Liposomes are one of the best representatives of lipid-based nanoparticles, and they are ideally suited as the drug delivery vehicles due to their ease in formulations as well as biocompatibility. Aside from drug carriers, the liposomal nanoparticles have potentials to form template surfaces against proteins (due to intrinsic mobility of their lipid monomers), and such features can be contrived to develop highly specific diagnostic and desensitization protocols for proteins of biomedical relevance. The proposed research will develop novel liposome-based artificial antibodies , which will find applications in isozyme specific detection and inhibition of four matrix metalloproteinases (viz., MMP-2, MMP-7, MMP-9, and MMP-10), which are known to be involved in the pathogenesis of a variety of human diseases. These fundamental, process developmental , research will be accomplished under the following specific aims: (i) Synthesis of lipid conjugates to serve as the initial anchor sites for MMPs, as well as for interaction at the protein surfaces. (ii) Template polymerization of liposomes in the presence of each of the MMPs (i.e., MMP-2, -7, -9 and -10), and testing the potentials of resultant (polymerized) liposomes in isozyme selective inhibition of their parent MMPs. (iii) Isozyme-selective detection of the MMPs by employing time-resolved luminescence spectroscopy of liposome-incorporated lanthanide ions. (iv) Mechanistic studies on the roles of protein-lipid interactions in isozyme-selective detection and inhibition of MMPs. These research objectives will be accomplished by employing the techniques of synthetic organic chemistry, molecular biology, fluorescence spectroscopy, and kinetic and thermodynamic analyses of enzyme-ligand interactions and enzyme catalyses. The successful completion of this research will provide insights into developing liposomal nanoparticle-based highly specific and facile diagnostic tools for other pathogenic as well as biomarker proteins under diverse pathophysiological conditions.

Public Health Relevance

The outcome of the proposed research will find long term applications in diagnosing and treating various cancers. During this application period, we will focus our attention in designing novel lipid nanoparticles, and in understanding the basic mechanistic principles intrinsic to the detection and inhibition of several enzymes involved in the progression and metastasis of various cancers. The successful completion of this research will establish foundation for developing diagnostic and therapeutic tools for other proteins responsible for causing different human diseases.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA132034-02
Application #
7638543
Study Section
Special Emphasis Panel (ZRG1-NANO-M (01))
Program Officer
Fu, Yali
Project Start
2008-06-16
Project End
2013-04-30
Budget Start
2009-05-01
Budget End
2010-04-30
Support Year
2
Fiscal Year
2009
Total Cost
$289,587
Indirect Cost
Name
North Dakota State University
Department
Pharmacology
Type
Schools of Pharmacy
DUNS #
803882299
City
Fargo
State
ND
Country
United States
Zip Code
58108
Kulkarni, P S; Haldar, M K; Confeld, M I et al. (2016) Mitochondria-targeted fluorescent polymersomes for drug delivery to cancer cells. Polym Chem 7:4151-4154
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
Nahire, Rahul; Hossain, Rayat; Patel, Rupa et al. (2014) pH-triggered echogenicity and contents release from liposomes. Mol Pharm 11:4059-68
Paul, Shirshendu; Nahire, Rahul; Mallik, Sanku et al. (2014) Encapsulated microbubbles and echogenic liposomes for contrast ultrasound imaging and targeted drug delivery. Comput Mech 53:413-435
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
Nyren-Erickson, Erin K; Jones, Justin M; Srivastava, D K et al. (2013) A disintegrin and metalloproteinase-12 (ADAM12): function, roles in disease progression, and clinical implications. Biochim Biophys Acta 1830:4445-55
Nahire, Rahul; Haldar, Manas K; Paul, Shirshendu et al. (2013) Polymer-coated echogenic lipid nanoparticles with dual release triggers. Biomacromolecules 14:841-53

Showing the most recent 10 out of 26 publications