logo
blue bar
header photo


Research Directions
line

I. Molecular basis of cooperativity

fig1Cooperativity broadly manifests itself from biology (hemoglobin-O2 binding) to society (Matthew effect). Biology uses the language of non-covalent chemistry and supramolecular self-assembly to communicate to each other and the outside environment. In materials science, non-covalent self-assembly offers a versatile and modular strategy in generating functional architectures that often display dynamic, cooperative behaviors in response to environmental stimuli. Recently, our lab has discovered several unique cooperative systems with all-or-nothing bistable states without intermediates. In one example, an anti-Hofmeister trend was shown where chaotropic anions induced 'phase out' of cationic block copolymers in contrary to 'phase in' for protein solubilization. In another example, hydrophobic micellization drove divergent proton distribution of transistor-like ultra-pH sensitive nanoprobes with a Hill coefficient of 51, by far the largest reported in the literature. We are using these systems to learn how the alphabets of self-assembly (e.g., hydrophobic, hydrogen bonding and electrostatic interactions) are constructed together to create the 'language of cooperativity'.

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
4. Li, Y.; Zhao, T.; Wang, C.; Lin, Z.; Huang, G.; Sumer, B.D.; Gao, J. Molecular basis of cooperativity in pH-triggered supramolecular self-assembly. Nature Comm. 2016, 7, 13214. PDF

| Back to top |

 

II. Threshold pH sensors for cancer imaging and surgery

imagingOver 1 million cancer surgeries are performed in the US and 5 million worldwide each year. Obtaining tumor-free surgical margins is important to achieve disease-free survival while minimizing removal of normal tissues is equally important to preserve quality of life. To achieve clear margin delineation in a broad set of tumors with diverse tissue origin and cancer genotypes/phenotypes, we have developed a transistor-like pH threshold sensor to image tumor acidosis, a universal cancer hallmark downstream of deregulated energetics (e.g., Warburg effect). HomoFRET-induced fluorescence quenching was employed at the micelle state to abolish fluorescent signals during blood circulation, but allow exponential activation in the mildly acidic tumor microenvironment. The signal amplification strategy allowed the detection of occult tumor nodules <1 mm in size. Real-time, fluorescence-guided surgery achieved >70 cancer cures in mice bearing head and neck tumors. We are further developing the technology for non-invasive tumor diagnosis, image-guided biopsy and surgery, and therapeutic monitoring.

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
3. Zhao,T.; Huang, G.; Li, Y.; Yang, S.; Ramazani, S.; Lin, Z.; Wang, Y.; Ma, X.; Zeng, Z.; Luo, M.; De Boer, E.; Sun, X.; Thibodeaux, J.; Brekken, R.A.; Sun, X.; Sumer, B.D.; Gao, J. A transistor-like pH nanoprobe for tumour detection and image-guided surgery. Nature Biomed. Eng. 2016, DOI: 10.1038/s41551-016-0006. (Featured by Science daily news, Dallas Morning News, NBC5 and CBS11) PDF

| Back to top |

 

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. We are currently adopting the technology for high throughput screening of small molecular drugs that activate autophagy and lysosome catabolism to improve multiple metabolic conditions.


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. 2015, 6, 8524. PDF
3. Wang, Y.; Wang, C.; Li, Y.; Huang, G.; Zhao, T.; Ma, X.; Wang, Z.; Sumer, B.D.; White, M.A.; Gao, J. Digitization of Endocytic pH by Hybrid Ultra-pH-Sensitive Nanoprobes at Single-Organelle Resolution. Adv. Mater. 2016, DOI: 10.1002/adma.201603794. PDF

| Back to top |



IV. Nanovaccines for cancer immunotherapy Nanovaccine width=

Cancer immunotherapy offers curable outcomes in late stage cancer patients as shown by durable responses after immune checkpoint inhibition therapy. However, majority of patients do not benefit from checkpoint therapy because of the lack of tumor-specific cytotoxic T cells. A major challenge in achieving a robust T cell response is the spatio-temporal orchestration of antigen cross-presentation in antigen presenting cells with innate stimulation. Recently, we designed a quantitative redox-activatable sensor to allow high throughput screening of polymer carriers for cytosolic delivery of proteins and biomacromolecules. Moreover, a cytotoxic T cell screen was used to identify a unique polymer composition to elicit strong T cell response against a variety of cancers. Besides antigen delivery, the polymer was able to stimulate the STING-type I interferon pathway. We are currently evaluating the use of STING-activating nanovaccine for HPV-induced cervical and head/neck cancers and its combination with radiation and checkpoint therapy.


Selected publications:

1. Wang, Z.; Luo, M.; Mao, C.; Wei, Q.; Zhao, T.; Li, Y.; Huang, G.; Gao, J. A Redox-Activatable Fluorescent Sensor for the High-Throughput Quantification of Cytosolic Delivery of Macromolecules. Angew. Chem. Int. Ed. 2016, DOI: 10.1002/anie.201610302. PDF
2. Luo, M.; Wang, H.; Wang, Z.; Cai, H.; Lu, Z.; Li, Y.; Du, M.; Huang, G.; Wang, C.; Chen, X.; Porembka, M.R.; Lea, J.; Frankel, A.E.; Fu, Y.; Chen, Z.J.; Gao, J. A STING-activating nanovaccine for cancer immunotherapy, Nature Nanotech. 2017, doi:10.1038/nnano.2017.52. PDF


| Back to top |