The aim of this research proposal is to develop a new class of fluorescent nanoparticles for highly sensitive and multicolor imaging of the tumor microenvironment in vivo toward understanding and improving nanoparticle drug delivery. We will focus on semiconductor quantum dots (QDs), which are nanocrystals that exhibit bright fluorescence and unique optical and electronic properties. We have recently designed a new class of quantum dots called 'alloyed quantum wells,'which have equalized fluorescence brightness across a broad spectrum of colors. This novel property is not available from organic dyes, fluorescent proteins, or conventional quantum dots, and will enable quantitative studies of nanoparticle drug delivery to solid tumors. The basic idea is that we can modify the size, surface chemistry, or targeting ligands on these multicolor probes to model nanoparticle drug formulations, which can then be quantitatively compared for uptake and penetration in solid tumors. Because these particles are immensely bright on the single molecule level, intravital microscopy of solid tumors will allow a single-molecule, mechanistic understanding of the rate-limiting steps of drug delivery in a multicolor fashion. This simultaneous multicolor approach is critical for comparisons in the heterogeneous tumor microenvironment, and is not possible with conventional optical probes. In this proposal, we will optically engineer these nanoparticles, develop inert surface coatings for compact sizes and long circulation times in blood, and develop new high-precision bioconjugation strategies based on self- assembly principles. We will use these new probes to image the microscopic processes of targeted-delivery to tumors, concentrating on caveolae-mediated transcytosis, an active transport process that has recently been shown to efficiently pump nanoparticles from the tumor blood vessels into the interstitial tissue. These studies will implement highly relevant orthotopic models of human breast cancer that will ensure clinical significance of the findings. During the mentored phase of this award, the candidate will be co-mentored by Dr. Shuming Nie of Emory University and Dr. Jan Schnitzer of the Proteogenomic Research Institute for Systems Medicine, and will be trained in the use of orthotopic models of human cancer, intravital microscopy techniques, and antibody- based tumor targeting strategies. Both of these mentors are leaders in their respective fields of nanotechnology and cancer biology, which will enable a convergence of expertise to guide this interdisciplinary research project and to facility the transition of the candidate from a mentored postdoctoral fellow to an independent investigator in an academic setting.
Nanoparticle-based drugs are a promising therapeutic approach for cancer, however our ability to rationally and optimally design these particles is currently limited by a poor understanding of their behavior in tumors. In this proposal, we will develop a new class of fluorescent nanoparticle probes that will enable highly sensitive, quantitative, single-molecule imaging and tracking of nanoparticles in cancer tissue. We will use these probes to understand the mechanisms of targeted nanoparticle delivery to tumors to inform design parameters that will enhance tumor uptake and therapeutic efficacy.
|Ma, Liang; Tu, Chunlai; Le, Phuong et al. (2016) Multidentate Polymer Coatings for Compact and Homogeneous Quantum Dots with Efficient Bioconjugation. J Am Chem Soc 138:3382-94|
|Lim, Sung Jun; McDougle, Daniel R; Zahid, Mohammad U et al. (2016) Lipoprotein Nanoplatelets: Brightly Fluorescent, Zwitterionic Probes with Rapid Cellular Entry. J Am Chem Soc 138:64-7|
|Grolman, Joshua M; Zhang, Douglas; Smith, Andrew M et al. (2015) Rapid 3D Extrusion of Synthetic Tumor Microenvironments. Adv Mater 27:5512-7|
|Chung, Eddie Y; Ochs, Christopher J; Wang, Yi et al. (2015) Activatable and Cell-Penetrable Multiplex FRET Nanosensor for Profiling MT1-MMP Activity in Single Cancer Cells. Nano Lett 15:5025-32|
|Lane, Lucas A; Qian, Ximei; Smith, Andrew M et al. (2015) Physical chemistry of nanomedicine: understanding the complex behaviors of nanoparticles in vivo. Annu Rev Phys Chem 66:521-47|
|Lim, Sung Jun; Zahid, Mohammad U; Le, Phuong et al. (2015) Brightness-equalized quantum dots. Nat Commun 6:8210|
|Dobrucki, Lawrence W; Pan, Dipanjan; Smith, Andrew M (2015) Multiscale Imaging of Nanoparticle Drug Delivery. Curr Drug Targets 16:560-70|
|Cai, En; Ge, Pinghua; Lee, Sang Hak et al. (2014) Stable small quantum dots for synaptic receptor tracking on live neurons. Angew Chem Int Ed Engl 53:12484-8|
|Lim, Sung Jun; Smith, Andrew; Nie, Shuming (2014) The More Exotic Shapes of Semiconductor Nanocrystals: Emerging Applications in Bioimaging. Curr Opin Chem Eng 4:137-143|
|Smith, Andrew M; Lane, Lucas A; Nie, Shuming (2014) Mapping the spatial distribution of charge carriers in quantum-confined heterostructures. Nat Commun 5:4506|
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