGD-LP demonstrated strongest interaction with B16 cells in surface plasmon resonance study and highest cellular uptake in B16 cells in real-time confocal analysis. The enhanced endocytosis of P-diRGD-LP was found to be αvβ3-mediated and P-diRGD-LP increased the involvement of the clathrin-dependent pathway. Importantly, P-diRGD-LP demonstrated the best targeting effect in B16-tumor bearing mice in both in vivo and ex vivo near-infrared fluorescent images, about 2.4-fold that of moRGD-LP and 2.8-fold that of diRGD-LP at 3 h. Further, we validated integrin αvβ3 clustering on B16 cells via a single-molecule imaging by a total internal reflection fluorescence microscopy. Finally, the 3D models of αvβ3 clustering suggested a receptor interval within 41.916-65.779 Å, while the molecular computation revealed an RGD ligand interval of 20.944 Å, 42.753 Å and 78.196 Å for diRGD-LP, P-diRGD-LP and moRGD-LP, respectively, confirming the best matching between clustered αvβ3 and P-diRGD-LP. In conclusion, P-diRGD-LP could achieve higher targeting to αvβ3-positive tumor via the enhanced interaction based on the better ligand-receptor compatibility. The design of targeted nanocarriers against receptor clustering might provide new insight into the nanotechnology-based anticancer therapy.
    Biomaterials 04/2014; DOI:10.1016/j.biomaterials.2014.04.031 · 8.31 Impact Factor
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    ABSTRACT: Abstract iRGD is a tumor tissue penetrating peptide due to its targeted binding of integrin and neuropilin-1 receptors. Whether iRGD carries the liposomes in a similar way as it penetrates the cancer drugs or conjugated drugs into tumor tissues and cells has not been fully defined. Here, iRGD-modified and doxorubicin-loaded sterically stabilized liposomes (iRGD-SSL-DOX) and passive liposomes (SSL-DOX) were prepared. A series of experiments were performed to evaluate the tissue penetration, cell penetration, tumor blood vessel damage and anti-tumor effect. The results of flow cytometry and confocal microscopy studies showed that iRGD-SSL-DOX with 5% DSPE-PEG2000-iRGD achieved higher cellular uptake level than that of SSL-DOX on B16 melanoma cells. iRGD-SSL-DOX also exhibited stronger cell growth inhibition in cytotoxicity experiments. The tumor penetrating effect of iRGD was further confirmed by imaging and cellular uptake studies in vivo, in which higher distribution of iRGD-modified liposomes in tumor tissue and tumor cells was observed. Moreover, iRGD-SSL-DOX displayed improved tumor growth inhibition and anti-angiogenesis with less systemic toxicity in an armpit B16 melanoma model. In conclusion, iRGD reserved its tumor-penetrating properties well when modified on the surface of liposomes at optimal density and iRGD-SSL-DOX would be a promising drug delivery system for active targeting tumor therapy.
    Drug Delivery 04/2014; DOI:10.3109/10717544.2014.903580 · 2.20 Impact Factor
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    ABSTRACT: A liposome system modified with chlorotoxin (ClTx), a scorpion venom peptide previously utilized for targeting brain tumors, was established. Its targeting efficiency and anti-metastasis behavior against metastatic breast cancer highly expressed MMP-2, the receptor of ClTx, were investigated. 4T1, a metastatic breast cancer cell line derived from a murine breast tumor, was selected as the cell model. As the results, the ClTx-modified liposomes displayed specific binding to 4T1 as determined by flow cytometry and confocal imaging. The cytotoxicity assay revealed that the ClTx modification increased the toxicity compared with non-modified liposomes. In addition, the modified liposomes also exhibited high in vivo targeting efficiency effect in the BALB/c mice bearing 4T1 tumors. Importantly, this system inhibited the growth of metastatic tumor and prevented the incidence of lung metastasis in mice bearing 4T1 tumors with only low systemic toxicity. The data obtained from the in vitro and in vivo studies confirmed that the ClTx-modified liposomes increased the drug delivery to metastatic breast cancers. This study proved that the ClTx-modified liposomes had the targeting ability to metastatic breast cancer in addition to brain cancer, and displayed obvious anti-metastasis effect. Generally, it may provide a promising strategy for metastatic breast cancer therapy.
    Molecular Pharmaceutics 02/2014; 11(10). DOI:10.1021/mp400691z · 4.79 Impact Factor
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    ABSTRACT: Receptor change induced by ligand binding is a new issue to face in the field of targeted delivery. Receptor clustering, the main pattern of receptor changes, decreases the affinity between ligand and receptor due to the redistribution of receptor position. In an attempt to respond to such challenge, we designed and constructed three RGD-modified nanocarriers with different ligand intervals: stealth liposomes modified with the monomeric RGD (moRGD-LP), dimeric RGD (diRGD-LP) and a special dimeric RGD with a linker between two cyclic RGD motifs (P-diRGD-LP). The αvβ3-positive and -negative tumor cells (Melanoma B16 and MCF-7) were used as the cell models. As a result, P-diRGD-LP demonstrated strongest interaction with B16 cells in surface plasmon resonance study and highest cellular uptake in B16 cells in real-time confocal analysis. The enhanced endocytosis of P-diRGD-LP was found to be αvβ3-mediated and P-diRGD-LP increased the involvement of the clathrin-dependent pathway. Importantly, P-diRGD-LP demonstrated the best targeting effect in B16-tumor bearing mice in both in vivo and ex vivo near-infrared fluorescent images, about 2.4-fold that of moRGD-LP and 2.8-fold that of diRGD-LP at 3 h. Further, we validated integrin αvβ3 clustering on B16 cells via a single-molecule imaging by a total internal reflection fluorescence microscopy. Finally, the 3D models of αvβ3 clustering suggested a receptor interval within 41.916–65.779 Å, while the molecular computation revealed an RGD ligand interval of 20.944 Å, 42.753 Å and 78.196 Å for diRGD-LP, P-diRGD-LP and moRGD-LP, respectively, confirming the best matching between clustered αvβ3 and P-diRGD-LP. In conclusion, P-diRGD-LP could achieve higher targeting to αvβ3-positive tumor via the enhanced interaction based on the better ligand-receptor compatibility. The design of targeted nanocarriers against receptor clustering might provide new insight into the nanotechnology-based anticancer therapy.
    Biomaterials 01/2014; 35(23):6106–6117. · 8.31 Impact Factor
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    ABSTRACT: Based on the hydrophobic interaction with biomembranes, PFVYLI (PFV), a hydrophobic penetration peptide (HPP), was initially introduced to modify doxorubicin-loaded stealth-sustained liposomes (PFV-SSLs-DOX) against different breast cancer cell phenotypes irrespective of their receptor expression or antigen presence. The physicochemical characteristics of PFV-SSLs were determined with approximately 100 nm size, satisfactory distribution and high encapsulation. In addition, drug release experiments demonstrated that modification with PFV has a negligible influence on the release profile of liposomes. Surface plasmon resonance (SPR) analysis revealed that PFV-modified liposomes could increase the binding proportion of PFV-SSLs with a model cell membrane. It was demonstrated that modification with PFV highly facilitated the intracellular delivery of DOX-loaded liposomes and enhanced cytotoxicity via a hydrophobic interaction. An endocytosis inhibition assay revealed a combination of cellular internalization mechanisms for PFV-SSLs involving lipid raft and clathrin-mediated endocytosis in a temperature-dependent manner. The PFV-modified liposomes displayed more lasting accumulation in the tumor and better tumor growth inhibition with relatively low systemic and cardiac toxicity. In conclusion, PFV-SSLs might be a promising delivery system for the delivery of different therapeutic or imaging agents to heterogeneous tumors. More significantly, this study provides a new perspective on developing HPP-modified drug delivery system for antitumor therapy.
    Biomaterials 12/2013; 35(7). DOI:10.1016/j.biomaterials.2013.11.088 · 8.31 Impact Factor
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    ABSTRACT: Abstract Low dissolution rate of a poorly water soluble drug often leads to low and variable oral bioavailability. Formulating drugs as nanocrystals can help to overcome these problems by increasing the solubility and dissolution velocity. But different preparation approaches may result in different nanocrystals with different characteristics. In this study, three types of fenofibrate nanocrystals (FNT-NCs) were prepared by bottom-up methods, antisolvent and thermal precipitation under different conditions. These FNT-NCs were characterized by scanning electron micrography, dissolution testing, differential scanning calorimetry and powder X-ray diffractometry. A significant increase of dissolution rate was observed in the drug nanocrystals compared to the crude FNT powder (from 20% to 80% in 5 min). The crystallinity of the FNT-NCs prepared by antisolvent precipitation increased slightly, while that by thermal precipitation decreased. The oral bioavailability of two types of FNT-NCs prepared by antisolvent precipitation in rats increased notably compared to that of the crude powder (5.5-folds and 5.0-folds, respectively). However, the oral absorption of FNT-NCs prepared by thermal precipitation did not increase, although its dissolution rate was higher than that of the crude powder. In conclusion, different bottom-up methods produce different FNT-NCs with different crystallinity, which results in different oral bioavailability. Namely, a careful study and rational choice on preparation approaches are significant for the nanocrystal techniques.
    Drug Delivery 12/2013; 21(8). DOI:10.3109/10717544.2013.865815 · 2.20 Impact Factor
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    ABSTRACT: Cancer metastasis is difficult to treat and its outcome becomes dreadful for a patient. Lung is a major metastatic site for many types of cancers and the need for finding effective treatment for lung metastasis cannot be overemphasized. In a previous study, we showed that camptothecin nanocrystals demonstrated greater anticancer efficacy and achieved significantly higher concentration in lungs than a conventional, solution-based formulation. In this study, we further determined the pharmacokinetics of camptothecin nanocrystals in rats and investigated treatment efficacy in mice against metastatic lung tumors. The results show that camptothecin nanocrystals were capable of eliciting greater anti-metastatic efficacy and achieve longer survival time in the murine model compared with camptothecin salt solution. The study suggests that using engineered, solid nanoparticles may be a feasible approach in the treatment of lung cancer and lung metastatic cancer.
    Molecular Pharmaceutics 12/2013; 11(1). DOI:10.1021/mp4004018 · 4.79 Impact Factor

Publication Stats

2k Citations
452.73 Total Impact Points

Institutions

  • 2004–2015
    • Peking University
      • • School of Pharmaceutical Sciences
      • • State Key Laboratory of Natural and Biomimetic Drugs
      • • Health Science Center
      Peping, Beijing, China
  • 2012
    • State Key Laboratory of Medical Genetics of China
      Ch’ang-sha-shih, Hunan, China
  • 2011
    • University of Kentucky
      • Department of Pharmaceutical Sciences
      Lexington, Kentucky, United States
  • 2004–2009
    • Fudan University
      • State Key Laboratory of Medical Neurobiology
      Shanghai, Shanghai Shi, China
  • 2003–2009
    • Peking University Health Science Center
      • Department of Biochemistry and Molecular Biology
      Beijing, Beijing Shi, China