Synthesis of drug/dye incorporated copolymer-protein hybrids and novel curcumin derivatives for imaging and therapeutic applications
Item
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Title
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Synthesis of drug/dye incorporated copolymer-protein hybrids and novel curcumin derivatives for imaging and therapeutic applications
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Identifier
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d_2009_2013:932496f504e2:10577
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identifier
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10925
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Creator
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Dolai, Sukanta,
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Contributor
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Krishnaswami Raja
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Date
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2010
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Language
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English
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Publisher
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City University of New York.
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Subject
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Polymer chemistry | Organic chemistry | Biomedical engineering | Bioconjugation | Biological Applications | Curcumin | Drug/Dye incorporated Copolymer | Functional Derivatives of Curcumin | Protein-Polymer Hybrids
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Abstract
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This thesis describes novel synthetic methodologies towards: (a) novel polymer-protein hybrids with a significantly increased number of functional units attached per protein and (b) the synthesis of curcumin derivatives with increased solubility and amplified bioactivity.;Azide terminated poly(tert-butyl acrylate) was synthesized via atom transfer radical polymerization [ATRP]. Subsequent deprotection was performed to yield poly(acrylic acid) (PAA) possessing a reactive chain-end. A one pot sequential amidation of the PAA with the amine derivatives of a near infrared fluorescent dye (ADS832WS) and glucose produced NIRF dye incorporated water soluble copolymers. End-group modifications were performed to produce alkyne/biotin terminated copolymers which were further employed to generate dye incorporated polymer-protein hybrids via the biotin-avidin interaction with avidin or "click" bioconjugation with azide modified bovine serum albumen or apoferritin. We have overcome two fundamental limitations in the synthesis of bioconjugates: (a) the basic restriction in the diversity of copolymers which can be synthesized for producing bioconjugates, (b) the limitation in the number of dyes/drug molecules that can be attached per protein molecule. The copolymers possessed enhanced optical properties compared to the dye due to increased solubility in water. Potential utility of these copolymers and conjugates in multiwell plate based assays, cell surface imaging and in vivo animal imaging were explored.;In order to overcome the difficulties associated with the low water/plasma solubility of the potent anti-oxidant, anti-inflammatory, anti-carcinogenic, anti-Alzheimer's active curcumin we have successfully synthesized several mono-functional derivatives via one-two step covalent modification methods. Freely water soluble derivatives or adducts of curcumin e.g. curcumin sugar conjugate, dendrimer-curcumin conjugate were synthesized. Antibody-curcumin adduct was produced to develop an intelligent drug delivery system. The curcumin mono-carboxylic acid was able to stain and dissolute amyloid-beta plaques at a much lower concentrations compared to curcumin. A curcumin sugar conjugate which was able to modulate Abeta aggregation in nM concentrations was synthesized compared to curcumin which is effective in muM concentrations, the sugar conjugate is ∼1000 times more potent. The curcumin sugar conjugate was found to be neuro-protective as well. The curcumin dimer which have the same numbers of free phenolic-OH as curcumin, was able to selectively destroy human neurotumor cells. The dendrimer-curcumin conjugate displays curcumin in a polyvalent architecture, it was freely soluble in water and was effective against BT459 mammalian cancer cells at much lower concentrations than curcumin. Towards the synthesis of targeted drug delivery module for curcumin, the synthesis of Antibody-curcumin adduct showed a great promise in destroying GL261 glioblastoma cells as well as B16F10 melanoma cells in nM concentrations compared to curcumin which is effective in muM concentrations. The in vivo studies in both glioblastoma and melanoma models for brain tumors indicated that mice treated with antibody-curcumin conjugate resulted in significant decrease in tumor size and a significant increase in survival life span.
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Type
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dissertation
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Source
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2009_2013.csv
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degree
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Ph.D.
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Program
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Chemistry
