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Synthesis of Biocompatible Nanoparticulate Coordination Polymers for Diagnostic and Therapeutic Applications

Kandanapitiye, Murthi S
http://orcid.org/0000-0001-8608-1574
http://rave.ohiolink.edu/etdc/view?acc_num=kent1429019837

Abstract Details

2015, PHD, Kent State University, College of Arts and Sciences / Department of Chemistry.
The combination of nanotechnology with medicinal chemistry has developed into a burgeoning research area. Nanomaterials (NMs) could be seamlessly interfaced with various facets in biology, biochemistry, medicinal chemistry and environmental chemistry that may not be available to the same material in the bulk scale. This dissertation research has focused on the development of nanoparticulate coordination polymers for diagnostic and therapeutic applications. Modern imaging techniques include X-ray computed tomography (CT), magnetic resonance imaging (MRI), single photon emission computed tomography (SPECT) and positron emission tomography (PET). We have successfully developed several types of nanoparticulate diagnostics and therapeutics that have some potential usefulness in biomedicine. Synthesis and characterization of nanoparticulate based PET (Positron emission tomography)/SPECT (Single photon emission computed tomography) are discussed in chapter 3. For the preparation of 68Ga-radiopharmaceuticals, fast formation kinetics are required owing to the short half-life of 68Ga. Our accelerated synthesis involving the aqueous solution and efficient-easy purification of PB NPs would be highly desirable. In addition, easy preparation and fast purification allow physicians to gain considerable time for imaging even with relatively low concentration of radiopharmaceuticals. We demonstrate for the first time the use of Ga(III) doped colloidal solutions of Prussian blue (PB) as a novel radioactive Ga(III) delivering agent. The PET/SPECT imaging modalities provide information on molecular processes using radiolabeled imaging agents; on the other hand PET and SPECT gives limited anatomical details and spatial resolution as a major disadvantage, regardless of their high-sensitivity in tracking in vivo biomarkers. Also we have described for the first time a novel nanoparticulate solid-state compound that contains both Gd(III) (f7, S=7/2) and Ga(III) as dopants in the network structure. The dopant Gd(III) and radioactive Ga(III) render the T1- weighted MRI imaging active and PET-SPECT imaging active, respectively. Prussian blue nanoparticles are the smartest option as a scaffold material for the development of multimodal agent due to their biocompatibility, high water dispersability and easy with which its surface can be modified to get better pharmacokinetic properties. Such hybrid imaging techniques allow physicians to precisely co-register anatomical and functional information in a single scanning session without removing the patient from the bed, which would offer increased diagnostic accuracy. In chapter 4, preparation and potential utility of non-gadolinium based MRI contrast agent are reported for T1-weighted application. As far as the solely effectiveness of relaxation is concerned, Gd-based T1-weighted MRI contrast agents have excellent enhancement of image contrast but they have risks of biological toxicity. Consequently, the search for T1-weighted CAs with high efficacy and low toxicity has gained attention toward the Mn(II) and Fe(III). Fe(III) is considered to be more toxic to cells because free ferric or ferrous ions can catalyze the production of reactive oxygen species via the Fenton reactions. Paramagnetic chelates of Mn(II) could be employed as T1-weighted CAs. However, it is challenging to design and synthesize highly stable Mn(II) complexes that could maintain the integrity when administered to living system. Chapter 4 describes the synthesis and utility of nanoparticulate Mn analogue of Prussian blue (K2Mn3[FeII(CN)6]2) as an effective T1 MRI contrast agent for cellular imaging X-ray computed tomography is capable of delineating the 3-D images of soft tissues with superb quality. The variation of X-ray attenuation from one tissue to another is used to generate the well spatial resolved superb quality images. Exogenous radiopaque agents are necessary for the superb visualization of different types of soft tissues. Heavy metals with high atomic number are better suited for biomedical applications to enhance the image contrast due to their high mass attenuation coefficient. Bismuth (Z- 83) is the nonradioactive, heaviest, nontoxic element available among the other closest neighbors (Hg, Tl, Pb and Po) of the periodic table. We have set out to search for compounds that are hydrolytically stable, more efficient and more amenable in terms of biocompatibility. Moreover this new discovery can significantly reduce the average radiation dose in one CT scan. We have discovered a simple one-step aqueous solution route for preparing biocompatible and ultra-small bismuth oxyiodide BiOI nanoparticles and investigated their potential application as an efficient CT contrast agent. Our ultra-small monodisperse BiOI NPs have excellent water dispersability, thermodynamic stability, kinetic inertness, high biocompatibility and superior attenuation power, suggesting their potential as an organ-specific CT contrast agent that may fill the gap left by the other nanoparticulate and iodine-based CT contrasting agents. The chapter 6 of this dissertation discusses synthesis and characterization of novel nanoparticulate therapeutics and theranostics. D-penicillamine has the highest efficacy, and hence is currently the most widely used drug for WD across the world. We have prepared the D-PEN-conjugated Au NPs of the average size of 16 ± 2 nm with superb water dispersability, and examined the kinetics and selectivity of copper binding of such NPs in aqueous solution. We also studied the cellular uptake, cytotoxicity and intracellular copper removal of these NPs to demonstrate their potential as a novel cell-penetrable copper detoxifying agent. To the best of our knowledge, this is the first attempt to show that D-PEN can be tailor-made as a new-generation biocompatible intracellular copper detoxifying drug. Despite of its many adverse side effects, D-PEN remains as a treatment for WD because of its proven efficacy. It seems clear that there is an unmet clinical need for a novel WD drug with improved organ-specificity and reduced systemic toxicity. Our approach of tackling these problems focuses on the development of cell-permeable copper-depleting nanoparticles that can be surface-engineered to be potentially organ-specific when targeting agents are used to form new-generation drugs for WD. The latter part of chapter 6, we describe the synthesis, characterization of zinc analogue of Prussian blue (K2Zn3[Fe(CN)6]2-ZnPB) for intracellular copper detoxification. ZnPB NPs are highly water-dispersible, biocompatible and capable of penetrating cells and selectively remove the intracellular copper. Besides the copper detoxification ability of K2Zn3[Fe(CN)6]2, the concomitant copper sensing activity of ZnPB NPs was investigated owing to its selective copper ion exchange kinetics and the change in r1 relaxivity. Further, our K2Zn3[Fe(CN)6]2 NPs exhibit anti-angiogenic activity and such effect on HuVEC cells could easily be reversed by replenishing the copper supply. This observation suggested that our nanoparticles show their activity on angiogenesis inhibition by depleting copper which acts as a cofactor in a number of angiogenesis promoters.
Songping Huang, Dr (Advisor)
Scott. D Bunge, Dr (Committee Member)
Mietek Jaroniec, Dr (Committee Member)
Gail.C Fraizer, Dr (Committee Member)
Torsten Hegmann, Dr (Committee Member)
201 p.
Chemistry
Nanoparticulate diagonostics, Therapeutics, Prussian blue, MRI contrast agents, PET imaging agent, SPECT imaging agents, CT contrasting agent

Recommended Citations

Citations

  • Kandanapitiye, M. S. (2015). Synthesis of Biocompatible Nanoparticulate Coordination Polymers for Diagnostic and Therapeutic Applications [Doctoral dissertation, Kent State University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=kent1429019837

    APA Style (7th edition)

  • Kandanapitiye, Murthi. Synthesis of Biocompatible Nanoparticulate Coordination Polymers for Diagnostic and Therapeutic Applications. 2015. Kent State University, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=kent1429019837.

    MLA Style (8th edition)

  • Kandanapitiye, Murthi. "Synthesis of Biocompatible Nanoparticulate Coordination Polymers for Diagnostic and Therapeutic Applications." Doctoral dissertation, Kent State University, 2015. http://rave.ohiolink.edu/etdc/view?acc_num=kent1429019837

    Chicago Manual of Style (17th edition)

kent1429019837
558
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This open access ETD is published by Kent State University and OhioLINK.