Hsing-Wen Sung

National Tsing Hua University, Hsin-chu-hsien, Taiwan, Taiwan

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Publications (158)1023.07 Total impact

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    ABSTRACT: Successful oral delivery of therapeutic proteins such as insulin can greatly improve the quality of life of patients. This study develops a bubble carrier system by loading diethylene triamine pentaacetic acid (DTPA) dianhydride, a foaming agent (sodium bicarbonate; SBC), a surfactant (sodium dodecyl sulfate; SDS), and a protein drug (insulin) in an enteric-coated gelatin capsule. Following oral administration to diabetic rats, the intestinal fluid that has passed through the gelatin capsule saturates the mixture; concomitantly, DTPA dianhydride produces an acidic environment, while SBC decomposes to form CO2 bubbles at acidic pH. The gas bubbles grow among the surfactant molecules (SDS) owing to the expansion of the generated CO2. The walls of the CO2 bubbles consist of a self-assembled film of water that is in nanoscale and may serve as a colloidal carrier to transport insulin and DTPA. The grown gas bubbles continue to expand until they bump into the wall and burst, releasing their transported insulin, DTPA, and SDS into the mucosal layer. The released DTPA and SDS function as protease inhibitors to protect the insulin molecules as well as absorption enhancers to augment their epithelial permeability and eventual absorption into systemic circulation, exerting their hypoglycemic effects. Copyright © 2015 Elsevier Ltd. All rights reserved.
    Biomaterials 09/2015; 64. DOI:10.1016/j.biomaterials.2015.06.035 · 8.31 Impact Factor
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    ABSTRACT: Repeated cancer treatments are common, owing to the aggressive and resistant nature of tumors. This work presents a chitosan (CS) derivative that contains self-doped polyaniline (PANI) side chains, capable of self-assembling to form micelles and then transforming into hydrogels driven by a local change in pH. Analysis results of small-angle X-ray scattering indicate that the sol-gel transition of this CS derivative may provide the mechanical integrity to maintain its spatial stability in the microenvironment of solid tumors. The micelles formed in the CS hydrogel function as nanoscaled heating sources upon exposure to near-infrared light, thereby enabling the selective killing of cancer cells in a light-treated area. Additionally, photothermal efficacy of the micellar hydrogel is evaluated using a tumor-bearing mouse model; hollow gold nanospheres (HGNs) are used for comparison. Given the ability of the micellar hydrogel to provide spatial stability within a solid tumor, which prevents its leakage from the injection site, the therapeutic efficacy of this hydrogel, as a photothermal therapeutic agent for repeated treatments, exceeds that of nanosized HGNs. Results of this study demonstrate that this in situ-formed micellar hydrogel is a highly promising modality for repeated cancer treatments, providing a clinically viable, minimally invasive phototherapeutic option for therapeutic treatment. Copyright © 2015 Elsevier Ltd. All rights reserved.
    Biomaterials 07/2015; 56. DOI:10.1016/j.biomaterials.2015.03.060 · 8.31 Impact Factor
  • Ming-Fan Chung · Hung-Yi Liu · Kun-Ju Lin · Wei-Tso Chia · Hsing-Wen Sung
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    ABSTRACT: Multidrug resistance (MDR) resulting from the overexpression of drug transporters such as P-glycoprotein (Pgp) increases the efflux of drugs and thereby limits the effectiveness of chemotherapy. To address this issue, this work develops an injectable hollow microsphere (HM) system that carries the anticancer agent irinotecan (CPT-11) and a NO-releasing donor (NONOate). Upon injection of this system into acidic tumor tissue, environmental protons infiltrate the shell of the HMs and react with their encapsulated NONOate to form NO bubbles that trigger localized drug release and serve as a Pgp-mediated MDR reversal agent. The site-specific drug release and the NO-reduced Pgp-mediated transport can cause the intracellular accumulation of the drug at a concentration that exceeds the cell-killing threshold, eventually inducing its antitumor activity. These results reveal that this pH-responsive HM carrier system provides a potentially effective method for treating cancers that develop MDR. © 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.
    Angewandte Chemie International Edition 07/2015; DOI:10.1002/anie.201504444 · 11.26 Impact Factor
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    ABSTRACT: Recent research in chemotherapy has prioritized overcoming the multidrug resistance (MDR) of cancer cells. In this work, liposomes that contain doxorubicin (DOX) and ammonium bicarbonate (ABC, a bubble-generating agent) are prepared and functionalized with an antinucleolin aptamer (AS1411 liposomes) to target DOX-resistant breast cancer cells (MCF-7/ADR), which overexpress nucleolin receptors. Free DOX and liposomes without functionalization with AS1411 (plain liposomes) were used as controls. The results of molecular dynamic simulations suggest that AS1411 functionalization may promote the affinity and specific binding of liposomes to the nucleolin receptors, enhancing their subsequent uptake by tumor cells, whereas plain liposomes enter cells with difficulty. Upon mild heating, the decomposition of ABC that is encapsulated in the liposomes enables the immediate activation of generation of CO2 bubbles, creating permeable defects in their lipid bilayers, and ultimately facilitating the swift intracellular release of DOX. In vivo studies in nude mice that bear tumors demonstrate that the active targeting of AS1411 liposomes can substantially increase the accumulation of DOX in the tumor tissues relative to free DOX or passively targeted plain liposomes, inhibiting tumor growth and reducing systemic side effects, including cardiotoxicity. The above findings indicate that liposomes that are functionalized with AS1411 represent an attractive therapeutic alternative for overcoming the MDR effect, and support a potentially effective strategy for cancer therapy. Copyright © 2015. Published by Elsevier B.V.
    Journal of Controlled Release 01/2015; 208. DOI:10.1016/j.jconrel.2015.01.032 · 7.26 Impact Factor
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    ABSTRACT: Eradicating subcutaneous bacterial infections remains a significant challenge. This work reports an injectable system of hollow microspheres (HMs) that can rapidly produce localized heat activated by near-infrared (NIR) light and control the release of an antibiotic via a "molecular switch" in their polymer shells, as a combination strategy for treating subcutaneous abscesses. The HMs have a shell of poly(D,L-lactic-co-glycolic acid) (PLGA) and an aqueous core that is comprised of vancomycin (Van) and polypyrrole nanoparticles (PPy NPs), which are photothermal agents. Experimental results demonstrate that the micro-HMs ensure efficiently the spatial stabilization of their encapsulated Van and PPy NPs at the injection site in mice with subcutaneous abscesses. Without NIR irradiation, the HMs elute a negligible drug concentration, but release substantially more when exposed to NIR light, suggesting that this system is suitable as a photothermally-responsive drug delivery system. The combination of photothermally-induced hyperthermia and antibiotic therapy with HMs increases cytotoxicity for bacteria in abscesses, to an extent that is greater than the sum of the two treatments alone, demonstrating a synergistic effect. This treatment platform may find other clinical applications, especially for localized hyperthermia-based cancer therapy. Copyright © 2014. Published by Elsevier B.V.
    Journal of Controlled Release 12/2014; 199. DOI:10.1016/j.jconrel.2014.12.011 · 7.26 Impact Factor
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    ABSTRACT: To celebrate the success of the Journal of Controlled Release and the research covered in the journal, here we highlight some of the most cited research articles in the history of the journal. Based on the literature search in Google Scholar in July 2013, we identified ~30 research articles that have received most number of citations. Authors of these articles were invited to provide a commentary on these articles. This compilation of commentaries gives a historical perspective and current status of research covered in these articles.
    Journal of Controlled Release 09/2014; 190:29-74. DOI:10.1016/j.jconrel.2014.07.012 · 7.26 Impact Factor
  • Zi-Xian Liao · Er-Yuan Chuang · Chun-Wen Hsiao · Hsing-Wen Sung
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    ABSTRACT: The oral route is a convenient and commonly employed way for drug delivery. However, therapeutic proteins have poor bioavailable upon oral administration due to the impermeable barrier from intestinal epithelial tight junction. Moreover, the small intestinal pH varies among different region of the intestinal tract where digestion and absorption occurs at different level. In this study, a tunable dual-emitting and pH-responsive nanocarrier that can alter the fluorescent color and emission intensity in response to pH changes and can trigger the opening of intestinal epithelial tight junction at different levels, were developed from chitosan-N-arginine and poly(γ-glutamic acid)-taurine conjugates. As pH increased from 6.0 to 8.0, the binding affinity of the oppositely charged polyions decreased, whereas the ratio of the intensity of the donor-to-acceptor emission intensity (ID/IA) increased by 27 folds. The fluorescent and pH-responsive nanocarrier that was able to monitor the pH change of intestinal environment and to control the release of an anti-angiogenic protein in response to the pH gradient. The nanocarrier triggered the opening of intestinal epithelial tight junction, consequently enhanced the permeation of the released protein through the intestinal epithelial barrier model (Caco-2 cell monolayer) to inhibit tube formation of human umbilical vein endothelial cells.
    ACS Applied Materials & Interfaces 09/2014; 6(20). DOI:10.1021/am505441p · 6.72 Impact Factor
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    ABSTRACT: Cell transplantation via direct intramuscular injection is a promising therapy for patients with ischemic diseases. However, following injections, retention of transplanted cells in engrafted areas remains problematic, and can be deleterious to cell-transplantation therapy. In this Progress Report, a thermoresponsive hydrogel system composed of aqueous methylcellulose (MC) blended with phosphate-buffered saline is constructed to grow cell sheet fragments and cell bodies for the treatment of ischemic diseases. The as-prepared MC hydrogel system undergoes a sol-gel reversible transition upon heating or cooling at ≈32 °C. Via this unique property, the grown cell sheet fragments (cell bodies) can be harvested without using proteolytic enzymes; consequently, their inherent extracellular matrices (ECMs) and integrative adhesive agents remain well preserved. In animal studies using rats and pigs with experimentally created myocardial infarction, the injected cell sheet fragments (cell bodies) become entrapped in the interstices of muscular tissues and adhere to engraftment sites, while a minimal number of cells exist in the group receiving dissociated cells. Moreover, transplantation of cell sheet fragments (cell bodies) significantly increases vascular density, thereby improving the function of an infarcted heart. These experimental results demonstrate that cell sheet fragments (cell bodies) function as a cell-delivery construct by providing a favorable ECM environment to retain transplanted cells locally and consequently, improving the efficacy of therapeutic cell transplantation.
    Advanced Healthcare Materials 08/2014; 3(8). DOI:10.1002/adhm.201300605 · 4.88 Impact Factor
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    ABSTRACT: As a cationic polysaccharide, chitosan (CS) has been identified for its potential use as a non-viral vector for exogenous gene transfection. However, owing to their electrostatic interactions, CS complexes may cause difficulties in gene release upon their arrival at the site of action, thus limiting their transfection efficiency. In this work, an attempt is made to facilitate the release of a gene by incorporating a negatively-charged poly(γ-glutamic acid) (γPGA) into CS complexes in order to diminish their attractive interactions. The mechanisms of exploiting γPGA to enhance the transfection efficiency of CS complexes are elucidated. The feasibility of using this CS/γPGA-based system for DNA or siRNA transfer is explored as well. Additionally, potential of the CS/γPGA formulation to deliver disulfide bond-conjugated dual PEGylated siRNAs for multiple gene silencing is also examined. Moreover, the genetic use of pKillerRed-mem, delivered using complexes of CS and γPGA, to express a membrane-targeted KillerRed as an intrinsically generated photosensitizer for photodynamic therapy is described.
    Journal of Controlled Release 04/2014; 193. DOI:10.1016/j.jconrel.2014.04.024 · 7.26 Impact Factor
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    ABSTRACT: As is widely suspected, lysolipid dissociation from liposomes contributes to the intravenous instability of ThermoDox® (Lysolipid liposomes), thereby impeding its antitumor efficacy. This work evaluates the feasibility of a thermoresponsive bubble-generating liposomal system without lysolipids for tumor-specific chemotherapy. The key component in this liposomal formulation is its encapsulated ammonium bicarbonate (ABC), which is used to actively load doxorubicin (DOX) into liposomes and trigger a drug release when heated locally. Incubating ABC liposomes with whole blood results in a significantly smaller decrease in the retention of encapsulated DOX than that by Lysolipid liposomes, indicating superior plasma stability. Biodistribution analysis results indicate that the ABC formulation circulates longer than its Lysolipid counterpart. Following the injection of ABC liposome suspension into mice with tumors heated locally, decomposition of the ABC encapsulated in liposomes facilitates the immediate thermal activation of CO2 bubble generation, subsequently increasing the intratumoral DOX accumulation. Consequently, the antitumor efficacy of the ABC liposomes is superior to that of their Lysolipid counterparts. Results of this study demonstrate that this thermoresponsive bubble-generating liposomal system is a highly promising carrier for tumor-specific chemotherapy, especially for local drug delivery mediated at hyperthermic temperatures.
    ACS Nano 04/2014; 8(5). DOI:10.1021/nn501162x · 12.88 Impact Factor
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    ABSTRACT: Chemotherapy-induced neutropenia often increases the likelihood of life-threatening infections. In this study, a nanoparticle (NP) system composed of chitosan and poly(γ-glutamic acid) conjugated with diethylene triamine pentaacetic acid (γPGA-DTPA) was prepared for oral delivery of granulocyte colony-stimulating factor (G-CSF), a hematopoietic growth factor. The therapeutic potential of this NP system for daily administration of G-CSF to treat neutropenia associated with chemotherapy was evaluated in a rat model. In vitro results indicate that the procedures of NP loading and release preserved the structural integrity and bioactivity of the G-CSF molecules adequately. Those results further demonstrated the enzymatic inhibition activity of γPGA-DTPA towards G-CSF against intestinal proteases. Additionally, the in vivo biodistribution study clearly identified accumulations of G-CSF in the heart, liver, bone marrow, and urinary bladder, an indication of systemic absorption of G-CSF; its relative bioavailability was approximately 13.6%. Moreover, significant glucose uptake was observed in bone marrow during G-CSF treatment, suggesting increased bone marrow metabolism and neutrophil production. Consequently, neutrophil count in the blood increased in a sustained manner; this fact may help a patient's immune system recover from the side effects of chemotherapy.
    Biomaterials 01/2014; 35(11). DOI:10.1016/j.biomaterials.2014.01.020 · 8.31 Impact Factor
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    ABSTRACT: Oxidative stress and reduced pH are involved in many inflammatory diseases. This study describes a nanoparticle-based system that is responsive to both oxidative stress and reduced pH in an inflammatory environment to effectively release its encapsulated curcumin, an immune-modulatory agent with potent anti-inflammatory and antioxidant capabilities. Due to the presence of Förster resonance energy transfer between curcumin and the carrier, this system also allowed us to monitor the intracellular release behavior. The curcumin released upon triggering could efficiently reduce the excess oxidants produced by the lipopolysaccharide (LPS)-stimulated macrophages. The feasibility of using the curcumin-loaded nanoparticles for anti-inflammatory applications was further validated in a mouse model with ankle inflammation induced by LPS. The results of these studies demonstrate that the proposed nanoparticle system is promising for treating oxidative stress-related diseases.
    ACS Nano 01/2014; 8(2). DOI:10.1021/nn4058787 · 12.88 Impact Factor
  • Ko-Jie Chen · Hsiang-Fa Liang · Hsing-Wen Sung
    Journal of Controlled Release 11/2013; 172(1):e46-7. DOI:10.1016/j.jconrel.2013.08.098 · 7.26 Impact Factor
  • Ping Yan · Ko-Jie Chen · Jun Wu · Lu Sun · Hsing-Wen Sung · Richard D Weisel · Jun Xie · Ren-Ke Li
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    ABSTRACT: The objective of this study was to synthesize a cationic microbubble (CMB) conjugated with an antibody against matrix metalloproteinase 2 (CMBMMP2) to increase microbubble accumulation and gene transfection in the infarcted myocardium and to restore ventricular function following an ischemic insult. We previously reported that our CMBs enhanced the efficiency of gene transfection following ultrasound-targeted microbubble destruction (UTMD) in rodent hearts. Therefore, we conjugated a thiolated MMP2 antibody to the PEG chains on the CMB surface, which was verified by fluorescent microscopy. Rats underwent ischemia/reperfusion injury 3 days prior to UTMD delivery of the control or Timp3 plasmid. The CMBMMP2 improved microbubble accumulation in the infarct region, with 57% more contrast intensity compared to the non-conjugated CMB. UTMD-mediated CMBMMP2 delivery of the Timp3 gene significantly increased TIMP3 protein levels in the infarct scar and border zone at 3 days post-UTMD compared to delivery by the non-conjugated CMB. Both MMP2 and MMP9 activity were reduced in the CMBMMP2Timp3 group, which resulted in smaller and thicker infarcts and improved cardiac function. UTMD therapy with this CMBMMP2 provides an efficient platform for the targeted delivery of factors intended to preserve ventricular structure and improve cardiac function after ischemic injury.
    Biomaterials 10/2013; 35(3). DOI:10.1016/j.biomaterials.2013.10.043 · 8.31 Impact Factor
  • Zi-Xian Liao · Yu-Chun Li · Hsiang-Ming Lu · Hsing-Wen Sung
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    ABSTRACT: Photodynamic therapy (PDT) has received considerable attention as a therapeutic treatment for cancer and other diseases; however, it is frequently accompanied by prolonged phototoxic reaction of the skin due to slow clearance of synthetic photosensitizers (PSs) administered externally. This study was designed to investigate the genetic use of pKillerRed-mem, delivered using complexes of chitosan (CS) and poly(γ-glutamic acid) (γPGA), to intracellularly express a membrane-targeted KillerRed protein that can be used as a potential PS for PDT. Following transfection with CS/pKillerRed/γPGA complexes, a red fluorescence protein of KillerRed was clearly seen at the cellular membranes. When exposed to green-light irradiation, the KillerRed-positive cells produced an excessive amount of reactive oxygen species (ROS) in a time-dependent manner. Data from viability assays indicate that ROS have an important role in mediating KillerRed-induced cytotoxicity, apoptosis, and anti-proliferation, suggesting that KillerRed can be used as an intrinsically generated PS for PDT treatments. Notably, the phototoxic reaction of KillerRed toward cells gradually became negligible over time, presumably because of its intracellular degradability. These experimental results demonstrate that this genetically encoded KillerRed is biodegradable and has potential for PDT-induced destruction of diseased cells.
    Biomaterials 10/2013; 35(1). DOI:10.1016/j.biomaterials.2013.09.075 · 8.31 Impact Factor
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    ABSTRACT: Cell transplantation for therapeutic neovascularization holds great promise for treating ischemic diseases. This work prepared three-dimensional aggregates of human umbilical vein endothelial cells (HUVECs) and cord-blood mesenchymal stem cells (cbMSCs) with different levels of internal hypoxia by a methylcellulose hydrogel system. We found that few apoptosis occurred in these cell aggregates, despite developing a hypoxic microenvironment in their inner cores. Via effectively switching on the hypoxia-inducible factor-1α-dependent angiogenic mechanisms, culturing the internally hypoxic HUVEC/cbMSC aggregates on Matrigel resulted in formation of extensive and persistent tubular networks and significant upregulation of pro-angiogenic genes. As the level of internal hypoxia created in cell aggregates increased, the robustness of the tubular structures developed on Matrigel increased, and expression levels of the pro-angiogenic genes also elevated. Transplantation of hypoxic HUVEC/cbMSC aggregates into a mouse model of an ischemic limb significantly promoted formation of functional vessels, improved regional blood perfusion, and attenuated muscle atrophy and bone losses, thereby rescuing tissue degeneration. Notably, their therapeutic efficacy was clearly dependent upon the level of internal hypoxia established in cell aggregates. These analytical results demonstrate that by establishing a hypoxic environment in HUVEC/cbMSC aggregates, their potential for therapeutic neovascularization can be markedly enhanced.
    Biomaterials 09/2013; 34(37). DOI:10.1016/j.biomaterials.2013.09.010 · 8.31 Impact Factor
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    ABSTRACT: Current insulin therapy via subcutaneous administration can lead to occasional hypoglycemia and peripheral hyperinsulinemia, due to its nonphysiological route. This study evaluates the feasibility of using bovine insulin and exendin-4 in a form of combination therapy, as orally delivered by nanoparticles composed of chitosan and poly(γ-glutamic acid) (CS/γPGA NPs), to control blood glucose levels in rats with type 2 diabetes mellitus (T2DM) undergoing the oral glucose tolerance test. Experimental results indicate that CS/γPGA NPs could enhance the intestinal paracellular permeation; consequently, the exogenous bovine insulin and exendin-4 could be delivered into the liver and pancreas, where they could elicit their glucoregulatory activities. In response to the stimulus of exogenously delivered bovine insulin and the endogenously secreted rat insulin stimulated by the ingested exendin-4, significant glucose utilizations were found in the cardiac and skeletal muscles, resulting in the glucose-lowering effect. Owing to its synergic stimulation effects, the hypoglycemic effect of oral ingestion of NPs containing bovine insulin and exendin-4 was significantly greater than that of the group solely treated with insulin NPs. Above results demonstrate that oral combination therapy with bovine insulin and exendin-4 improves the modulation of blood glucose levels in T2DM rats, making it highly promising for treating those T2DM patients not adequately controlled by the current insulin therapy.
    Biomaterials 07/2013; 34(32). DOI:10.1016/j.biomaterials.2013.07.021 · 8.31 Impact Factor
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    ABSTRACT: Cell-based therapeutic neovascularization is a promising method for treating ischemic disorders. In this work, human umbilical vein endothelial cells (HUVECs) were thoroughly premixed with cord-blood mesenchymal stem cells (cbMSCs) and cultivated to form three-dimensional (3D) cell aggregates for cellular cardiomyoplasty. In the in vitro study, tubular networks were formed at day 1 after the co-culturing of dissociated HUVECs and cbMSCs on Matrigel; however, as time progressed, the grown tubular networks regressed severely. Conversely, when 3D cell aggregates were grown on Matrigel, mature and stable tubular networks were observed over time, under the influence of their intensive cell‒extracellular matrix (ECM) interactions and cell‒cell contacts. 3D cell aggregates were transplanted into the peri-infarct zones of rats with myocardial infarction (MI) via direct intramyocardial injection. Based on our pinhole single photon emission computed tomography (SPECT) myocardial-perfusion observations, echocardiographic heart-function examinations and histological analyses, the engrafted 3D cell aggregates considerably enhanced the vascular densities and the blood flow recovery in the ischemic myocardium over those of their dissociated counterparts, thereby reducing the size of perfusion defects and restoring cardiac function. These results demonstrate that the intramuscular delivery of 3D cell aggregates of HUVECs/cbMSCs can be a valuable cell-based regenerative therapeutic strategy against MI.
    Journal of Controlled Release 07/2013; 172(2). DOI:10.1016/j.jconrel.2013.06.025 · 7.26 Impact Factor
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    ABSTRACT: Many human diseases carry at least two independent gene mutations, further exacerbating clinical disorders. In this work, disulfide bond-conjugated dual PEGylated siRNAs were synthesized, capable of specifically targeting and silencing two genes simultaneously. To achieve efficient delivery, the conjugated siRNAs were formulated with the cationic chitosan together with an anionic polymer, poly(γ-glutamic acid) (γPGA), to form a ternary complex. Experimental results indicate that the incorporated γPGA could significantly enhance their intracellular delivery efficiency, allowing for reduction of the disulfide bond-conjugated PEGylated siRNAs delivered to the PEGylated siRNAs in the reductive cytoplasmic environment. The PEGylated siRNAs could more significantly increase their enzymatic tolerability, effectively silence multiple genes, and prolong the duration of their gene silencing capability than the unmodified siRNAs could. Silencing of different genes simultaneously significantly contributes to the efforts to treat multiple gene disorders, and prolonged duration of gene silencing can reduce the need for frequent administrations.
    Biomaterials 06/2013; 34(28). DOI:10.1016/j.biomaterials.2013.05.049 · 8.31 Impact Factor

Publication Stats

6k Citations
1,023.07 Total Impact Points


  • 2000–2015
    • National Tsing Hua University
      • Department of Chemical Engineering
      Hsin-chu-hsien, Taiwan, Taiwan
  • 2004
    • National Yang Ming University
      T’ai-pei, Taipei, Taiwan
  • 1999–2000
    • National Central University
      • Department of Chemical & Materials Engineering
      Taoyuan City, Taiwan, Taiwan