Jinming Gao

University of Texas at Dallas, Richardson, Texas, United States

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Publications (104)556.36 Total impact

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    ABSTRACT: Endosomes, lysosomes and related catabolic organelles are a dynamic continuum of vacuolar structures that impact a number of cell physiological processes such as protein/lipid metabolism, nutrient sensing and cell survival. Here we develop a library of ultra-pH-sensitive fluorescent nanoparticles with chemical properties that allow fine-scale, multiplexed, spatio-temporal perturbation and quantification of catabolic organelle maturation at single organelle resolution to support quantitative investigation of these processes in living cells. Deployment in cells allows quantification of the proton accumulation rate in endosomes; illumination of previously unrecognized regulatory mechanisms coupling pH transitions to endosomal coat protein exchange; discovery of distinct pH thresholds required for mTORC1 activation by free amino acids versus proteins; broad-scale characterization of the consequence of endosomal pH transitions on cellular metabolomic profiles; and functionalization of a context-specific metabolic vulnerability in lung cancer cells. Together, these biological applications indicate the robustness and adaptability of this nanotechnology-enabled â detection and perturbation ' strategy.
    Nature Communications 10/2015; 6:8524. DOI:10.1038/ncomms9524 · 11.47 Impact Factor
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    ABSTRACT: Current cancer chemotherapy lacks specificity and is limited by undesirable toxic side-effects, as well as a high rate of recurrence. Nanotechnology has the potential to offer paradigm-shifting solutions to improve the outcome of cancer diagnosis and therapy. β-Lapachone (β-lap) is a novel anticancer agent whose mechanism of action is highly dependent on NAD(P)H:quinone oxidoreductase 1 (NQO1), a phase II detoxifying enzyme overexpressed in solid tumors from a variety of cancer types. However, the poor water solubility of β-lap limits its clinical potential. A series of drug formulations were developed for systemic administration in preclinical evaluations. Encapsulation of β-lap into polymeric micelles showed less side-effects and higher maximum tolerated dose (MTD), prolonged blood circulation time and preferential accumulation in tumors with greatly improved safety and antitumor efficacy. The prodrug strategy of β-lap further decreases the crystallization of β-lap by introducing esterase degradable side chains to the rigid fused ring structure. β-Lap prodrugs considerably increased the stability, drug-loading content and delivery efficiency of nanoparticles. The optimized formulation of β-lap-dC3 prodrug micelles showed excellent antitumor efficacy in treating orthotopic non-small cell lung tumors that overexpress NQO1, with target validation using pharmacodynamic endpoints.
    Journal of Drug Targeting 09/2015; 23(7-8):672-680. DOI:10.3109/1061186X.2015.1073296 · 2.74 Impact Factor
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    ABSTRACT: Lung cancer is one of the most lethal forms of cancer and current chemotherapeutic strategies lack broad specificity and efficacy. Recently, β-lapachone (β-lap) was shown to be highly efficacious in killing non-small cell lung cancer (NSCLC) cells regardless of their p53, cell cycle and caspase status. Pre-clinical and clinical use of β-lap (clinical form, ARQ501 or 761) is hampered by poor pharmacokinetics and toxicity due to hemolytic anemia. Here, we report the development and preclinical evaluation of β-lap prodrug nanotherapeutics consisting of diester derivatives of β-lap encapsulated in biocompatible and biodegradable poly(ethylene glycol)-b-poly(d,l-lactic acid) (PEG-b-PLA) micelles. Compared to the parent drug, diester derivatives of β-lap showed higher drug loading densities inside PEG-b-PLA micelles. After esterase treatment, micelle-delivered β-lap-dC3 and -dC6 prodrugs were converted to β-lap. Cytotoxicity assays using A549 and H596 lung cancer cells showed that both micelle formulations maintained NAD(P)H:quinone oxidoreductase 1 (NQO1)-dependent cytotoxicity. However, antitumor efficacy study of β-lap-dC3 micelles against orthotopic A549 NSCLC xenograft-bearing mice showed significantly greater long-term survival over β-lap-dC6 micelles or β-lap-HPβCD complexes. Improved therapeutic efficacy of β-lap-dC3 micelles correlated with higher area under the concentration-time curves of β-lap in tumors, and enhanced pharmacodynamic endpoints (e.g., PARP1 hyperactivation, γH2AX, and ATP depletion). β-Lap-dC3 prodrug micelles provide a promising strategy for NQO1-targeted therapy of lung cancer with improved safety and antitumor efficacy. Copyright © 2014. Published by Elsevier B.V.
    Journal of Controlled Release 12/2014; 200. DOI:10.1016/j.jconrel.2014.12.027 · 7.71 Impact Factor

  • Cancer Research 10/2014; 74(19 Supplement):787-787. DOI:10.1158/1538-7445.AM2014-787 · 9.33 Impact Factor
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    ABSTRACT: Objective: Folate receptor (FR) expression, while known to be elevated in many types of cancer and inflammatory cells, has not been well characterized in head and neck squamous cell carcinoma (HNSCC). We hypothesized that tumor infiltrating inflammatory cells expressing FR-β could allow fluorescent visualization of HNSCC tumors using folate conjugated dyes even when FR expression in cancer cells is low. Study Design: Retrospective review of clinical pathologic specimens and in vivo animal study. Methods: A tissue microarray (TMA) with tumor and tumor free tissue from 22 patients with HNSCC was stained with antibodies to FR-α and FR-β. We characterized FR-β(+) cells by examining CD45, CD68, CD206 and TGF-β expression. To investigate fluorescent imaging, mice with orthotopic tumor xenografts were imaged in vivo after intravenous injections of folate conjugated fluorescein isothiocyanate (folate-FITC) and were histologically evaluated ex vivo. Results: All tumor samples demonstrated significant FR-β staining and negligible FR-α staining. FR-β(+) cells found in tumors coexpressed CD68 and had increased expression of CD206 and TGF-β characteristic of tumor-associated macrophages. In the xenograft models, tumors showed strong in vivo fluorescence after folate-FITC injection in contrast to surrounding normal tissues. Histologic examination of the xenograft tissue similarly showed folate-FITC uptake in areas of inflammatory cellular infiltrate. Conclusion: While HNSCC tumor cells do not express FR, HNSCC tumors contain a significant population of FR-β expressing macrophages. Folate conjugated fluorescent dye is able to specifically target and label tumor xenografts to permit macroscopic fluorescence imaging due to FR-β expression on the infiltrating inflammatory cells.
    The Laryngoscope 08/2014; 124(8). DOI:10.1002/lary.24606 · 2.14 Impact Factor
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    ABSTRACT: β-Lap prodrug micelle strategy improves the formulation properties of β-lap therapeutics. The resulting micelles yield apparent high β-lap solubility (>7 mg mL(-1) ), physical stability, and ability to reconstitute after lyophilization. In the presence of esterase, β-lap prodrugs are efficiently converted into parent drug (i.e., β-lap), resulting in NQO1-dependent lethality of NSCLC cells.
    Advanced Healthcare Materials 08/2014; 3(8). DOI:10.1002/adhm.201300590 · 5.80 Impact Factor
  • Yang Li · Yiguang Wang · Gang Huang · Xinpeng Ma · Kejin Zhou · Jinming Gao ·
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    ABSTRACT: Traditional micelle self-assembly is driven by the association of hydrophobic segments of amphiphilic molecules forming distinctive core-shell nanostructures in water. Here we report a surprising chaotropic-anion-induced micellization of cationic ammonium-containing block copolymers. The resulting micelle nanoparticle consists of a large number of ion pairs (≈60 000) in each hydrophobic core. Unlike chaotropic anions (e.g. ClO4 (-) ), kosmotropic anions (e.g. SO4 (2-) ) were not able to induce micelle formation. A positive cooperativity was observed during micellization, for which only a three-fold increase in ClO4 (-) concentration was necessary for micelle formation, similar to our previously reported ultra-pH-responsive behavior. This unique ion-pair-containing micelle provides a useful model system to study the complex interplay of noncovalent interactions (e.g. electrostatic, van der Waals, and hydrophobic forces) during micelle self-assembly.
    Angewandte Chemie International Edition in English 07/2014; 53(31). DOI:10.1002/anie.201402525 · 13.45 Impact Factor
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    ABSTRACT: pH is an important physiological parameter that plays a critical role in cellular and tissue homeostasis. Conventional small molecular pH sensors (e.g. fluorescein, Lysosensor) are limited by broad pH response and restricted fluorescent emissions. Previously, we reported the development of ultra-pH sensitive (UPS) nanoprobes with sharp pH response using fluorophores with small Stokes shifts (<40 nm). In this study, we expand the UPS design to a library of nanoprobes with operator-predetermined pH transitions and wide fluorescent emissions (400-820 nm). A copolymer strategy was employed to fine tune the hydrophobicity of the ionizable hydrophobic block, which led to desired transition pH based on standard curves. Interestingly, matching the hydrophobicity of the monomers was critical to achieve a sharp pH transition. To overcome the fluorophore limitations, we introduced copolymers conjugated with fluorescence quenchers (FQs). In the micelle state, the FQs effectively suppressed the emission of fluorophores regardless of their Stokes shifts, and further increased the fluorescence activation ratios. As a proof of concept, we generated a library of 10 nanoprobes each encoded with a unique fluorophore. The nanoprobes cover the entire physiologic range of pH (4-7.4) with 0.3 pH increments. Each nanoprobe maintained a sharp pH transition (on/off < 0.25 pH) and high fluorescence activation ratio (>50-fold between on and off states). The UPS library provides a useful toolkit to study pH regulation in many pathophysiological indications (e.g. cancer, lysosome catabolism) as well as establishing tumor-activatable systems for cancer imaging and drug delivery.
    Journal of the American Chemical Society 07/2014; 136(31). DOI:10.1021/ja5053158 · 12.11 Impact Factor
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    ABSTRACT: Phosphatidylserine (PS), normally restricted to the inner leaflet of the plasma membrane, becomes exposed on the outer surface of viable endothelial cells in tumor vasculature, but not in normal blood vessels. In the present study, we report the use of PGN635, a novel human monoclonal antibody that specifically targets PS, for in vivo molecular MRI of tumor vasculature. The F(ab')2 fragments of PGN635 were conjugated to polyethylene glycol (PEG) coated iron oxide nanoparticles (IO). Targeting specificity of the PS-targeted Nanoprobe, IO-PGN635F(ab')2 was first confirmed by in vitro MRI and histological staining. In vivo longitudinal MRI was then performed before and after i.v. injection of IO-PGN635F(ab')2 into mice bearing 4T1 breast tumors. T2-weighted MR images at 9.4 T revealed inhomogeneous signal loss in tumor as early as 2 h post injection. Furthermore, ionizing radiation induced a significant increase in PS exposure on tumor vascular endothelial cells, resulting in significantly enhanced and sustained tumor contrast (p < 0.05). Spatially heterogeneous MRI contrast correlated well with histological staining of tumor vascular endothelium. Our studies suggest that PS exposed within the lumen of tumor vasculature is a highly specific and useful biomarker for targeted MRI contrast agents.
    Journal of Biomedical Nanotechnology 05/2014; 10(5):846-55. DOI:10.1166/jbn.2014.1851 · 5.34 Impact Factor
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    ABSTRACT: Poly (ADP-ribose) polymerases (PARPs) are a family of related enzymes that share the ability to catalyze the transfer of ADP-ribose to target proteins. PARPs play an important role in various cellular processes, including modulation of chromatin structure, transcription, replication, recombination, and DNA repair. The role of PARP proteins in DNA repair is of particular interest, in view of the finding that certain tumors defective in homologous recombination mechanisms, may rely on PARP-mediated DNA repair for survival, and are sensitive to its inhibition. PARP inhibitors may also increase tumor sensitivity to DNA-damaging agents. Clinical trials of PARP inhibitors are investigating the utility of these approaches in cancer. The hyperactivation of PARP has also been shown to result in a specific programmed cell death pathway involving NAD+/ATP depletion, mu-calpain activation, loss of mitochondrial membrane potential, and the release of apoptosis inducing factor. Hyperactivation of the PARP pathway may be exploited to selectively kill cancer cells. Other PARP forms, including tankyrase 1 (PARP 5a), which plays an important role in enhancing telomere elongation by telomerase, have been found to be potential targets in cancer therapy. The PARP pathway and its inhibition thus offers a number of opportunities for therapeutic intervention in both cancer and other disease states.
    Critical Reviews in Eukaryotic Gene Expression 03/2014; 24(1):15-28. DOI:10.1615/CritRevEukaryotGeneExpr.2013006875 · 1.57 Impact Factor
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    ABSTRACT: Stimuli-responsive nanomaterials are increasingly important in a variety of applications such as biosensing, molecular imaging, drug delivery and tissue engineering. For cancer detection, a paramount challenge still exists in the search for methods that can illuminate tumours universally regardless of their genotypes and phenotypes. Here we capitalized on the acidic, angiogenic tumour microenvironment to achieve the detection of tumour tissues in a wide variety of mouse cancer models. This was accomplished using ultra pH-sensitive fluorescent nanoprobes that have tunable, exponential fluorescence activation on encountering subtle, physiologically relevant pH transitions. These nanoprobes were silent in the circulation, and then strongly activated (>300-fold) in response to the neovasculature or to the low extracellular pH in tumours. Thus, we have established non-toxic, fluorescent nanoreporters that can nonlinearly amplify tumour microenvironmental signals, permitting the identification of tumour tissue independently of histological type or driver mutation, and detection of acute treatment responses much more rapidly than conventional imaging approaches.
    Nature Material 12/2013; 13(2). DOI:10.1038/nmat3819 · 36.50 Impact Factor
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    ABSTRACT: Amide proton transfer (APT) imaging is one of the chemical exchange saturation transfer (CEST) imaging methods which images the exchange between protons of free tissue water and the amide groups (-NH) of endogenous mobile proteins and peptides. Previous work suggested the ability of APT imaging for characterization of the tumoral grade in the brain tumor. In this study, we tested the feasibility of in-vivo APT imaging of lung tumor and investigated whether the method could differentiate the tumoral types on orthotopic tumor xenografts from two malignant lung cancer cell lines. The results revealed that APT imaging is feasible to quantify lung tumors in the moving lung. The measured APT effect was higher in the tumor which exhibited more active proliferation than the other. The present study demonstrates that APT imaging has the potential to provide a characterization test to differentiate types or grade of lung cancer noninvasively, which may eventually reduce the need invasive needle biopsy or resection for lung cancer.
    PLoS ONE 10/2013; 8(10):e77019. DOI:10.1371/journal.pone.0077019 · 3.23 Impact Factor
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    ABSTRACT: We report an jet rollable nanoimprint lithography tool as a low cost method to produce micro- and nano-structures rapidly over large areas. We integrated a piezoelectric nozzle to deposit resist in-line in a low-waste, high-precision manner. We demonstrate the capabilities of this system by creating a variety of microstructures in SU8 resist with high pattern transfer fidelity.
    2013 IEEE 13th International Conference on Nanotechnology (IEEE-NANO); 08/2013
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    ABSTRACT: Imaging all the people: Using ionizable diblock copolymers a series of nanoprobes encoded with different (19) F reporters for specific pH transitions is prepared for use in MRI. The pH response of the nanoprobes is extremely sharp (ΔpHON/OFF ≈0.25 pH), and results from the disassembly of polymer micelles. A collection of three nanoprobes provides the proof of concept and allows for a qualitative measurement of environmental pH values.
    Angewandte Chemie International Edition 07/2013; 52(31). DOI:10.1002/anie.201301135 · 11.26 Impact Factor
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    ABSTRACT: Improving patient outcome by personalized therapy involves a thorough understanding of an agent's mechanism of action. β-Lapachone (clinical forms, Arq501/Arq761) has been developed to exploit dramatic cancer-specific elevations in the phase II detoxifying enzyme, NAD(P)H:quinone oxidoreductase (NQO1). NQO1 is dramatically elevated in solid cancers, including primary and metastatic (e.g., triple-negative (ER-, PR-, Her2/Neu-)) breast cancers. To define cellular factors that influence the efficacy of β-lapachone using knowledge of its mechanism of action, we confirmed that NQO1 was required for lethality and mediated a futile redox cycle where ~120 moles of superoxide were formed per mole of β-lapachone in 5 min. β-Lapachone induced reactive oxygen species (ROS), stimulated DNA single strand break-dependent PARP1 hyperactivation, caused dramatic loss of essential nucleotides (NAD+/ATP) and elicited programmed necrosis in breast cancer cells. While PARP1 hyperactivation and NQO1 expression were major determinants of β-lapachone-induced lethality, alterations in catalase expression, including treatment with exogenous enzyme, caused marked cytoprotection. Thus, catalase is an important resistance factor, and highlights H2O2 as an obligate ROS for cell death from this agent. Exogenous superoxide dismutase (SOD) enhanced catalase-induced cytoprotection. β-Lapachone-induced cell death included AIF translocation from mitochondria to nuclei, TUNEL+ staining, atypical PARP1 cleavage, and GAPDH S-nitrosylation, which were abrogated by catalase. We predict that the ratio of NQO1:catalase activities in breast cancer versus associated normal tissue are likely to be the major determinants affecting the therapeutic window of β-lapachone and other NQO1 bioactivatable drugs.
    Molecular Cancer Therapeutics 07/2013; 12(10). DOI:10.1158/1535-7163.MCT-12-0962 · 5.68 Impact Factor
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    ABSTRACT: In this communication, we report that ionizable, tertiary amine-based block copolymers can be used as pH-responsive contrast agents for magnetic resonance imaging (MRI) through the chemical exchange saturation transfer (CEST) mechanism. The CEST signal is essentially "off" when the polymers form micelles near physiological pH but is activated to the "on" state when the micelles dissociate in an acidic environment.
    Chemical Communications 06/2013; 49(57). DOI:10.1039/c3cc42452a · 6.83 Impact Factor

  • Cancer Research 04/2013; 73(8 Supplement):589-589. DOI:10.1158/1538-7445.AM2013-589 · 9.33 Impact Factor
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    Ruhai Tian · Suresh Regonda · Jinming Gao · Yaling Liu · Walter Hu ·

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    ABSTRACT: Here we demonstrate the use of multiple Si nanochannel (NC) or nanograting (NG) instead of the conventional single nanochannel or nanowire design in biosensors. The NG devices can significantly reduce device-to-device variation, and improve device performance, e.g. higher current, higher ON/OFF ratio, smaller subthreshold slope, lower threshold voltage Vt in buffer solution. NG devices also result in higher sensor stability in buffer and diluted human serum. We believe such improvements are due to reduced discrete dopant fluctuation in the Si nanowires and biochemical noise in the solution because of the multiple-channel design. The improved devices allow us to sense pH linearly with 3-aminopropyltriethoxysilane coated devices, and to selectively detect insulin with limit of detection down to 10fM in both buffer solution and diluted human serum without pre-purification.
    Biosensors & Bioelectronics 02/2013; 45C(1):245-251. DOI:10.1016/j.bios.2013.01.027 · 6.41 Impact Factor
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    ABSTRACT: Superparamagnetic iron oxide nanoparticles (SPION) are an important and versatile nano- platform with broad biological applications. Despite extensive studies, the biological and pharmacological activities of SPION have not been exploited in therapeutic applications. Recently, β-lapachone (β-lap), a novel anticancer drug, has shown considerable cancer specificity by selectively increasing reactive oxygen species (ROS) stress in cancer cells. In this study, we report that pH-responsive SPION-micelles can synergize with β-lap for improved cancer therapy. These SPION-micelles selectively release iron ions inside cancer cells, which interact with hydrogen peroxide (H(2)O(2)) generated from β-lap in a tumor-specific, NQO1-dependent manner. Through Fenton reactions, these iron ions escalate the ROS stress in β-lap-exposed cancer cells, thereby greatly enhancing the therapeutic index of β-lap. More specifically, a 10-fold increase in ROS stress was detected in β-lap-exposed cells pretreated with SPION-micelles over those treated with β-lap alone, which also correlates with significantly increased cell death. Catalase treatment of cells or administration of an iron chelator can block the therapeutic synergy. Our data suggest that incorporation of SPION-micelles with ROS-generating drugs can potentially improve drug efficacy during cancer treatment, thereby provides a synergistic strategy to integrate imaging and therapeutic functions in the development of theranostic nanomedicine.
    Theranostics 02/2013; 3(2):116-26. DOI:10.7150/thno.5411 · 8.02 Impact Factor

Publication Stats

5k Citations
556.36 Total Impact Points


  • 2006-2015
    • University of Texas at Dallas
      • • Chemistry
      • • Department of Electrical Engineering
      Richardson, Texas, United States
  • 2006-2014
    • University of Texas Southwestern Medical Center
      • • Simmons Comprehensive Cancer Center
      • • Department of Pharmacology
      • • Harold C. Simmons Comprehensive Cancer Center
      Dallas, Texas, United States
  • 2011
    • Lehigh University
      • Department of Mechanical Engineering and Mechanics
      Bethlehem, Pennsylvania, United States
  • 2010-2011
    • Comprehensive Cancer Centers of Nevada
      Las Vegas, Nevada, United States
  • 2001-2008
    • Case Western Reserve University
      • • Department of Biomedical Engineering
      • • Department of Macromolecular Science and Engineering
      Cleveland, Ohio, United States
  • 2004
    • Case Western Reserve University School of Medicine
      • Department of Radiology
      Cleveland, Ohio, United States