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.

Public Health Relevance

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.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Transition Award (R00)
Project #
5R00CA153914-05
Application #
8689972
Study Section
Special Emphasis Panel (NSS)
Program Officer
Farrell, Dorothy F
Project Start
2010-09-03
Project End
2015-07-31
Budget Start
2014-08-01
Budget End
2015-07-31
Support Year
5
Fiscal Year
2014
Total Cost
$231,206
Indirect Cost
$75,887
Name
University of Illinois Urbana-Champaign
Department
Engineering (All Types)
Type
Schools of Engineering
DUNS #
041544081
City
Champaign
State
IL
Country
United States
Zip Code
61820
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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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