402 research outputs found
Synthesis, Characterization and In-vivo Testing of Photoactivatable Insulin Depots for Continuously Variable and Minimally Invasive Insulin Delivery
Title from PDF of title page viewed May 15, 2020Dissertation advisor: Simon H. FriedmanVitaIncludes bibliographical references (pages 275-290)Thesis (Ph.D.)--School of Pharmacy and Department of Chemistry. University of Missouri--Kansas City, 2019Proteins are macromolecules involved in a diverse array of functions. Mutations or
abnormal levels of proteins are indicated in several diseases. Despite showing early
promise, the translation of protein therapeutics into the clinics has been challenging. The
stability of these macromolecules, their delivery, and penetration inside the cells have been
the main hurdles limiting their true potential. In the dissertation, various strategies to
overcome such protein delivery challenges are discussed.
Insulin is a lifesaving peptide for millions of diabetics around the world. Despite
significant progress in insulin therapies, the quality of life in diabetics is constrained by the
burden of multiple daily injections, invasive nature of therapy and inability to control the
blood glucose tightly. To address these concerns, we constructed a photoactivatable insulin
depot (PAD). In the approach, an insoluble depot of modified insulin was created by
linking insulin covalently to photolabile caging moieties. Transcutaneous irradiation
breaks the bond to release insulin from the depot into the systemic circulation. Chapter 3
describes the first successful testing on our PAD technology in diabetic animal models. In
Chapters 2 and 4, I describe second-generation materials incorporating more efficient
photolabile groups utilizing visible light wavelengths and PAD material with greater
insulin loading. These changes improved the overall performance by several folds when
tested in-vivo.
Chapter 5 discusses the strategies addressed to deliver siRNA inside cells for
effective light-activated RNA interference (LARI). LARI can be used for studying biology
and cellular processes.
Once administered, proteins are prone to degradation by ubiquitous proteases,
limiting their circulation time and therapeutic effect significantly. Chapter 6 discusses
prodrug strategies to temporarily modify proteins to shield them against proteases. We
envisioned cross-linking amino acid residues on the surface via small crosslinkers. The
tight bridges would hinder proteases from binding to proteins and unwinding the helices
preventing their proteolysis. We also attempted integration of this approach to achieve
intracellular protein delivery which is another obstacle in protein delivery. Here, the cross
linking was performed via disulfide linkages. The disulfide groups would be reduced once
inside the cells, yielding native proteins.Introduction: photoactivatable insulin depot -- Synthesis of insulin macro polymer -- In-vivo testing of first-generation pad material -- Synthesis and testing of advanced second-generation material -- Light activated SiRNA nanoparticles -- Intracellular protein delivery using protein prodrug
Local Atomic Structure of Martensitic NiMnGa: An EXAFS Study
The local atomic structure of NiMnGa with 0
0.16 alloys was explored using Mn and Ga K-edge Extended X-ray Absorption Fine
Structure (EXAFS) measurement. Inorder to study the atomic re-arrangements that
occur upon martensitic transformation, room temperature and low temperature
EXAFS were recorded. The changes occurring in the L2 unit cell and the bond
lengths obtained from the analysis enables us to determine the modulation
amplitudes over which the constituent atoms move giving rise to shuffling of
the atomic planes in the modulated structure. The EXAFS analysis also suggests
the changes in hybridization of Ga- and Ni- orbitals associated with the
local symmetry breaking upon undergoing martensitic transition.Comment: Accepted for publication in Physical Review
Local atomic arrangement and martensitic transformation in NiMnIn: An EXAFS Study
Heusler alloys that undergo martensitic transformation in ferromagnetic state
are of increasing scientific and technological interest. These alloys show
large magnetic field induced strains upon martensitic phase change thus making
it a potential candidate for magneto-mechanical actuation. The crystal
structure of martensite is an important factor that affects both the magnetic
anisotropy and mechanical properties of such materials. Moreover, the local
chemical arrangement of constituent atoms is vital in determining the overall
physical properties. NiMnIn is one such ferromagnetic
shape memory alloy that displays exotic properties like large magnetoresistance
at moderate field values. In this work, we present the extended x-ray
absorption fine-structure measurements (EXAFS) on the bulk
NiMnIn which reveal the local structural change that
occurs upon phase transformation. The change in the bond lengths between
different atomic species helps in understanding the type of hybridization which
is an important factor in driving such Ni-Mn based systems towards martensitic
transformation
Effect of Oxygen Content on Magnetic Properties of Layered Cobaltites PrBaCo2O5+\delta
The effect of oxygen content on the magnetic properties of the layered
perovskites has been investigated. The samples, PrBaCoO
(0.35 0.80) were prepared by sol-gel method and
characterized by X-ray diffraction and DC magnetization. A detailed magnetic
phase diagram for PrBaCoO is presented. It is found that
unlike in the case of heavier rare-earths, ferromagnetic interactions are
present at all temperatures below Tc and even in the antiferromagnetically
ordered phase. Moreover, in compounds with lower oxygen content, short range
ferromagnetic interactions are present even above Tc. This dependence of
magnetic properties on oxygen content in these layered perovskites has been
linked to the changes in polyhedra around the Co ions.Comment: 20 pages, 10 figures; J. Appl. Phys. vol. 110 issue 5 (2011
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