The long term objective of the proposed research is to investigate the role of gelatinases in promoting invasion and metastasis in cancerous tissues, and its prevention by designing the mechanism based inhibitors as potential drugs. Besides their physiological roles in tissue remodeling, wound healing etc., gelatinase-A and -B are intimately involved in cancer progression and metastasis. Hence, the design of selective inhibitors against these enzymes as potential drugs, and their controlled delivery to the tumor sites are of significant importance in the area of the cancer research. During the proposed research, we will investigate the fundamental mechanism by which gelatinase-A and -B cleave their sequence specific (synthetic) triple-helical peptides (conjugated with fatty acids as well as incorporated in the lipid vesicles), synthesize the mechanism based inhibitors against these enzymes, and standardize the procedures for targeted delivery to selected cancer cell lines.
The specific aims of the proposed research include the following: (1) Probe the selectivity and efficiency of gelatinase-A and -B in cleaving the sequence specific triple helical peptides and their fatty acid conjugates, (2) Design the structure based inhibitors for gelatinase- A and -B, and ascertain their potencies, (3) Develop strategy for delivering the inhibitors in selected carcinoma cell lines, and assess their effectiveness in preventing cellular invasions. These objectives will be accomplished by employing the techniques of synthetic organic chemistry, cellular and molecular biology, electronic spectroscopy, enzyme kinetics and thermodynamics, and molecular model building approaches. The outcome of the proposed research will lead to the prevention and/or treatment of cancers. ? ?

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
1R01CA113746-01A1
Application #
7033473
Study Section
Macromolecular Structure and Function A Study Section (MSFA)
Program Officer
Lees, Robert G
Project Start
2006-03-16
Project End
2011-02-28
Budget Start
2006-03-16
Budget End
2007-02-28
Support Year
1
Fiscal Year
2006
Total Cost
$245,394
Indirect Cost
Name
North Dakota State University
Department
Chemistry
Type
Schools of Arts and Sciences
DUNS #
803882299
City
Fargo
State
ND
Country
United States
Zip Code
58108
Anajafi, Tayebeh; Mallik, Sanku (2015) Polymersome-based drug-delivery strategies for cancer therapeutics. Ther Deliv 6:521-34
Singh, Raushan K; Cho, Kyongshin; Padi, Satish K R et al. (2015) Mechanism of N-Acylthiourea-mediated activation of human histone deacetylase 8 (HDAC8) at molecular and cellular levels. J Biol Chem 290:6607-19
Sule, Nitesh V; Ugrinov, Angel; Mallik, Sanku et al. (2015) Bridging of a substrate between cyclodextrin and an enzyme's active site pocket triggers a unique mode of inhibition. Biochim Biophys Acta 1850:141-9
Nahire, Rahul; Haldar, Manas K; Paul, Shirshendu et al. (2014) Multifunctional polymersomes for cytosolic delivery of gemcitabine and doxorubicin to cancer cells. Biomaterials 35:6482-97
Singh, Raushan K; Suzuki, Takayoshi; Mandal, Tanmay et al. (2014) Thermodynamics of binding of structurally similar ligands to histone deacetylase 8 sheds light on challenges in the rational design of potent and isozyme-selective inhibitors of the enzyme. Biochemistry 53:7445-58
Kulkarni, Prajakta S; Haldar, Manas K; Nahire, Rahul R et al. (2014) Mmp-9 responsive PEG cleavable nanovesicles for efficient delivery of chemotherapeutics to pancreatic cancer. Mol Pharm 11:2390-9
Singh, Raushan K; Lall, Naveena; Leedahl, Travis S et al. (2013) Kinetic and thermodynamic rationale for suberoylanilide hydroxamic acid being a preferential human histone deacetylase 8 inhibitor as compared to the structurally similar ligand, trichostatin a. Biochemistry 52:8139-49
Nahire, Rahul; Haldar, Manas K; Paul, Shirshendu et al. (2013) Polymer-coated echogenic lipid nanoparticles with dual release triggers. Biomacromolecules 14:841-53
Nahire, Rahul; Paul, Shirshendu; Scott, Michael D et al. (2012) Ultrasound enhanced matrix metalloproteinase-9 triggered release of contents from echogenic liposomes. Mol Pharm 9:2554-64
Scott, Michael D; Dutta, Rinku; Haldar, Manas K et al. (2012) Fluorescent polymer-based post-translational differentiation and subtyping of breast cancer cells. Analyst 137:5487-90

Showing the most recent 10 out of 36 publications