Yuan Huang

Sichuan University, Hua-yang, Sichuan, China

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Publications (60)203.75 Total impact

  • [Show abstract] [Hide abstract]
    ABSTRACT: Tumor cell nucleus-targeted delivery of antitumor agents is of great interest in cancer therapy, since the nucleus is one of the most frequent targets of drug action. Here we report a smart polymeric conjugate platform, which utilizes stimulus-responsive strategies to achieve multistage nuclear drug delivery upon systemic administration. The conjugates composed of a backbone based on N-(2-hydroxypropyl) methacrylamide (HPMA) copolymer and detachable nucleus transport sub-units that sensitive to lysosomal enzyme. The sub-units possess a biforked structure with one end conjugated with the model drug, H1 peptide, and the other end conjugated with a novel pH-responsive targeting peptide (R8NLS) that combining the strength of cell penetrating peptide and nuclear localization sequence. The conjugates exhibited prolonged circulation time and excellent tumor homing ability. And the activation of R8NLS in acidic tumor microenvironment facilitated tissue penetration and cellular internalization. Once internalized into the cell, the sub-units were unleashed for nuclear transport through nuclear pore complex. The unique features resulted in 50-fold increase of nuclear drug accumulation relative to the original polymer-drug conjugates in vitro, and excellent in vivo nuclear drug delivery efficiency. Our report provides a strategy in systemic nuclear drug delivery by combining the microenvironment-responsive structure and detachable sub-units. Copyright © 2015 Elsevier Ltd. All rights reserved.
    Biomaterials 10/2015; 65. DOI:10.1016/j.biomaterials.2015.06.042 · 8.56 Impact Factor
  • Lei Wu · Min Liu · Xi Zhu · Wei Shan · Yuan Huang
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    ABSTRACT: Mucosal drug delivery is considered as a convenient, mild and safe route, especially for the treatment of chronic diseases. In general, mucosal routes include buccal, ocular, intranasal, pulmonary, vaginal and oral delivery. To increase the efficiency of mucosal delivery, nanocarriers have been extensively explored, of which lipid-based nanocarriers attract much attention due to their great biocompatibility, cell membrane affinity and other excellent physicochemical properties by using different kinds of lipids. However, the effectiveness of lipid-based nanocarriers is limited by numerous in vivo physiological barriers (e.g. chemical environment, mucus and epithelium) in tracts or cavities. Herein, modification strategies of these nanocarriers are widely investigated and show great improvement of drug bioavailability. The aim of this review is to introduce applications of lipid-based nanocarriers in different mucosal routes and discuss typical modification strategies.
    Current pharmaceutical design 09/2015; · 3.45 Impact Factor
  • Jiexiu Chen · Chong Liu · Wei Shan · Zhijian Xiao · Han Guo · Yuan Huang
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    ABSTRACT: Oral insulin delivery is often limited by protease degradation. 2-(Dimethylamino)-2-oxoethyl 4-(4-guanidinobenzoyloxy)phenylacetate methanesulphonate (Camostat mesylate) is reported to have the ability to inhibit trypsin activity, which is the main protease responsible for protein degradation. This study attempted to form a novel nanoparticle by covalently conjugating 4-(2-(2-aminoethylamino)-2-oxoethyl)phenyl 4-guanidinobenzoyloxy (FOY-251), an active derivative of camostat mesylate, to the backbone of poly (γ-glutamic acid) (γ-PGA), in order to improve insulin stability against protease. Goblet cell targeting CSKSSDYQC (CSK) peptide was demonstrated to effectively improve the epithelial absorption of insulin. Therefore, the novel nanoparticle was prepared by mixing cationic peptide modified trimethyl chitosan (TMC-CSK) with anionic γPGA-FOY conjugate using multi-ion crosslinked method. Results showed that not only the γPGA-FOY conjugate but also the prepared novel nanoparticle could inhibit trypsin activity both in vitro environment and on the intestinal mucosal surface. This study would be beneficial for peptide modified nanoparticles in oral insulin delivery.
    Journal of Microencapsulation 09/2015; DOI:10.3109/02652048.2015.1065920 · 1.59 Impact Factor
  • Wei Sun · Lian Li · Qingqing Yang · Wei Shan · Zhirong Zhang · Yuan Huang
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    ABSTRACT: Galectin-3 is over-expressed by numerous carcinomas, and is a potential target for active tumor treatments. On the other hand, galectin-3 also plays a key role in cancer progression and prevents cells from undergoing apoptosis, thereby offsetting the benefits of active targeting drugs. However, the relative contribution of the protective antiapoptotic effects of galectin-3 and the proapoptotic effects of galectin-3-targeted therapies has remained yet unrevealed. Here, we show a galectin-3-binding peptide G3-C12 could reverse galectin-3 from foe to friend for active targeting delivery system. Results showed G3-C12 modified N-(2-hydroxypropyl) methacrylamide copolymer doxorubicin conjugates (G3-C12-HPMA-Dox) could internalize into galectin-3 over-expressed PC-3 cells via a highly specific ligand-receptor pathway (2.2 times higher cellular internalization than HPMA-Dox). The internalized Dox stimulated the translocation of galectin-3 to the mitochondria to prevent from apoptosis. In turn, this caused G3-C12-HPMA-Dox to concentrate into the mitochondria after binding to galectin-3 intracellularly. Initially, mitochondrial galectin-3 weakened Dox-induced mitochondrial damage; however, as time progressed, G3-C12 active-mediation allowed increasing amounts of Dox to be delivered to the mitochondria, which eventually induced higher level of apoptosis than non-targeted copolymers. In addition, G3-C12 down-regulates galectin-3 expression, 0.43 times lower than control cells, which could possibly be responsible for the suppressed cell migration. Thus, G3-C12 peptide exerts sequential targeting to both cell membrane and mitochondria via regulating galectin-3, and eventually reverses and overcomes the protective effects of galectin-3; therefore, it could be a promising agent for the treatment of galectin-3-overexpressing cancers.
    Molecular Pharmaceutics 09/2015; DOI:10.1021/acs.molpharmaceut.5b00568 · 4.38 Impact Factor
  • Chong Liu · Wei Shan · Min Liu · Xi Zhu · Juan Xu · Yining Xu · Yuan Huang
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    ABSTRACT: In order to enhance the interaction between nanocarrier and gastrointestinal epithelial cells, we developed nanoparticles (NPs) modified with targeting ligand FQSIYPpIK (FQS), which specifically interact with integrin αvβ3 receptor expressing on the intestinal epithelium. The targeting NPs were prepared by coating the insulin-loaded poly(lactide-co-glycolide)-monomethoxy-poly(polyethylene glycol) micelle cores with FQS modified trimethyl chitosan chloride. In in vitro study, the fabricated NPs showed ameliorated drug release profile and improved enzymatic stability compared with micelles alone. In the integrin αvβ3 receptor over-expressed Caco-2 cells model, FQS modified NPs exhibited significantly accelerated intracellular uptake due to the active ligand-receptor mediation. Meanwhile, the targeting NPs also showed enhanced transport across the Caco-2 monolayer cells via both transcellular and paracellular pathways. Besides, orally administered FQS modified NPs produced a prominent hypoglycemic response and an increase of the serum insulin concentration in diabetic rats. Both in vitro and in vivo results demonstrated the FQS peptide modified NPs as promising intestinal cell-targeting nanocarriers for efficient oral delivery of insulin.
    Drug Delivery 07/2015; DOI:10.3109/10717544.2015.1058433 · 2.56 Impact Factor
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    ABSTRACT: The nucleus is the final target of many first-line chemotherapeutics, but the need to overcome multiple physiological barriers imposes conflicting requirements for size and charge on systemically administered drug delivery systems. Here, an N-(2-hydroxypropyl) methacrylamide (HPMA) polymer-based nanovehicle (PNV) that self-assembles from anionic HPMA copolymers with charge-reversal ability and cationic HPMA copolymers with intracellularly detachable subgroups (IDS) is described. The IDS, bearing an anticancer drug and nuclear-homing cell-penetrating peptide (R8NLS ligand), is grafted onto the HPMA copolymer via hydrazone linkage. The large, neutrally charged, self-assembled PNV (≈55 nm) shows good blood persistence and preferential tumor accumulation. After tumoral arrival, the extracellular milieu actuates the disassembly of PNV to linear conjugates (≈10 nm/39 kDa). This first-stage size reduction exposes R8NLS and allows for deeper tissue penetration and greater cellular internalization. After endocytosis, a second-stage size reduction occurs when the more acidic endolysosomal pH cleaved the ≈2.4 kDa IDS off the HPMA copolymer backbone and guaranteed the successful nuclear entry via nuclear localization signal assistance. Based on the stepwise size reduction and on-demand R8NLS exposure, the PNV inhibits growth of HeLa tumors in nude mice by 75%. This work gives important insights into the design of systemic nuclear-targeted delivery via a multistage size/charge changing way.
    Advanced Functional Materials 05/2015; 25(26). DOI:10.1002/adfm.201501248 · 11.81 Impact Factor
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    ABSTRACT: The purpose of this study was to formulate nanoparticles with an elaborate structure for oral delivery of exendin-4 using a simple preparation process. The nanoparticles possessed a mixed lipid shell and an aqueous core which contained drug-loaded micelles. Formulation was optimized by a central composite design and the structure of the nanoparticles was validated. The efficacy for delivery of exendin-4 was evaluated both in vitro and in vivo. The drug encapsulation efficiency of the nanoparticles reached 97.7%. The nanoparticles greatly enhanced the cellular uptake and transport of encapsulated exendin-4 in vitro. The in situ study showed that exendin-4 could be transported across the epithelium into intestinal capillaries, while the lipid materials largely remained in the epithelium. Pharmacodynamic studies in diabetic KKAy mice demonstrated that the exendin-4-loaded nanoparticles exhibited a marked hypoglycemia effect with a pharmacological availability of 12.7% after intestinal administration.
    Journal of Biomedical Nanotechnology 05/2015; 11(5). DOI:10.1166/jbn.2015.1971 · 5.34 Impact Factor
  • Zhou Zhou · Xiuli Xu · Lian Li · Yuan Huang
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    ABSTRACT: Non-small cell lung carcinoma is one of the most frequently occurred cancers with a very high rate of recurrence. Self-assembly N-(2-hydroxypropyl) methacrylamide (HPMA) micelles and cross-linked micelles were developed to improve antitumor ability of linear HPMA copolymer. The characters of HPMA micelles were investigated and compared using human non-small cell lung carcinoma 3-D culture model and nude mice xenograft model. Cross-linked micelles showed highest cytotoxicity on A549 cell monolayers after a short time treatment in vitro. Moreover, both of the two micelles exhibited better in vitro anti-tumor activity on A549 tumor spheroids than linear HPMA conjugates especially the cross-linked micelles. On BALB/c nude mice bearing A549 xenograft tumors, the cross-linked micelles exhibited the greatest tumor accumulation and the best anti-tumor activity due to the highly improved stabilities and the more pronounced enhanced permeability and retention (EPR) effect, which were followed by the non-cross-linked micelles. Meanwhile, neither the two micelles nor the linear HPMA copolymers showed significant toxicity on the main organs of mice while free doxorubicin (DOX) showed obvious cardiac toxicity. All the results suggested that micellization improved the anti-tumor activity of HPMA copolymers on A549 human non-small cell lung carcinoma, furthermore, cross-linked HPMA copolymer micelles with pH-sensitivity and biodegradability showed more excellent anti-tumor activity.
    Journal of Drug Targeting 04/2015; DOI:10.3109/1061186X.2015.1025076 · 2.74 Impact Factor
  • Zhiyang Ke · Han Guo · Xi Zhu · Yun Jin · Yuan Huang
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    ABSTRACT: We investigated the effect of vitamin B12 (VB12) modification on the insulin absorption from trimethyl chitosan(TMC) nanoparticles (NPs) under the influence of mucus. TMC and TMC-VB12 were synthesized and insulin loaded TMC/TMC-VB12 nanoparticles were prepared and characterized. Modified and unmodified nanoparticles were studied with Caco-2/HT29-MTX cell model and ligated rat ileum loop. Compared with unmodified NPs, VB12 modified NPs showed significantly higher drug internalization in Caco-2/HT29-MTX cell model. The internalization mechanism via VB12 mediation included caveolae and clathrin-mediated endocytosis pathway. Meanwhile, an increased transportation of drugs was observed for VB12 modified NPs, possibly due to the ligand-receptor interaction via an intrinsic factor-dependent fashion. Although the uptake and transport of VB12 modified NPs could be partially influenced by mucus, they still showed higher drug permeation through Caco-2/HT29-MTX co-cultured cells than unmodified NPs in the presence or absence of mucus. Moreover, in situ study in ligated rat ileum loop demonstrated that VB12 modified nanoparticles could reduce the residual insulin in intestinal lumen (0.59 times) and increase their absorption in epithelial tissue (4.8 times) compared with the unmodified ones. VB12 modified trimethyl chitosan nanoparticle is a promising carrier for peroral delivery of insulin. This article is open to POST-PUBLICATION REVIEW. Registered readers (see "For Readers") may comment by clicking on ABSTRACT on the issue's contents page.
    Journal of Pharmacy and Pharmaceutical Sciences 04/2015; 18(2):155-70. · 1.86 Impact Factor
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    Qingqing Yang · Yang Yang · Lian Li · Wei Sun · Xi Zhu · Yuan Huang
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    ABSTRACT: To improve the therapeutic efficacy of anticancer combination therapy, we designed a nano-platform based on N-(2-hydroxypropyl) methacrylamide (HPMA) copolymers that allows covalent bonding of two chemotherapeutics acting via different anticancer mechanisms and that can enter target cells by receptor-mediated endocytosis. Doxorubicin (DOX) was covalently conjugated to a nano-sized HPMA copolymer using a pH-sensitive hydrazone bond and 5-fluorouracil (5-Fu) was conjugated to the same backbone using an enzymatically degradable oligopeptide Gly-Phe-Leu-Gly sequence. Then the conjugate was decorated with galectin-3 targeting peptide G3-C12 [P-(G3-C12)-DOX-Fu]. The two drugs showed similar in vitro release profiles, suggesting that they may be able to work synergistically in the co-delivery system. In galectin-3 overexpressed PC-3 human prostate carcinoma cells, P-(G3-C12)-DOX-Fu surprisingly exhibited comparable cytotoxicity to free DOX at high concentration by increasing cell internalization and exerting synergistic genotoxic effects of cell cycle arrest, caspase-3 activation and DNA damage. In mice bearing PC-3 tumor xenografts, the use of tumor-targeting ligand substantially enhanced the intracellular delivery of P-(G3-C12)-DOX-Fu in tumors. The targeted dual drug-loaded conjugate inhibited tumor growth to a greater extent (tumor inhibition of 81.6%) than did non-targeted P-DOX-Fu (71.2%), P-DOX (63%), DOX.HCl (40.5%), P-Fu (32.0%) or 5-Fu (14.6%), without inducing any obvious side effects. These results demonstrate the potential of synergistic combination therapy using targeted nanocarriers for efficient treatment of prostate cancer.
    ACS Applied Materials & Interfaces 03/2015; 7(12). DOI:10.1021/am509204u · 6.72 Impact Factor
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    Min Liu · Jian Zhang · Wei Shan · Yuan Huang
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    ABSTRACT: Mucus can effectively protect the exposed mucosal surfaces due to its adhesive and viscoelastic properties. Most foreign particulates are efficiently trapped in mucus layers via steric obstruction and adhesion. Trapped particles are typically removed from the mucosal tissue within seconds to a few hours depending on their location sites. This article focuses on describing the tenacious mucus barrier properties, the strategies to investigate the interaction of nanoparticles with the mucus as well as the novel developments of mucus penetrating nanoparticles.
    Asian Journal of Pharmaceutical Sciences 02/2015; 55(4). DOI:10.1016/j.ajps.2014.12.007
  • Wei Shan · Xi Zhu · Min Liu · Lian Li · Jiaju Zhong · Wei Sun · Zhirong Zhang · Yuan Huang
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    ABSTRACT: Nanoparticles (NPs) have demonstrated great potential for the oral delivery of protein drugs that have very limited oral bioavailability. Orally administered NPs could be absorbed by the epithelial tissue only if they successfully permeated through the mucus that covering the epithelium. However, efficient epithelial absorption and mucus permeation require very different surface properties of a nanocarrier. We herein reported self-assembled NPs for efficient oral delivery of insulin by facilitating both of these two processes. The NPs possessed a nanocomplex core composed of insulin and cell penetrating peptide (CPP), and a dissociable hydrophilic coating of N-(2-hydroxypropyl) methacrylamide copolymer (pHPMA) derivatives. After systematic screening using mucus-secreting epithelial cells, NPs exhibited excellent permeation in mucus due to the "mucus-inert" pHPMA coating, as well as high epithelial absorption mediated by CPP. The investigation of NP behavior showed that the pHPMA molecules graduated dissociated from the NP surface as it permeated through mucus, and the CPP-rich core was revealed in time for subsequent transepithelial transport through the secretory endoplasmic reticulum/Golgi pathway and endocytic recycling pathway. The NPs exhibited 20-fold higher absorption than free insulin on mucus-secreting epithelium cells, and orally administered NPs generated a prominent hypoglycemic response and an increase of the serum insulin concentration in diabetic rats. Our study provided the evidence of using pHPMA as dissociable "mucus-inert" agent to enhance mucus permeation of NPs, and validated a strategy to overcome the multiple absorption barriers using NP platform with dissociable hydrophilic coating and drug-loaded CPP-rich core.
    ACS Nano 02/2015; 9(3). DOI:10.1021/acsnano.5b00028 · 12.88 Impact Factor
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    Qingqing Yang · Lian Li · Xi Zhu · Wei Sun · Zhou Zhou · Yuan Huang
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    ABSTRACT: Thanks to the enhanced cancer cell affinity, modification of polymeric drug carriers with an active targeting ligand has been one of the most effective strategies to achieve better therapeutic efficacy. However, hydrophobic ligands (e.g. folate), when conjugated to hydrophilic carriers, encounter the problem of reduced targeting effectiveness due to the fact that the ligand may be buried inside the carrier. In the present study, we studied the impact of the hydrophilic polymer structure on the targeting efficiency of the conjugated folate (FA). After modification with folate, the linear N-(2-hydroxypropyl)-methacrylamide (HPMA) polymer (P-FA, 27.3 kDa) exhibited a neutral surface charge (1.5 mV), while the graft HPMA polymer (GP-FA, 117.4 kDa) possessed a mild negative charge (−7.2 mV), which suggests different exposure levels of negatively charged folate on the surface of P-FA and GP-FA. Notably, on folate receptor positive MCF-7 cells, P-FA exhibited comparable cell uptake with the unmodified linear polymer, whereas GP-FA resulted in 2-fold higher cell internalization over the untargeted graft polymer. Meanwhile, the involvement of folate receptor mediated endocytosis and augmented folate binding affinity of GP-FA were observed in comparison with P-FA. Moreover, GP-FA exhibited significantly enhanced tumor accumulation relative to GP, while marginally improved tumor accumulation was observed for P-FA compared with P. In summary, the structure of the hydrophilic polymer plays a vital role in the targeting efficiency of the conjugated hydrophobic ligand.
    RSC Advances 01/2015; 5(19):14858-14870. DOI:10.1039/C4RA16085A · 3.84 Impact Factor
  • Yuan Huang · Xun Sun
    Molecular Pharmaceutics 10/2014; 11(10):3231-2. DOI:10.1021/mp5005542 · 4.38 Impact Factor
  • Zhou Zhou · Lian Li · Yang Yang · Xiuli Xu · Yuan Huang
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    ABSTRACT: Increasing the molecular weight of N-(2-hydroxypropyl) methacrylamide (HPMA) copolymers by using micellar structures could result in more pronounced enhanced permeability and retention effect, thus increase the tumor accumulation of drug. However, most micellar formulations are relatively unstable and release their drug non-specifically. To improve on these disadvantages, we developed a micellar drug delivery system based on self-assembly of HPMA copolymers. Amphiphilic conjugates were synthesized by conjugating the hydrophobic drug doxorubicin and hydrophobic β-sitosterol to the hydrophilic HPMA polymer backbone via pH-sensitive hydrazone linkages. This linkage is quite stable at physiological pH but hydrolyzes easily at acidic pH. After conjugates self-assembly into micelles, HPMA copolymer side chains were cross-linked through the hydrazone linkages to ensure micelle stability in the blood. Using this approach, cross-linked micelles were obtained with molecular weight of 1030 KD and diameter of 10–20 nm. These micelles remained stable with undetectable doxorubicin release at pH 7.4 or mouse plasma, whereas collapsed quickly with 80% of the drug released at pH 5 which corresponds to the pH of lyso/endosome compartments of tumor cells. Both cross-linked and non-cross-linked micelles displayed similar in vitro anti-tumor activity as linear copolymer conjugates in Hep G2 and A549 cancer cell lines with internalization mechanism by caveolin, clathrin, and giant macropinocytosis. In vivo studies in an H22 mouse xenograft model of hepatocarcinoma showed the tumor accumulation (1633 μCi/L*h) and anti-tumor rate (71.8%) of cross-linked micelles were significantly higher than non-cross-linked ones (698 μCi/L*h, 64.3%). Neither type of micelle showed significant toxicity in heart, lung, liver, spleen or kidney. These results suggest that cross-linked HPMA copolymer micelles with pH-sensitivity and biodegradability show excellent potential as carriers of anti-cancer drugs.
    Biomaterials 08/2014; 35(24):6622–6635. DOI:10.1016/j.biomaterials.2014.04.059 · 8.56 Impact Factor
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    ABSTRACT: Designing feasible and effective peptide ligand modified solid lipid nanoparticles (SLNs) to improve oral bioavailability of protein drugs and evaluating the influence of mucus remains important. In the present work, two kinds of peptide ligand modified SLNs loaded with salmon calcitonin (sCT), namely, sCT CSK-SLNs and sCT IRQ-SLNs, were prepared by coupling the peptide ligand CSKSSDYQC (CSK) which was reported to show affinity with goblet cells, or IRQRRRR (IRQ), a cell penetrating peptide, to polyoxyethylene (40) stearate (SA-PEG2000). Compared with unmodified SLNs, CSK or IRQ modified SLNs with better drug protection ability could facilitate the internalization of drug on Caco-2/HT29-MTX co-cultured cells and permeation in excised rat duodenum mucosa. The internalization mechanism of two kinds of peptide ligand modified SLNs was mainly active transport via both clathrin- and caveolae-dependent endocytosis. Although mucus was an impediment to the transport of SLNs, the peptide ligand modified SLNs still showed improved drug absorption. The absolute bioavailability of sCT CSK-SLNs (12.41 ± 3.65%) and sCT IRQ-SLNs (10.05 ± 5.10%) raised to 2.45-fold and 1.98-fold compared with unmodified SLNs (5.07 ± 0.54%), implying the feasibility and effectiveness of CSK and IRQ peptide modification for the enhancement of the oral bioavailability of protein drugs. In summary, the nanoparticles modified with CSK or IRQ peptide ligand could be the potential carriers for the transport of protein drugs across intestinal barriers.
    European Journal of Pharmaceutics and Biopharmaceutics 06/2014; 88(2). DOI:10.1016/j.ejpb.2014.06.011 · 3.38 Impact Factor
  • Yang Yang · Lian Li · Zhou Zhou · Qingqing Yang · Chong Liu · Yuan Huang
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    ABSTRACT: Prostate carcinoma is the second leading cause of cancer-related deaths. Increased expression of membrane-bound galectin-3 by prostate carcinoma cell has been found to correlate with more poorly differentiated and increased metastatic potential. In the present study, different amount of galectin-3-binding peptide, G3-C12 (the sequence ANTPCGPYTHDCPVKR), was attached to N-(2-hydroxypropyl) methacrylamide (HPMA) copolymers as targeting moiety. The results of qPCR and competitive binding test indicated that the expression level of galectin-3 in two metastatic prostate carcinoma cell lines (PC-3 and DU145 cells) could be significantly suppressed by the addition of G3-C12-modified HPMA copolymers (PG1 and PG2), demonstrating the high affinity of PG1 and PG2 to galectin-3. Due to the multivalent effects of moieties, the uptake of copolymers was remarkably enhanced with the increasing amount of conjugated G3-C12 peptide. A higher internalization of PG1 and PG2 was occurred in PC-3 cells via caveolin- and clathrin-mediated endocytosis while clathrin-mediated uptake process was involved in DU145 cells. The in vivo biodistribution and pharmacokinetics of non-modified (131I-pHPMA) and G3-C12-modified (131I-PG1 and 131I-PG2) copolymers were estimated on a well-established mice model bearing PC-3 xenografts by 131I-SPECT-imaging. Higher tumor accumulation of 131I-PG1 (1.60 ± 0.08 % ID/g, p<0.05) and 131I-PG2 (1.54 ± 0.06 % ID/g, p<0.05) was observed compared with 131I-pHPMA (1.19 ± 0.04 % ID/g) at 2h post intravenous injection. Although the amount of conjugated G3-C12 peptide performed a remarkable in vitro effect on the affinity and internalization of HPMA copolymers to the galectin-3 over-expressed prostate carcinoma cells, the molecular weight and ligand modification all play important roles on their in vivo tumor accumulation.
    Molecular Pharmaceutics 06/2014; 11(10). DOI:10.1021/mp500083u · 4.38 Impact Factor
  • Lian Li · Qingqing Yang · Zhou Zhou · Jiaju Zhong · Yuan Huang
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    ABSTRACT: Although folate exhibits many advantages over other targeting ligands, it has one major defect: poor water solubility. Once it was conjugated to hydrophilic drug carrier such as N-(2-hydroxypropyl) methacrylamide (HPMA) copolymer, the hydrophobic folate may be buried inside the random polymer coil and not exposed to be accessible to its receptor on the cell surface, thus losing its active targeting ability. To address this folate dilemma, the positive charge was introduced in the present study. The obtained cationic folate-functionalized HPMA copolymers exhibited a synergistic enhancing effect on cellular uptake by folate receptor (FR) positive Hela cells via electrostatic absorptive endocytosis and folate receptor-mediated endocytosis, with the involvement of multiple internalization pathways including clathrin-mediated endocytosis, caveolae-mediated endocytosis, macropinocytosis and energy-dependent endocytosis. As demonstrated in binding efficiency study, the FR antibody bound to 71.2% of tested cells in the competition with neutral folate modified HPMA copolymers, while the FR antibody-bounded cells decreased to only 34.0% in competition with cationic folate modified HPMA copolymers, indicating that the positively charge could probably amplify the binding efficiency of folate to its receptor due to close proximity of the conjugates to the cell surface by the electronic adhesion. In addition, the cell uptake study on FR negative A549 cells also confirmed the specific role of folate as targeting ligand. Then, to avoid non-specific binding by positive charge in the circulation, the charge shielding/deshielding approach was further employed. With selective hydrolysis of the charge shielding groups 2,3-dimethylmaleic anhydride (DMA) at tumor extracellular pH 6.8, the conjugates underwent a quick charge-reversible process with more than 80% DMA cleavage within 2 h and endocytosed into the endo/lysosomes much more rapidly than at physiological pH 7.4. And then the drug release was triggered by the cleavage of hydrazone spacer at another level of pH 5 in endo/lysosomal compartment. Furthermore, the anticancer activity results showed that Dox-loaded, charge-switchable, folate modified HPMA copolymer conjugates could indeed lead to enhanced cytotoxicity, stronger apoptosis and greater tumor spheroid inhibition towards Hela cells, indicating the great potential feasibility of this multiple responsive drug delivery system.
    Biomaterials 06/2014; 35(19):5171–5187. DOI:10.1016/j.biomaterials.2014.03.027 · 8.56 Impact Factor
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    ABSTRACT: Abstract Somatostatin receptor 2 (SSTR2), specifically over-expressed on many tumor cells, is a potential receipt for active targeting in cancer therapy. In the present study, octreotide (Oct), which had high affinity to SSTR2, was attached to N-(2-hydroxypropyl) methacrylamide (HPMA) polymeric system to enhance the antitumor efficiency of the anticancer drug doxorubicin (DOX). Two kinds of cell lines (HepG2 and A549), which overexpress SSTR2, were chosen as cell models. Compared with non-modified conjugates, Oct-modified conjugates exhibited superior cytotoxicity and intracellular uptake on both HepG2 and A549 cell lines. This might be due to the mechanism of receptor-mediated endocytosis. Subsequently, the in vivo biodistribution and antitumor activity evaluations showed that Oct modification significantly improved the tumor accumulation and antitumor efficacy of HPMA copolymer conjugates in SSTR2 over-expressed Kunming mice bearing H22 tumor xenografts. In summary, Oct-modified HPMA polymer-DOX conjugates might be a promising system for the treatment of SSTR2 over-expressed cancers.
    Drug Delivery 05/2014; DOI:10.3109/10717544.2014.911991 · 2.56 Impact Factor
  • Jian Zhang · Xi Zhu · Yun Jin · Wei Shan · Yuan Huang
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    ABSTRACT: Modifying nanoparticles with targeting peptides which can specifically bind to intestinal epithelium was recently suggested as a strategy to further enhance their ability for the oral delivery of macromolecular drugs. However, few studies were focused on comprehensively understanding of the uptake and transport processes as well as the underlying molecular signaling pathways mediated by the ligand modification. In the present study, the mechanisms of cellular uptake and the tight junctions opening associated with the trimethyl chitosan based nanoparticles (M-NPs) and their goblet cell-targeting CSK (CSKSSDYQC) peptide modified nanoparticles (CSK-M-NPs) were investigated. Compared with single ion crosslinked nanoparticles (S NPs), M-NPs and CSK-M-NPs, prepared with multiple agents, exhibited superior stability which could effectively protect drugs against the degradation of trypsin. Caveolae-mediated endocytosis and macropinocytosis were involved in the intracellular uptake of both M-NPs and CSK-M-NPs on Caco-2/HT29-MTX co-cultured cells. However, CSK peptide modification could further induce clathrin-mediated endocytosis of the NPs. Intriguingly, most of endocytosis sub-pathways have been altered after CSK peptide modification. Moreover, the opening of epithelial tight junctions was investigated at both protein and gene levels. The results indicated that both M-NPs and CSK-M-NPs could transiently and reversibly open the epithelial tight junctions via C-Jun NH2-terminal kinase-dependent pathway. However, CSK peptide modification enabled a more rapid opening and recovering of the tight junctions. In all, the enhanced uptake and transport capacity of nanoparticles after CSK peptide modification may be attributed to the alteration of internalization pathways and the stronger ability of opening tight junctions.
    Molecular Pharmaceutics 03/2014; 11(5). DOI:10.1021/mp400685v · 4.38 Impact Factor

Publication Stats

471 Citations
203.75 Total Impact Points


  • 2003–2015
    • Sichuan University
      • • Key Laboratory of Drug Targeting and Novel Drug Delivery System
      • • Department of Pharmaceutics
      Hua-yang, Sichuan, China