Cancer, the uncontrolled growth and spread of malignant cells that can affect almost any tissue of the body, continues to be a major burden to public health. Anticancer chemotherapy is the most important adjuvant therapy, but the targeted and effective therapy to the tumorous tissues or organs, however, remains as a significant challenge in chemotherapy. The proposed work will develop molecular nanofibers of small molecules for controlling the behavior and the fate of cells. The goal of this work is to explore cellular responses to enzyme-instructed formation of molecular nanofibers and eventually develop new nanomedicines to target cancer cells. This application is both hypothesis and design driven. We hypothesize that enzyme- instructed molecular self-assembly, as a unique way to create molecular nanofibers, can modulate extra- and intracellular microenvironment and selectively lead to death of cancer cells. To validate the hypothesis, we will design molecules that self-assemble to form nanofibers upon the action of extra- or intracellular enzyme(s), characterize the physiochemical properties of the nanofibers, and assess the biological properties and effects of the formation of molecular nanofibers in vitro and in vivo. Specifically, this proposed research will (i) design and synthesize substrates that can be converted into molecular nanofibers by enzyme catalysis;(ii) characterize the enzyme-catalyzed reactions of the designed precursors and the behavior and properties of the corresponding molecular nanofibers;(iii) evaluate the activity of the molecular nanofibers against representative cancer cell lines in vitro;and (iv) examine formation and anticancer effects of the molecular nanofibers in vivo using animal models. This research will potentially provide a new platform for creating synthetic nanostructures as nanomedicine to target cancer cells. We anticipate that this new approach will improve fundamental understanding of cancer therapy, provide guiding principles to design anticancer agents at nanoscale, and ultimately lead to a new paradigm of cancer therapy that are based on the integration of molecular self-assembly and enzyme catalysis.

Public Health Relevance

The overall goal of this work is to develop a novel approach for creating nanomedicine to target cancer cells. Using enzyme to instruct the formation of synthetic nanostructures, this approach will ultimately lead to a new paradigm of cancer therapy for improving health and quality of life for the millions of people who will need anticancer treatment in the future.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA142746-03
Application #
8214707
Study Section
Nanotechnology Study Section (NANO)
Program Officer
Forry, Suzanne L
Project Start
2010-02-08
Project End
2015-01-31
Budget Start
2012-02-01
Budget End
2013-01-31
Support Year
3
Fiscal Year
2012
Total Cost
$318,015
Indirect Cost
$116,740
Name
Brandeis University
Department
Chemistry
Type
Schools of Arts and Sciences
DUNS #
616845814
City
Waltham
State
MA
Country
United States
Zip Code
02454
Li, Jie; Du, Xuewen; Powell, Devon J et al. (2018) Down-regulating Proteolysis to Enhance Anticancer Activity of Peptide Nanofibers. Chem Asian J 13:3464-3468
Zhou, Jie; Du, Xuewen; Chen, Xiaoyi et al. (2018) Enzymatic Self-Assembly Confers Exceptionally Strong Synergism with NF-?B Targeting for Selective Necroptosis of Cancer Cells. J Am Chem Soc 140:2301-2308
Wang, Jiaqing; Zhou, Jie; He, Hongjian et al. (2018) Cell-compatible Nanoprobes for Imaging Intracellular Phosphatase Activities. Chembiochem :
Zhou, Jie; Du, Xuewen; Berciu, Cristina et al. (2018) Cellular Uptake of A Taurine-Modified, Ester Bond-Decorated D-Peptide Derivative via Dynamin-Based Endocytosis and Macropinocytosis. Mol Ther 26:648-658
Li, Jie; Bullara, Domenico; Du, Xuewen et al. (2018) Kinetic Analysis of Nanostructures Formed by Enzyme-Instructed Intracellular Assemblies against Cancer Cells. ACS Nano 12:3804-3815
Wang, Huaimin; Feng, Zhaoqianqi; Del Signore, Steven J et al. (2018) Active Probes for Imaging Membrane Dynamics of Live Cells with High Spatial and Temporal Resolution over Extended Time Scales and Areas. J Am Chem Soc 140:3505-3509
Wang, Huaimin; Feng, Zhaoqianqi; Yang, Cuihong et al. (2018) Unraveling the Cellular Mechanism of Assembling Cholesterols for Selective Cancer Cell Death. Mol Cancer Res :
Zhou, Jie; Du, Xuewen; Chen, Xiaoyi et al. (2018) Adaptive Multifunctional Supramolecular Assemblies of Glycopeptides Rapidly Enable Morphogenesis. Biochemistry 57:4867-4879
Wang, Huaimin; Feng, Zhaoqianqi; Qin, Yanan et al. (2018) Nucleopeptide Assemblies Selectively Sequester ATP in Cancer Cells to Increase the Efficacy of Doxorubicin. Angew Chem Int Ed Engl 57:4931-4935
He, Hongjian; Wang, Jiaqing; Wang, Huaimin et al. (2018) Enzymatic Cleavage of Branched Peptides for Targeting Mitochondria. J Am Chem Soc 140:1215-1218

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