Benedict Law

North Dakota State University, Fargo, North Dakota, United States

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Publications (26)126.66 Total impact

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    ABSTRACT: Recent studies have suggested that the Receptor for Advanced Glycation End products (RAGE) participates in melanoma progression by promoting tumor growth. However, the mechanisms of RAGE activation in melanoma tumors are not clearly understood. To get deeper insights into these mechanisms, we transfected a melanoma cell line, which was established from a human melanoma primary tumor, with RAGE, and studied the effect of RAGE overexpression on cell proliferation and migration in vitro. We observed that overexpression of RAGE in these cells not only resulted in significantly increased migration rates compared to control cells, but also in decreased proliferation rates (Meghnani, V., Vetter, S.W and Leclerc, E. 2014, RAGE overexpression confers a metastatic phenotype to the WM115 human primary melanoma cell line, Biochimica et Biophysica Acta, 1842, 1017-1027). In the present study, we compared the growth of xenograft tumors established from RAGE overexpressing WM115 cells, to that of control cells. We observed that when implanted in mice, RAGE overexpressing cells generated tumors faster than control cells. Analysis of protein tumor extracts showed increased levels of the RAGE ligands S100B, S100A2, S100A4, S100A6 and S100A10 in RAGE overexpressing tumors compared to control tumors. We show that the tumor growth was significantly reduced when the mice were treated with anti-RAGE antibodies, suggesting that RAGE, and probably several S100 proteins, were involved in tumor growth. We further demonstrate that the anti-RAGE antibody treatment significantly enhanced the efficacy of the alkylating drug dacarbazine in reducing the growth rate of RAGE overexpressing tumors.
    No preview · Article · Oct 2014 · The International Journal of Biochemistry & Cell Biology
  • Anil Wagh · Benedict Law
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    ABSTRACT: Antibodies are one of the most commonly used targeting ligands for nanocarriers, mainly because they are specific, have a strong binding affinity, and are available for a number of disease biomarkers. The bioconjugation chemistry can be a crucial factor in determining the targeting efficiency of drug delivery and should be chosen on a case-by-case basis. An antibody consists of a number of functional groups which offer many flexible options for bioconjugation. This chapter focuses on discussing some of the approaches including periodate oxidation, carbodiimide, maleimide, and heterofunctional linkers, for conjugating antibodies to different nanocarriers. The advantages and limitations are described herein. Specific examples are selected to demonstrate the experimental procedures and to illustrate the potential for applying to other nanocarrier system.
    No preview · Article · Aug 2013 · Methods in molecular biology (Clifton, N.J.)
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    ABSTRACT: The ability to map multiple biomarkers at the same time has far-reaching biomedical and diagnostic applications. Here, a series of biocompatible poly(d,l-lactic-co-glycolic acid) and polyethylene glycol particles for multicolor and multiplexed imaging are reported. More than 30 particle formulations that exhibit distinct emission signatures (ranging from the visible to NIR wavelength region) are designed and synthesized. These particles are encapsulated with combinations of carbocyanine-based fluorophores DiO, Dil, DiD, and DiR, and are characterized as <100 nm in size and brighter than commercial quantum dots. A particle formulation is identified that simultaneously emits fluorescence at three different wavelengths upon a single excitation at 485 nm via sequential and multiple FRET cascade events for multicolor imaging. Three other particles that display maximum fluorescence intensities at 570, 672, or 777 nm for multiplexed imaging are also identified. These particles are individually conjugated with specific (Herceptin or IgG2A11 antibody) or nonspecific (heptaarginine) ligands for targeting and, thus, could be applied to differentiate different cancer cells from a cell mixture according to the expressions of cell-surface human epidermal growth factor receptor 2 and the receptor for advanced glycation endproducts. Using an animal model subcutaneously implanted with the particles, it is further demonstrated that the developed platform could be useful for in vivo multiplexed imaging.
    No preview · Article · Jun 2013 · Small
  • Ruchi Malik · Anil Wagh · Steven Qian · Benedict Law
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    ABSTRACT: A multivalent system is often employed to enhance the effectiveness of a targeted therapy. In the present study, we report a single-layer peptide nanofiber (NFP) as a multivalent targeting platform to improve the cytotoxicity of trastuzumab (anti-HER), a monoclonal antibody targeting the human epidermal growth factor receptor 2 (HER-2) in approximately 20 % of breast cancer patients. The trastuzumab-conjugated nanofiber (anti-HER/NFP) was 100 × 4 nm in size and was assembled from multiple peptide units (mPEG-BK(FITC)SGASNRA-kldlkldlkldl-CONH2). The optimized preparation was attached with approximately 10 antibodies at the surface. Because of an increase in the multivalency, anti-HER/NFP was able to truncate more cell surface HER-2 and, thus, showed an enhanced cytotoxicity toward HER-2 positive SKBr-3 human breast cancer as compared to the free anti-HER. Western blot analysis and fluorescence microscopic studies confirmed that there was a significant downregulation of the HER-2 level and also inhibition of the cell survival cell signaling pathways including the phosphatidylinositol 3-kinase (PI3K) and the mitogen activated protein kinase (MAPK) pathway. Our data suggested that NFP can be useful as a multivalent platform for immunotherapy, especially in combination with other chemotherapeutic agents in the future.
    No preview · Article · Jun 2013 · Journal of Nanoparticle Research
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    ABSTRACT: Targeted nano-particulate systems hold extraordinary potential for delivery of therapeutics across blood brain barrier (BBB). In this work, we investigated the potential of novel bi-ligand (transferrin-poly-L-arginine) liposomal vector for delivery of desired gene to brain, in vivo. The in vivo evaluation of the delivery vectors is essential for clinical translation. We followed an innovative approach of combining transferrin receptor targeting with enhanced cell penetration to design liposomal vectors for improving the transport of molecules into brain. The biodistribution profile of 1, 1'-dioctadecyl-3,3,3',3'-tetramethyl-indocarbocyanine iodide(DiR)-labeled liposomes was evaluated in adult rats after single intravenous injection at dose of 15.2μmoles of phospholipids/kg body weight. We demonstrated that bi-ligand liposomes accumulated in rat brain at significantly (p<0.05) higher concentrations as compared to the single-ligand (transferrin) or plain liposomes. In addition, the bi-ligand liposomes resulted in increased expression of β-galactosidase(β-gal) plasmid in rat brain tissue in comparison to the single-ligand liposomes. Histological examination of the transfected tissues did not show any signs of tissue necrosis or inflammation. Hemolysis assay further authenticated the biocompatibility of bi-ligand liposomes in blood up to 600 nmoles of phospholipids/1.4x10(7) erythrocytes. The findings of this study provide important and detailed information regarding the distribution of bi-ligand liposomes in vivo and accentuate their ability to demonstrate improved brain penetration and transfection potential over single-ligand liposomes.
    No preview · Article · Jan 2013 · Journal of Controlled Release
  • Yan Gu · Yi Xu · Benedict Law · Steven Y Qian
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    ABSTRACT: Through free radical-mediated peroxidation, cyclooxygenase (COX) can metabolize dihomo-γ-linolenic acid (DGLA) and arachidonic acid(AA) to form well-known bioactive metabolites, namely, the 1-series of prostaglandins (PGs1) and 2-series of prostaglandins(PGs2), respectively. Unlike PGs2, which are generally viewedas pro-inflammatory and pro-carcinogenic PGs, PGs1 may possess anti-inflammatoryand anti-cancer activity. Previous studiesusing ovine COX along with spin trapping and the LC/ESR/MS technique have shown that certainexclusive free radicals aregenerated from different free radical reactions in DGLA and AA peroxidation. However, it has been unclear whether the differences were associated with the contrasting bioactivity of DGLA vs. AA.The aim of this study was to refine the LC/MS and spin-trapping technique to make it possible for the association between free radicalsand cancer cell growth to be directly tested. Using a colon cancer cell line,HCA-7 colony 29, and LC/MS along with a solid phase extraction,we were able to characterizethe reduced forms of radical adducts (hydroxylamines) as the free radicals generated from cellular COX-catalyzed peroxidation. For the first time, free radicalsformed in the COX-catalyzed peroxidation of AA vs. DGLAand their association with cancer cell growth was assessed (cell proliferation via MTS and cell cycle distribution via PI staining) in the same experimental setting. The exclusive free radicalsformed from the COX-catalyzed peroxidation of AA and DGLA were shown to becorrelatedwith the cell growth response. Our results indicate that free radicals generated from the distinct radical reactionsin COX-catalyzed peroxidation may represent the novel metabolites of AA and DGLA that correspondto theircontrastingbioactivity.
    No preview · Article · Dec 2012 · Free Radical Biology and Medicine
  • Anil Wagh · Jagdish Singh · Steven Qian · Benedict Law
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    ABSTRACT: Unlabelled: The cellular interactions and in vivo distribution of the nanomaterials are known to be strongly influenced by their physiochemical properties. Here, we investigated and compared the biocompatibility, pharmacokinetics, and biodistribution of previously reported peptide-based nanofiber (NFP), with commercially available nanomaterials. The NFP was a 2-dimensional (2D) structure with an extremely narrow width (4 nm) and a controllable length (50 to 400 nm). NFP was found to be non-toxic, hemocompatible, and with a minimum uptake by macrophages. In vivo studies further demonstrated that NFP could be delivered to the tumor site more effectively, and within a very shorter period of time, than spherical nanoparticles. Importantly, the undelivered NFP was rapidly eliminated by renal clearance and, thus, avoiding its accumulation in the spleen or liver. Overall, our data suggested a new paradigm in drug delivery via using a short circulating NFP, rather than a long circulating 3D nanoparticle, as a delivery cargo. From the clinical editor: In this study, the role of small peptide-based nanocarriers is investigated for tumor-specific delivery, reporting excellent targeting properties and a favorable toxicity profile.
    No preview · Article · Nov 2012 · Nanomedicine: nanotechnology, biology, and medicine
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    ABSTRACT: Herein, we report the application of synthesized fluorescent, water soluble polymers for post-translational subtyping and differentiation of breast cancer cells in vitro. The fluorescence emission spectra from these polymers were modulated differently in the presence of conditioned cell culture media from various breast cancer cells. These polymers differentiate at a post-translation level possibly due to their ability to interact with extracellular enzymes that are over-expressed in cancerous conditions.
    No preview · Article · Oct 2012 · The Analyst
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    ABSTRACT: Semiconductor nanoparticles conjugated with organic- and dye-molecules to yield high efficiency visible photoluminescence (PL) hold great potential for many future technological applications. We show that folic acid (FA)-conjugated to nanosize TiO(2) and CeO(2) particles demonstrates a dramatic increase of photoemission intensity at wavelengths between 500 and 700 nm when derivatized using aminopropyl trimethoxysilane (APTMS) as spacer-linker molecules between the metal oxide and FA. Using density-functional theory (DFT) and time-dependent DFT calculations we demonstrate that the strong increase of the PL can be explained by electronic transitions between the titania surface oxygen vacancy (OV) states and the low-energy excited states of the FA/APTMS molecule anchored onto the surface oxygen bridge sites in close proximity to the OVs. We suggest this scenario to be a universal feature for a wide class of metal oxide nanoparticles, including nanoceria, possessing a similar band gap (∼3 eV) and with a large surface-vacancy-related density of electronic states. We demonstrate that the molecule-nanoparticle linker can play a crucial role in tuning the electronic and optical properties of nanosystems by bringing optically active parts of the molecule and of the surface close to each other.
    No preview · Article · May 2012 · ACS Nano
  • Anil Wagh · Steven Y Qian · Benedict Law
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    ABSTRACT: The majority of near-infrared (NIR) fluorophores are organic molecules that show significant overlap between the excitation and emission spectra and therefore exhibit high fluorescence backgrounds during in vivo imaging. Recently, cyanine dyes with a large Stokes shift have shown great promise for NIR imaging but often undergo rapid photodegradation and nonspecific protein adsorption. Alternatively, fluorescence resonance energy transfer (FRET) is a promising technique to generate a larger gap between the excitation and emission maxima and thus can reduce the background signal. Here, we report the rational design of FRET-based polymeric nanoparticles for NIR and FRET imaging. The particles were assembled from diblock copolymers of poly(d,l-lactic-co-glycolic acid) and maleimide-activated poly(ethylene glycol), which were also encapsulated with both the donor (1,1'-dioctadecyl-3,3,3',3'-tetramethylindodicarbocyanine) and acceptor (1,1'-dioctadecyl-3,3,3',3'-tetramethylindotricarbocyanine) fluorophores. Because of their extreme hydrophobicity, thousands of fluorophores could be encapsulated inside a single particle without causing leakage. FRET resulted in a large Stokes shift (>100 nm) of the emission maxima, and the transfer efficiency could be fine-tuned by further adjusting the doping ratio of the donor and acceptor fluorophores. The optimized formulation was less than 100 nm in size, brighter than quantum dots, stable in biological media, and demonstrated similar biodistribution to most nanomaterials. Additional animal phantom studies demonstrated that the FRET imaging platform developed could have far-reaching applications in optical imaging.
    No preview · Article · Apr 2012 · Bioconjugate Chemistry
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    ABSTRACT: Docosapentaenoic acid (DPA) is a unique fatty acid that exists in two isomeric forms (n-3 and n-6), which differ in their physiological behaviors. DPA can undergo free radical-mediated peroxidation via lipoxygenase (LOX). 15-LOX, one of the LOX isomers, has received much attention in cancer research because of its very different expression level in normal tissues compared to tumors and some bioactive fatty acid metabolites modulating the tumorigenic pathways in cancer. However, the mechanism linking 15-LOX, DPA metabolites, and their bioactivities is still unclear, and the free radicals generated in DPA peroxidation have never been characterized. In this study, we have studied radicals formed from both soybean and human cellular (PC3-15LOS cells) 15-LOX-catalyzed peroxidation of DPAs at various pH's using a combination of LC/ESR/MS with the spin trapping technique. We observed a total of three carbon-centered radicals formed in 15-LOX-DPA (n-3) stemming from its 7-, 17-, and 20-hydroperoxides, whereas only one formed from 17-hydroperoxide in DPA (n-6). A change in the reaction pH from 8.5 (15-LOX enzyme optimum) to 7.4 (physiological) and to 6.5 (tumor, acidic) not only decreased the total radical formation but also altered the preferred site of oxygenation. This pH-dependent alteration of radical formation and oxygenation pattern may have significant implications and provide a basis for our ongoing investigations of LOXs as well as fatty acids in cancer biology.
    Full-text · Article · Jul 2011 · Free Radical Biology and Medicine
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    F Wang · K Bhat · M Doucette · S Zhou · Y Gu · B Law · X Liu · E T Wong · J X Kang · T-C Hsieh · SY Qian · E Wu
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    ABSTRACT: In this study, we investigated whether DHA, a nutritionally important n-3 unsaturated fatty acid, modulated the sensitivity of brain tumor cells to the anticancer drug, etoposide (VP16). Medulloblastoma (MB) cell lines, Daoy and D283, and glioblastoma (GBM) cell lines, U138 and U87, were exposed to DHA or VP16 alone or in combination. The effects on cell proliferation and the induction of apoptosis were determined by using MTS and Hoechest 33342/PI double staining. U87 and U138 cells were found to be insensitive to the addition of DHA and VP16, whereas the two MB cell lines showed high sensitivity. DHA or VP16 alone showed little effect on cell proliferation or death in either the MB or GBM cell lines, but pretreatment with DHA enhanced the responsiveness to VP16 in the MB cell lines. To understand the mechanisms of combined DHA and VP16 on MB cells, pathway specific oligo array analyses were performed to dissect possible signaling pathways involved. The addition of DHA and VP16, in comparison to VP16 added alone, resulted in marked suppression in the expression of several genes involved in DNA damage repair, cell proliferation, survival, invasion, and angiogenesis, including PRKDC, Survivin, PIK3R1, MAPK14, NFκB1, NFκBIA, BCL2, CD44, and MAT1. These results suggest (1) that the effects of DHA and VP16 in brain tumor cells are mediated in part by the down regulation of events involved in DNA repair and the PI3K/MAPK signaling pathways and (2) that brain tumors genotypically mimicked by MB cells may benefit from therapies combining DHA with VP16.
    Full-text · Article · Jun 2011 · Current Molecular Medicine
  • Ruchi Malik · Steven Qian · Benedict Law
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    ABSTRACT: Abnormal proteolysis is often observed during disease progression. Up-regulation of certain tumor-associated proteases such as urokinase plasminogen activator (uPA) can be a hallmark of malignant transformation. Here we report the design and synthesis of a near-infrared nanofiber precursor (NIR-NFP) for detecting uPA activity. NIR-NFP, which is optically silent in its native state, is composed of multiple self-assembled peptide units (PEG(54)-BK(NIR664)SGRSANA-kldlkldlkldl-CONH(2)). On uPA activation, NIR-NFP releases peptide fragments (PEG(54)-BK(NIR664)SGR-CONH(2)) that contribute to a significant fluorescence amplification at 684nm. NIR-NFP was able to detect cell-secreted uPA from human cancer cells (SKBR-3, PANC-1, MCF-7, SKOV-3, MDA-MB-231, PC-3, and HT-1080) expressing various levels of uPA. Fluorescence changes were uPA dependent, as confirmed with both Western blot analysis and enzyme activity assay. Our data suggest that an optimized preparation may be useful for imaging uPA activity in vivo.
    No preview · Article · May 2011 · Analytical Biochemistry
  • Anil V. Wagh · Ruchi Malik · Benedict Law
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    ABSTRACT: IntroductionDoped NanoparticlesConclusions and OutlookAcknowledgmentsReferences
    No preview · Chapter · Mar 2011
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    ABSTRACT: Like arachidonic acid (AA), dihomo-γ-linolenic acid (DGLA) is a 20-carbon ω-6 polyunsaturated fatty acid and a substrate of cyclooxygenase (COX). Through free radical reactions, COX metabolizes DGLA and AA to form well-known bioactive metabolites, namely, the 1 and 2 series of prostaglandins (PGs1 and PGs2), respectively. Unlike PGs2, which are viewed as proinflammatory, PGs1 possess anti-inflammatory and anticancer activities. However, the mechanisms linking the PGs to their bioactivities are still unclear, and radicals generated in COX-DGLA have not been detected. To better understand PG biology and determine whether different reactions occur in COX-DGLA and COX-AA, we have used LC/ESR/MS with a spin trap, α-(4-pyridyl-1-oxide)-N-tert-butyl nitrone (POBN), to characterize the carbon-centered radicals formed from COX-DGLA in vitro, including cellular peroxidation. A total of five types of DGLA-derived radicals were characterized as POBN adducts: m/z 266, m/z 296, and m/z 550 (same as or similar to COX-AA) and m/z 324 and m/z 354 (exclusively from COX-DGLA). Our results suggest that C-15 oxygenation to form PGGs occurs in both COX-DGLA and COX-AA; however, C-8 oxygenation occurs exclusively in COX-DGLA. This new finding will be further investigated for its association with various bioactivities of PGs, with potential implications for inflammatory diseases.
    Full-text · Article · Feb 2011 · Free Radical Biology and Medicine
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    ABSTRACT: A liposome-based amplified detection system is presented for the cancer cell secreted pathogenic enzyme matrix metalloproteinase-9 which does not require the use of biological antibodies.
    No preview · Article · May 2010 · Chemical Communications
  • Benedict Law · Ching-Hsuan Tung
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    ABSTRACT: In many diseases, protease expressions are found deregulated when compared with them at the healthy states. The unique ability to hydrolyze protein amide bonds has made those deregulated proteases attractive biological triggers in drug development. Proteolysis has been widely applied in pro-drug design to achieve favorable pharmacokinetics. Controlled drug delivery systems are also reported by incorporating protease-sensitive motifs onto bio-, inorganic-, or organic- materials. In addition, protease responsive molecular probes are developed for in vitro bioanalysis and in vivo diagnostic imaging. This review focuses on various proteolysis-dependent approaches to drug delivery, therapy, and imaging. References are selected to illustrate the concepts and demonstrate the potentials of these enzyme-responsive strategies.
    No preview · Article · Sep 2009 · Bioconjugate Chemistry
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    ABSTRACT: Liposomes have been widely used as a drug delivery vehicle, and currently, more than 10 liposomal formulations are approved by the Food and Drug Administration for clinical use. However, upon targeting, the release of the liposome-encapsulated contents is usually slow. We have recently demonstrated that contents from appropriately formulated liposomes can be rapidly released by the cancer-associated enzyme matrix metalloproteinase-9 (MMP-9). Herein, we report our detailed studies to optimize the liposomal formulations. By properly selecting the lipopeptide, the major lipid component, and their relative amounts, we demonstrate that the contents are rapidly released in the presence of cancer-associated levels of recombinant human MMP-9. We observed that the degree of lipid mismatch between the lipopepides and the major lipid component profoundly affects the release profiles from the liposomes. By utilizing the optimized liposomal formulations, we also demonstrate that cancer cells (HT-29) which secrete low levels of MMP-9 failed to release a significant amount of the liposomal contents. Metastatic cancer cells (MCF7) secreting high levels of the enzyme rapidly release the encapsulated contents from the liposomes.
    Full-text · Article · Aug 2009 · Bioconjugate Chemistry
  • Benedict Law · Ching-Hsuan Tung
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    ABSTRACT: As many proteases such as urokinase plasminogen activator (uPA) are overexpressed in various tumors, a new type of peptide-based smart delivery system (hydrogel matrix) that could be degraded by uPA was previously described (Law, B.; Weissleder, R.; Tung, C. H. Peptide-based biomaterials for protease-enhanced drug delivery. Biomacromolecules 2006, 7 (4), 1261-1265). Subsequently, we designed nanometer-sized fluorescent nanofibers by introducing a hydrophilic component (methoxyl polyethylene glycol) to the core peptide [MPEG 2000-BK(FITC)SGRSANA-kldlkldlkldl-NH 2]. Preliminary studies showed that these nanofibers could detect uPA activity by optical imaging in vitro (Law, B.; Weissleder, R.; Tung, C. H. Protease-sensitive fluorescent nanofibers. Bioconjugate Chem. 2007, 18 (6), 1701-1704). Here, we further extend our studies to the structural responses of these nanofiber precursors (NFP). In the presence of a model protease, the FITC-containing hydrophilic fragments were released from the NFPs that contributed to fluorescence amplification. Simultaneously, the remaining self-assembling residues were mechanically driven to transform into interfibril networking of micrometer size hydrogel. These unique morphological changes, together with the optical property, may have considerable biomedical applications as diagnostic sensors for specific protease or dual systemic and functional delivery nanoplatforms to target protease-associated diseases.
    No preview · Article · Mar 2008 · Biomacromolecules
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    Benedict Law · Ralph Weissleder · Ching-Hsuan Tung
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    ABSTRACT: We report the design and synthesis of enzyme-responsive nanofibers. The fibers are composed of self-assembled hydrophobic beta-sheet peptides incorporating protease-sensitive domains, fluorescent reporters, and hydrophilic poly(ethylene glycol) (PEG) units. Using urokinase plasminogen activator (uPA) as a model system, nanofibers were developed to release fluorescent fragments upon uPA incubation. These protease-sensitive nanofibers may have considerable biomedical applications as diagnostic sensors or for protease-assisted drug deliveries.
    Preview · Article · Nov 2007 · Bioconjugate Chemistry

Publication Stats

514 Citations
126.66 Total Impact Points


  • 2007-2014
    • North Dakota State University
      • • College of Pharmacy, Nursing and Allied Sciences
      • • Department of Chemistry and Biochemistry
      Fargo, North Dakota, United States
  • 2008
    • Harvard University
      Cambridge, Massachusetts, United States
  • 2005-2006
    • Harvard Medical School
      • Department of Medicine
      Boston, Massachusetts, United States