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)
Type
Research Project (R01)
Project #
5R01CA142746-05
Application #
8608491
Study Section
Nanotechnology Study Section (NANO)
Program Officer
Forry, Suzanne L
Project Start
Project End
Budget Start
Budget End
Support Year
5
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Brandeis University
Department
Chemistry
Type
Schools of Arts and Sciences
DUNS #
City
Waltham
State
MA
Country
United States
Zip Code
02453
Wang, Huaimin; Feng, Zhaoqianqi; Wu, Dongdong et al. (2016) Enzyme-Regulated Supramolecular Assemblies of Cholesterol Conjugates against Drug-Resistant Ovarian Cancer Cells. J Am Chem Soc 138:10758-61
Zhou, Jie; Du, Xuewen; Yamagata, Natsuko et al. (2016) Enzyme-Instructed Self-Assembly of Small D-Peptides as a Multiple-Step Process for Selectively Killing Cancer Cells. J Am Chem Soc 138:3813-23
Feng, Zhaoqianqi; Wang, Huaimin; Du, Xuewen et al. (2016) Minimal C-terminal modification boosts peptide self-assembling ability for necroptosis of cancer cells. Chem Commun (Camb) 52:6332-5
Zhou, Jie; Du, Xuewen; Xu, Bing (2016) Regulating the Rate of Molecular Self-Assembly for Targeting Cancer Cells. Angew Chem Int Ed Engl 55:5770-5
Zhou, Rong; Kuang, Yi; Zhou, Jie et al. (2016) Nanonets Collect Cancer Secretome from Pericellular Space. PLoS One 11:e0154126
Wang, Huaimin; Feng, Zhaoqianqi; Xu, Bing (2016) D-amino acid-containing supramolecular nanofibers for potential cancer therapeutics. Adv Drug Deliv Rev :
Yuan, Dan; Shi, Junfeng; Du, Xuewen et al. (2016) The Enzyme-instructed assembly of the core of yeast prion Sup35 to form supramolecular hydrogels. J Mater Chem B Mater Biol Med 4:1318-1323
Li, Jie; Kuang, Yi; Shi, Junfeng et al. (2015) Enzyme-Instructed Intracellular Molecular Self-Assembly to Boost Activity of Cisplatin against Drug-Resistant Ovarian Cancer Cells. Angew Chem Int Ed Engl 54:13307-11
Zhou, Jie; Du, Xuewen; Li, Jie et al. (2015) Taurine Boosts Cellular Uptake of Small D-Peptides for Enzyme-Instructed Intracellular Molecular Self-Assembly. J Am Chem Soc 137:10040-3
Wu, Dongdong; Du, Xuewen; Shi, Junfeng et al. (2015) The first CD73-instructed supramolecular hydrogel. J Colloid Interface Sci 447:269-72

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