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Research Directions
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I. Ultra-pH sensitive (UPS) nanoparticles

fig1Responsive nanomaterials have received considerable attention that allow highly selective recognition, catalysis, and transfer operations in a wide range of photonic, electronic, and biological applications. Their underlying science resides in the chemistry of molecular self-assembly. Our lab pioneers the development of a series of tunable, ultra pH-sensitive (UPS) micelles from block copolymers with precisely controlled hydrophobic blocks. Hydrophobic micellization dramatically sharpens to render "transistor-type" of binary response (∆pHoff/on < 0.2 pH), compared to 2 pH units for small-molecular pH sensors. The UPS micelles offer an excellent model system to study the fundamental process of self-assembly through the interplay of noncovalent forces (e.g. electrostatic, van der Waals, and hydrophobic interactions) in aqueous environments. This fundamental knowledge offers useful insights for the development of other types of biosensors to achieve similar binary response (0/1) to simplify diagnostic readouts and minimize subjective interpretations of gray scale signals in biosensing applications.

Selected publications:

1. Li Y, Wang YG, Huang G, Ma X, Gao J. A Surprising Chaotropic Anion-Induced Supramolecular Self-Assembly of Ionic Polymeric Micelles. Angew. Chem. Int. Ed. 2014, 53, 8074-8078. PDF
2. Ma X, Wang YG, Zhao T, Li Y, Su LC, Wang Z, Huang G, Sumer BD, Gao J. Ultra-pH Sensitive Nanoprobe Library with Broad pH Tunability and Fluorescence Response. J. Am. Chem. Soc. 2014, 136, 11085-11092. (Selected as ACS Editor's Choice) PDF
3. Huang X, Huang G, Zhang SR, Sagiyama K, Togao O, Ma X, Wang Y, Li Y, Soesbe TC, Takahashi M, Sherry AD, Gao J. Multi-Chromatic pH-Activatable 19F-MRI Nanoprobes with Binary ON/OFF pH Transitions and Chemical Shift Barcodes. Angew. Chem. Int. Ed. 2013, 52, 8074-8078. PDF

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II. Tumor acidosis imaging

lysosome imagingDysregulated pH is emerging as a universal hallmark of cancer, where cancer cells display a "reversed" pH gradient with a constitutively increased intracellular pH (pHi) and decreased extracellular pH (pHe) compared to normal tissues. The decreased pHe, or tumor acidosis in the microenvironment, stimulates acid-activated proteases for increased local invasion and metastasis. Conventional pH sensors only offer gray scale readout of the small differences between tumor pHe (avg. 6.84) and normal pH (7.2-7.4), therefore lack in pH resolution to robustly detect tumor acidosis. To overcome these limitations, we adopted our pH nanotransistor technology for tumor acidosis imaging. HomoFRET-induced fluorescence quenching was employed at the micelle state to abolish fluorescent signals during blood circulation (pH 7.4), but allow exponential activation in the mildly acidic tumor microenvironment (tumor/blood ratio >300-fold). Currently, we are exploring the use of this technology to improve diagnostic accuracy following FDG-PET/CT, image-guided surgery, and therapeutic monitoring of tumor acidosis inhibitors.

Selected publications:

1. Zhou K, Liu H, Zhang S, Huang X, Wang Y, Huang G, Sumer BD, Gao J. Multicolored pH-Tunable and Activatable Fluorescence Nanoplatform Responsive to Physiologic pH Stimuli. J. Am. Chem. Soc., 2012, 134, 7803-11. PDF
2. Wang Y, Zhou K, Huang G, Hensley C, Huang X, Ma X, Zhao T, Sumer BD, DeBerardinis RJ, Gao J. A Nanoparticle-based Strategy for the Imaging of a Broad Range of Tumours by Nonlinear Amplification of Microenvironment Signals. Nat. Mater. 2014, 13, 204-212. (Featured by SciBX, Nature Materials News and Views, Materials 360, Nano Today and Chemistry World) PDF

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III. Lysosome imaging and catabolism lysosome imaging

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. To support quantitative investigation of these processes in living cells we have developed 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. Deployment in cells allowed quantification of the proton pumping rate from endosomes; discovery of distinct pH thresholds required for mTORC1 activation by free amino acids versus polypeptides; 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 image and perturb paradigm to study lysosome biology and related disease indications.


Selected publications:

1. Zhou KJ, Wang YG, Huang X, Luby-Phelps K, Sumer BD, Gao J. Tunable, Ultra-Sensitive pH Responsive Nanoparticles Targeting Specific Endocytic Organelles in Living Cells. Angew. Chem. Int. Ed. 2011, 50, 6109-6114. PDF
2. Wang C, Wang Y, Li Y, Bodemann B, Zhao T, Ma X, Huang G, Hu Z, DeBerardinis RJ, White MA, Gao J. A Nanobuffer Reporter Library for Fine-Scale Imaging and Perturbation of Endocytic Organelles. Nature Comm. In press.

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IV. Theranostic nanomedicine Theranostic nanomedicine

Multifunctional nanomedicine with integrated imaging and therapeutic functions is rapidly evolving for personalized therapy of cancer. Compared with small molecular-based contrast agents or therapeutic drugs, this new nanomedicine paradigm holds considerable promise that allows for the molecular diagnosis of disease, simultaneous monitoring and treatment, and targeted therapy with minimal toxicity. Our research interests in this area involve the development of multifunctional micelles that incorporate cancer-targeting, imaging sensitivity, and drug delivery functions. More recently, we are focusing on a new drug, β-lapachone, which is bioactivated by an oxidoreductase enzyme, NQO1. NQO1 is highly expressed in a variety of tumors including lung, pancreatic, breast and prostate cancers. Micelle delivery of β-lapachone prodrugs has overcome the hemolysis side effect as observed in ARQ501 (a clinical formulation using cyclodextrin) while leading to increased antitumor efficacy.


Selected publications:

1. Sumer B, Gao J. Theranostic Nanomedicine for Cancer (Editorial). Nanomedicine, 2008, 3, 137-140. PDF
2. Nasongkla N, Bey EA, Ren J, Ai H, Khemtong C, Setti JG, Chin SF, Sherry AD, Boothman DA, Gao J. Multifunctional Polymeric Micelles as Cancer-Targeted, MRI-Ultrasensitive Drug Delivery Systems. Nano Letters 2006, 6, 2427-2430. (Featured by MIT Technology Review) PDF
3. Huang G, Chen H, Luo X, Yu H, Moore Z, Bey EA, Boothman DA, Gao J. Superparamagnetic Iron Oxide Nanoparticles: Amplifying ROS Stress to Improve Anticancer Drug Efficacy. Theranostics, 2013, 3, 116-126. (Selected as the Cover Article) PDF
4. Ma X, Huang XM, Moore Z, Huang G, Kilgore JA, Wang YG, Hammer S, Williams NS, Boothman DA, Gao J. Esterase-activatable β-lapachone prodrug micelles for NQO1-targeted lung cancer therapy. J. Controlled Release, 2015, 200, 201-211. PDF

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