In this project, we proposed to develop a new drug delivery vehicle based on dendrimer nanotechnology for personalized medicine. This new nanoparticle contains imaging probe and molecular medicine with a cancer-specific targeting capability which is able to target cancer cells, monitor drug delivery and tumor response to achieve a "see and treat" strategy as a new concept of molecular medicine. This nanoparticle platform will be very flexible for adopting any new cell targeting molecule or any forms of therapeutic agents. One of the most exciting developments in molecular medicine has been the step-by-step construction of signaling cascades that trace the effect path of extracellular stimuli, including soluble growth factors, hormone, matrices, stress, and cell-cell contact, all the way from the external membrane to the cell nucleus. Altered signaling pathways are often found in malignant or non-malignant diseases. Knowledge from protein biochemistry has revealed specific functional motif associated with signaling protein responsible for this action. Thus, targeting these defective signal pathways with small molecule, particular small peptide or peptido-memtics, is now becoming an active research area of drug development because peptide is a natural compound in human body with less concern of side effect. In order to increase therapeutic index of these agents, we have designed a target-specific delivery system from a unique group of peptide with cell permeability. To date, the rapid evolving nanotechnology has yielded many biocompatible nanocarriers for imaging and/or therapeutic application. In this project, a dendrimer nanoparticle equipped cell specific cell permeable peptide was designed and synthesized to have molecular imaging capabilities and carry various therapeutic agents. This particle will be tested for locate target cell and monitor the drug response of tumor cells in a real-time manner. We believe that this experimental therapy has a great potential to translate into clinical application in an immediate future because all the materials do not expect to post any significant toxicity to human body. Most importantly, this proposal is to explore a new avenue of tailored molecular therapy for metastatic prostate cancer in contrast to conventional therapeutic strategy since prostate cancer has become the second leading cause of cancer death among US men. Most men died of prostate cancer are due to metastatic disease that has not been controlled effectively. Thus, the success outcome of this study will certainly bring one step close to the ultimate cure of this disease. This work is carried out by a team with highly productive collaborations with numbers of publications. The Simanek's laboratory will make dendrimers that bear a functional handle for the chelating agent provided by Dr. Sun and several peptides provided by Dr. Hsieh. Dr. Simanek's lab is responsible installing both the chelate and the peptides onto the dendrimer and characterizing the resulting materials before return to Drs. Sun's and Hsieh's laboratory for evaluating the application of molecular imaging and therapy.

Public Health Relevance

Today, nanotechnology has produced many unique drug delivery platforms that can be integrated into a theranostic agent. Non-invasive molecular imaging techniques have advantages over anatomic imaging techniques to better define the location and extent of disease and to better assess the response of target tissue or organ to drugs in a real-time manner. By teaming up experts from various areas, the goal of this project is to invent mechanism-specific targeting agents using dendrimer then test their translational ability into future clinical application, which has many potentials to spin off a new biotechnology entity and further revolutionize current cancer therapy.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA159144-03
Application #
8509520
Study Section
Developmental Therapeutics Study Section (DT)
Program Officer
Fu, Yali
Project Start
2011-09-21
Project End
2016-07-31
Budget Start
2013-08-01
Budget End
2014-07-31
Support Year
3
Fiscal Year
2013
Total Cost
$305,137
Indirect Cost
$91,514
Name
University of Texas Sw Medical Center Dallas
Department
Urology
Type
Schools of Medicine
DUNS #
800771545
City
Dallas
State
TX
Country
United States
Zip Code
75390
Hao, Guiyang; Kumar, Amit; Dobin, Timothy et al. (2013) A multivalent approach of imaging probe design to overcome an endogenous anion binding competition for noninvasive assessment of prostate specific membrane antigen. Mol Pharm 10:2975-85
Lo, Su-Tang; Kumar, Amit; Hsieh, Jer-Tsong et al. (2013) Dendrimer nanoscaffolds for potential theranostics of prostate cancer with a focus on radiochemistry. Mol Pharm 10:793-812
Patra, Subrata; Kozura, Brittany; Huang, Adela Y-T et al. (2013) Dendrimers terminated with dichlorotriazine groups provide a route to compositional diversity. Org Lett 15:3808-11