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Tao Jiang

Bio: Tao Jiang is an academic researcher from University of California, San Diego. The author has contributed to research in topics: Cell-penetrating peptide & Epidermal growth factor. The author has an hindex of 13, co-authored 19 publications receiving 3058 citations.

Papers
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Journal ArticleDOI
TL;DR: In mice xenografted with human tumor cells secreting matrix metalloproteinases 2 and 9, ACPPs bearing a far-red-fluorescent cargo show in vivo contrast ratios of 2-3 and a 3.1-fold increase in standard uptake value for tumors relative to contralateral normal tissue or control peptides with scrambled linkers.
Abstract: We have devised and tested a new strategy for selectively delivering molecules to tumor cells. Cellular association of polyarginine-based, cell-penetrating peptides (CPPs) is effectively blocked when they are fused to an inhibitory domain made up of negatively charged residues. We call these fusions activatable CPPs (ACPPs) because cleavage of the linker between the polycationic and polyanionic domains, typically by a protease, releases the CPP portion and its attached cargo to bind to and enter cells. Association with cultured cells typically increases 10-fold or more upon linker cleavage. In mice xenografted with human tumor cells secreting matrix metalloproteinases 2 and 9, ACPPs bearing a far-red-fluorescent cargo show in vivo contrast ratios of 2-3 and a 3.1-fold increase in standard uptake value for tumors relative to contralateral normal tissue or control peptides with scrambled linkers. Ex vivo slices of freshly resected human squamous cell carcinomas give similar or better contrast ratios. Because CPPs are known to import a wide variety of nonoptical contrast and therapeutic agents, ACPPs offer a general strategy toward imaging and treating disease processes associated with linker-cleaving activities such as extracellular proteases.

819 citations

Journal ArticleDOI
TL;DR: In vivo visualization of matrix metalloproteinase activities by MRI and fluorescence of dendrimeric nanoparticles coated with activatable cell penetrating peptides, labeled with Cy5, gadolinium, or both shows that uptake via this mechanism is comparable to that of other near infrared protease sensors, with the added advantage that the approach is translatable to MRI.
Abstract: High-resolution imaging of molecules intrinsically involved in malignancy and metastasis would be of great value for clinical detection and staging of tumors. We now report in vivo visualization of matrix metalloproteinase activities by MRI and fluorescence of dendrimeric nanoparticles coated with activatable cell penetrating peptides (ACPPs), labeled with Cy5, gadolinium, or both. Uptake of such nanoparticles in tumors is 4- to 15-fold higher than for unconjugated ACPPs. With fluorescent molecules, we are able to detect residual tumor and metastases as small as 200 μm, which can be resected under fluorescence guidance and analyzed histopathologically with fluorescence microscopy. We show that uptake via this mechanism is comparable to that of other near infrared protease sensors, with the added advantage that the approach is translatable to MRI. Once activated, the Gd-labeled nanoparticles deposit high levels (30–50 μM) of Gd in tumor parenchyma with even higher amounts deposited in regions of infiltrative tumor, resulting in useful T1 contrast lasting several days after injection. These results should improve MRI-guided clinical staging, presurgical planning, and intraoperative fluorescence-guided surgery. The approach may be generalizable to deliver radiation-sensitizing and chemotherapeutic agents.

533 citations

Journal ArticleDOI
TL;DR: A method to visualize tumors during surgery using activatable cell-penetrating peptides (ACPPs), in which the fluorescently labeled, polycationic cell-peptide (CPP) is coupled via a cleavable linker to a neutralizing peptide, resulting in improved precision of tumor resection.
Abstract: The completeness of tumor removal during surgery is dependent on the surgeon’s ability to differentiate tumor from normal tissue using subjective criteria that are not easily quantifiable. A way to objectively assess tumor margins during surgery in patients would be of great value. We have developed a method to visualize tumors during surgery using activatable cell-penetrating peptides (ACPPs), in which the fluorescently labeled, polycationic cell-penetrating peptide (CPP) is coupled via a cleavable linker to a neutralizing peptide. Upon exposure to proteases characteristic of tumor tissue, the linker is cleaved, dissociating the inhibitory peptide and allowing the CPP to bind to and enter tumor cells. In mice, xenografts stably transfected with green fluorescent protein show colocalization with the Cy5-labeled ACPPs. In the same mouse models, Cy5-labeled free ACPPs and ACPPs conjugated to dendrimers (ACPPDs) delineate the margin between tumor and adjacent tissue, resulting in improved precision of tumor resection. Surgery guided by ACPPD resulted in fewer residual cancer cells left in the animal after surgery as measured by Alu PCR. A single injection of ACPPD dually labeled with Cy5 and gadolinium chelates enabled preoperative whole-body tumor detection by MRI, intraoperative guidance by real-time fluorescence, intraoperative histological analysis of margin status by fluorescence, and postoperative MRI tumor quantification. Animals whose tumors were resected with ACPPD guidance had better long-term tumor-free survival and overall survival than animals whose tumors were resected with traditional bright-field illumination only.

475 citations

Journal ArticleDOI
TL;DR: An approach that should generally deliver imaging agents and chemotherapeutics to sites of invasion, tumor-promoting inflammation, and metastasis is validated, and accumulation is strongest at the tumor-stromal interface in primary tumors and associated metastases, indicating better spatial resolution than other currently available MMP-cleavable probes.
Abstract: Activatable cell penetrating peptides (ACPPs) are novel in vivo targeting agents comprised of a polycationic cell penetrating peptide (CPP) connected via a cleavable linker to a neutralizing polyanion (). Adsorption and uptake into cells are inhibited until the linker is proteolyzed. An ACPP cleavable by matrix metalloproteinase-2 (MMP-2) in vitro was the first one demonstrated to work in a tumor model in vivo, but only HT-1080 xenografts and resected human squamous cell carcinomas were tested. Generality to other cancer types, in vivo selectivity of ACPPs for MMPs, and spatial resolution require further characterization. We now show that ACPPs can target many xenograft tumor models from different cancer sites, as well as a thoroughly studied transgenic model of spontaneous breast cancer (mouse mammary tumor virus promoter driving polyoma middle T antigen, MMTV-PyMT). Pharmacological inhibitors and genetic knockouts indicate that current ACPPs are selective for MMP-2 and MMP-9 in the above in vivo models. In accord with the known local distribution of MMP activity, accumulation is strongest at the tumor-stromal interface in primary tumors and associated metastases, indicating better spatial resolution (<50 mum) than other currently available MMP-cleavable probes. We also find that background uptake of ACPPs into normal tissues such as cartilage can be decreased by appending inert macromolecules of 30-50 KDa to the polyanionic inhibitory domain. Our results validate an approach that should generally deliver imaging agents and chemotherapeutics to sites of invasion, tumor-promoting inflammation, and metastasis.

270 citations

Journal ArticleDOI
01 Jun 1997-Neuron
TL;DR: It is shown that parallel fiber synapses onto Purkinje neurons in acute cerebellar slices undergo long-term depression when presynaptic activity coincides with postsynaptic depolarization can be respectively replaced by nitric oxide and Ca2+ photolytically released inside thePurkinje neuron, showing that these two messengers are sufficient for LTD induction.

244 citations


Cited by
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Journal ArticleDOI
02 Apr 2010-Cell
TL;DR: In addition to their role in extracellular matrix turnover and cancer cell migration, MMPs regulate signaling pathways that control cell growth, inflammation, or angiogenesis and may even work in a nonproteolytic manner.

4,185 citations

Book
15 Aug 2002
TL;DR: A comparison of single and two-dimensional neuron models for spiking neuron models and models of Synaptic Plasticity shows that the former are superior to the latter, while the latter are better suited to population models.
Abstract: Neurons in the brain communicate by short electrical pulses, the so-called action potentials or spikes. How can we understand the process of spike generation? How can we understand information transmission by neurons? What happens if thousands of neurons are coupled together in a seemingly random network? How does the network connectivity determine the activity patterns? And, vice versa, how does the spike activity influence the connectivity pattern? These questions are addressed in this 2002 introduction to spiking neurons aimed at those taking courses in computational neuroscience, theoretical biology, biophysics, or neural networks. The approach will suit students of physics, mathematics, or computer science; it will also be useful for biologists who are interested in mathematical modelling. The text is enhanced by many worked examples and illustrations. There are no mathematical prerequisites beyond what the audience would meet as undergraduates: more advanced techniques are introduced in an elementary, concrete fashion when needed.

2,814 citations

Journal ArticleDOI
TL;DR: In this paper, the authors review the barriers to the delivery of cancer therapeutics and summarize strategies that have been developed to overcome these barriers and discuss design considerations for optimizing the nanoparticles to tumors.
Abstract: Recent advances in nanotechnology have offered new hope for cancer detection, prevention, and treatment. While the enhanced permeability and retention effect has served as a key rationale for using nanoparticles to treat solid tumors, it does not enable uniform delivery of these particles to all regions of tumors in sufficient quantities. This heterogeneous distribution of therapeutics is a result of physiological barriers presented by the abnormal tumor vasculature and interstitial matrix. These barriers are likely to be responsible for the modest survival benefit offered by many FDA-approved nanotherapeutics and must be overcome for the promise of nanomedicine in patients to be realized. Here, we review these barriers to the delivery of cancer therapeutics and summarize strategies that have been developed to overcome these barriers. Finally, we discuss design considerations for optimizing the delivery of nanoparticles to tumors.

2,688 citations

Journal ArticleDOI
14 Apr 2006-Science
TL;DR: The focus is on protein detection in live versus fixed cells: determination of protein expression, localization, activity state, and the possibility for combination of fluorescent light microscopy with electron microscopy.
Abstract: Advances in molecular biology, organic chemistry, and materials science have recently created several new classes of fluorescent probes for imaging in cell biology. Here we review the characteristic benefits and limitations of fluorescent probes to study proteins. The focus is on protein detection in live versus fixed cells: determination of protein expression, localization, activity state, and the possibility for combination of fluorescent light microscopy with electron microscopy. Small organic fluorescent dyes, nanocrystals ("quantum dots"), autofluorescent proteins, small genetic encoded tags that can be complexed with fluorochromes, and combinations of these probes are highlighted.

2,632 citations

Journal ArticleDOI
TL;DR: In this article, complex and redundant pathways involving the tumor cell and the microenvironment mediate tumor invasion at the primary site, survival and arrest in the bloodstream, and progressive outgrowth at a distant site.
Abstract: Metastatic disease is the primary cause of death for most cancer patients. Complex and redundant pathways involving the tumor cell and the microenvironment mediate tumor invasion at the primary site, survival and arrest in the bloodstream, and progressive outgrowth at a distant site. Understanding these pathways and their dynamic interactions will help identify promising molecular targets for cancer therapy and key obstacles to their clinical development.

1,953 citations