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Polymer-Based Nanostructures for Encapsulation, Conjugation, and Therapeutic Delivery.

紀錄類型:	書目-電子資源 : Monograph/item
正題名/作者:	Polymer-Based Nanostructures for Encapsulation, Conjugation, and Therapeutic Delivery./
作者:	Jafari, Amin .
出版者:	Ann Arbor : ProQuest Dissertations & Theses, : 2019,
面頁冊數:	184 p.
附註:	Source: Dissertations Abstracts International, Volume: 81-10, Section: B.
Contained By:	Dissertations Abstracts International81-10B.
標題:	Pharmaceutical sciences. -
電子資源:	http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=27737297
ISBN:	9781658421904

Polymer-Based Nanostructures for Encapsulation, Conjugation, and Therapeutic Delivery.
Jafari, Amin .

Polymer-Based Nanostructures for Encapsulation, Conjugation, and Therapeutic Delivery. - Ann Arbor : ProQuest Dissertations & Theses, 2019 - 184 p.

Source: Dissertations Abstracts International, Volume: 81-10, Section: B.

Thesis (Ph.D.)--State University of New York at Buffalo, 2019.

This item must not be sold to any third party vendors.

Effective delivery of therapeutic agents, such as free drug molecules and genes, to specific biological sites presents a significant challenge for biomedical researchers. Several biological barriers are hindering the delivery of free therapeutic materials directly to the diseased tissue, such as degradation by serum protein absorption, macrophage internalization, sequestration in the reticuloendothelial system, clearance by the kidney, etc. Over the past decades, nanocarriers have emerged as promising biomaterials that may overcome biological barriers, protect the therapeutic cargo, and effectively deliver them to the diseased tissue. Polymer-based nanocarriers have drawn tremendous interest because of their significant potential to improve therapeutic biocompatibility, solubility, bioavailability, controlled release, and also minimizing therapeutic toxicity, and nonspecific interactions. With a thoughtful structural design, they can exhibit provide biomedical-relevant stimuli-responsive behavior via variables such as pH, light, and temperatures. The formulation of novel polymer-based nanocarriers for therapeutic delivery has been the focus of many researchers over the past decades. Aligned with such a research direction, this dissertation research includes two major projects: 1) nanocapsules preparation by layer-by-layer (LBL) self-assembly, and 2) synthesis and development of multiple polycaprolactone (PCL)-based nanocarriers for drug and gene delivery applications. Before presenting details of each project, Chapter 1 provides an overview of the emergence of nanostructures for therapeutics delivery purposes. The relevant general aspects are presented at first, including a brief history of therapeutic biomaterials, drug function, the importance of drug delivery, and how nanotechnology plays a significant role in overcoming the challenges. Then several key concepts, such as self-assembly, encapsulation, and conjugation, are explained. The rest of the chapter describes the representative examples of nanostructures for anticancer drug delivery and gene delivery.Thin films and coatings are the critical structural elements of functional materials as they often control and dictate the interactions of materials with the surrounding environment. Therefore, methods for depositing thin films are essential in creating functional materials for various applications. As one of the most common techniques for the preparation of thin films and coating, layer-by-layer (LBL) self-assembly was established and used for the first time in our lab to prepare nanocapsules (NCs). Polymeric NCs are promising nanocarriers for various encapsulation and delivery applications. Chapter 2 describes the synthesis and characterization of well-defined polyelectrolyte multilayer NCs by LBL alternating coating of oppositely charged polyelectrolytes (PEs) over crystallized miniemulsion nanoparticles as the sacrificial templates. The sacrificial templates were prepared by the miniemulsion technique, using acrylate-functionalized cationic surfactants, with n-docosane as the oil phase and water as the continuous phase. The surface of these crystallized nanodroplets was covalently crosslinked by UV light to provide colloidal stability during the LBL process. Subsequently, poly(acrylic acid) (PAA) as the anionic PE and poly(allylamine hydrochloride) (PAH) as the cationic PE were LBL deposited on crystallized core nanodroplets to give nanostructures with multilayer polyelectrolyte shells. Well-defined crosslinked NCs were obtained by chemical crosslinking of the PAA/PAH-based layers, following with the mild removal of crystallized n-docosane cores through dialysis against tetrahydrofuran (THF). Chemical crosslinking was an essential measure to structurally stabilize NCs upon the changes in environmental conditions. Overall, the innovation in this synthetic approach allows well-controlled dimensions of NCs due to the high colloidal stability of the templates, and may also permit a broad composition range of NCs because of the mild conditions for template removal.Aliphatic polyesters have favorably appealing attributes, including biodegradability, non-toxicity, and the ability to include functional groups within the polymer backbone. Such distinctive properties have rendered aliphatic polyesters as a class of highly promising biomaterials for the development of nanocarriers for therapeutic delivery. Polylactides (PLAs) and polycaprolactones (PCLs) are the most studied aliphatic polyesters. Functional PLAs for therapeutic delivery was well studied in our lab. The development and synthesis of functional PCLs, which possess the advantage of higher hydrolytic stability than PLAs, was the major research focus of this dissertation. Chapter 3 reports the studies of well-defined poly(ethylene glycol)-b-poly(caprolactone) (PEG-b-PCL) based biomaterials for pH-responsive delivery of doxorubicin (DOX). In the field of biomaterials, amphiphilic block copolymers have been widely investigated since they can self-assemble into micelle structure and carry hydrophobic therapeutics by either physical encapsulation or covalent conjugation. The polymer-drug conjugate (PDC) system was designed based on the synthesis of alkyne-functionalized ε-caprolactone as the monomer of its building blocks. Such functional monomers provide flexibility in the inclusion of different functionalities on the PCL backbone, such as anticancer drugs. As a living polymerization technology, ring-opening polymerization the monomer was conducted with poly(ethylene glycol) (PEG) as the macroinitiator and 1,5,7-triazabicyclo[4.4.0]dec-5-ene (TBD) as the organocatalyst. In order to endow acid-trigger DOX release behavior of the final PDC micelle, a pH-responsive spacer was designed, synthesized, and conjugated to the PCL block through CuAAC click reaction to form modified PEG-b-PCL. The product was further conjugated to DOX with a pH-responsive covalent bond to form PEG-b-PCL-g-DOX PDC. The resulting micellar nanoparticles were tested on MCF-7 cells, showing improved anticancer efficiency as compared to free DOX.In Chapter 4, well-defined PEG-b-PCL based biomaterials are investigated as a novel non-viral vector for the delivery of plasmid DNA (pDNA). Through thiol-ene post-polymerization modification, tertiary amine moieties were conjugated on the allyl-functionalized PCL block. As a result, poly(ethylene glycol)-block-poly(α-(propylthio-N,N-diethylethanamine hydrochloride)-ε-caprolactone) diblock polymer (PEG-b-CPCL) with one poly(ethylene glycol) (PEG) block and one tertiary amine-functionalized cationic poly(ε-caprolactone) (CPCL) block was obtained. With a degradable polymeric structure, PEG-b-CPCL showed remarkable hydrolytic stability over multiple weeks. The optimal ratio of the PEG-b-CPCL to pDNA for nanocomplex formation, serum stability, and pDNA release were investigated using agarose gel electrophoresis technique. Nanoparticle characterization for size and zeta potential were investigated by DLS and TEM imaging. The inclusion of PEG in PEG-b-CPCL led to better solubility over a wide range of pH compared to CPCL homopolymers. Overall, PEG-b-CPCL demonstrated the properties of a promising non-viral vector for gene delivery applications.Chapter 5 investigates the modification of PCL homopolymers with zwitterionic moieties. This chapter discussed the emerging limitations of PEG in nanocarrier design and why researchers are looking for viable alternatives to PEG. Zwitterionic sulfobetaine molecules with both azide and thiol functionalities were synthesized successfully. Such molecules can be used to conduct post-polymerization modification reactions through CuAAC, thiol-ene, and thiol-yne click reactions. Here, a well-defined PCL homopolymer, which was resulted from ring-opening polymerization of alkyne-functionalized caprolactone, was modified with azide-functionalized sulfobetaine molecules using CuAAC click reaction.

ISBN: 9781658421904Subjects--Topical Terms:

3173021
Pharmaceutical sciences.
Subjects--Index Terms:

Biodegradable polymer

Polymer-Based Nanostructures for Encapsulation, Conjugation, and Therapeutic Delivery.
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500 $a Source: Dissertations Abstracts International, Volume: 81-10, Section: B.
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502 $a Thesis (Ph.D.)--State University of New York at Buffalo, 2019.
506 $a This item must not be sold to any third party vendors.
506 $a This item must not be sold to any third party vendors.
520 $a Effective delivery of therapeutic agents, such as free drug molecules and genes, to specific biological sites presents a significant challenge for biomedical researchers. Several biological barriers are hindering the delivery of free therapeutic materials directly to the diseased tissue, such as degradation by serum protein absorption, macrophage internalization, sequestration in the reticuloendothelial system, clearance by the kidney, etc. Over the past decades, nanocarriers have emerged as promising biomaterials that may overcome biological barriers, protect the therapeutic cargo, and effectively deliver them to the diseased tissue. Polymer-based nanocarriers have drawn tremendous interest because of their significant potential to improve therapeutic biocompatibility, solubility, bioavailability, controlled release, and also minimizing therapeutic toxicity, and nonspecific interactions. With a thoughtful structural design, they can exhibit provide biomedical-relevant stimuli-responsive behavior via variables such as pH, light, and temperatures. The formulation of novel polymer-based nanocarriers for therapeutic delivery has been the focus of many researchers over the past decades. Aligned with such a research direction, this dissertation research includes two major projects: 1) nanocapsules preparation by layer-by-layer (LBL) self-assembly, and 2) synthesis and development of multiple polycaprolactone (PCL)-based nanocarriers for drug and gene delivery applications. Before presenting details of each project, Chapter 1 provides an overview of the emergence of nanostructures for therapeutics delivery purposes. The relevant general aspects are presented at first, including a brief history of therapeutic biomaterials, drug function, the importance of drug delivery, and how nanotechnology plays a significant role in overcoming the challenges. Then several key concepts, such as self-assembly, encapsulation, and conjugation, are explained. The rest of the chapter describes the representative examples of nanostructures for anticancer drug delivery and gene delivery.Thin films and coatings are the critical structural elements of functional materials as they often control and dictate the interactions of materials with the surrounding environment. Therefore, methods for depositing thin films are essential in creating functional materials for various applications. As one of the most common techniques for the preparation of thin films and coating, layer-by-layer (LBL) self-assembly was established and used for the first time in our lab to prepare nanocapsules (NCs). Polymeric NCs are promising nanocarriers for various encapsulation and delivery applications. Chapter 2 describes the synthesis and characterization of well-defined polyelectrolyte multilayer NCs by LBL alternating coating of oppositely charged polyelectrolytes (PEs) over crystallized miniemulsion nanoparticles as the sacrificial templates. The sacrificial templates were prepared by the miniemulsion technique, using acrylate-functionalized cationic surfactants, with n-docosane as the oil phase and water as the continuous phase. The surface of these crystallized nanodroplets was covalently crosslinked by UV light to provide colloidal stability during the LBL process. Subsequently, poly(acrylic acid) (PAA) as the anionic PE and poly(allylamine hydrochloride) (PAH) as the cationic PE were LBL deposited on crystallized core nanodroplets to give nanostructures with multilayer polyelectrolyte shells. Well-defined crosslinked NCs were obtained by chemical crosslinking of the PAA/PAH-based layers, following with the mild removal of crystallized n-docosane cores through dialysis against tetrahydrofuran (THF). Chemical crosslinking was an essential measure to structurally stabilize NCs upon the changes in environmental conditions. Overall, the innovation in this synthetic approach allows well-controlled dimensions of NCs due to the high colloidal stability of the templates, and may also permit a broad composition range of NCs because of the mild conditions for template removal.Aliphatic polyesters have favorably appealing attributes, including biodegradability, non-toxicity, and the ability to include functional groups within the polymer backbone. Such distinctive properties have rendered aliphatic polyesters as a class of highly promising biomaterials for the development of nanocarriers for therapeutic delivery. Polylactides (PLAs) and polycaprolactones (PCLs) are the most studied aliphatic polyesters. Functional PLAs for therapeutic delivery was well studied in our lab. The development and synthesis of functional PCLs, which possess the advantage of higher hydrolytic stability than PLAs, was the major research focus of this dissertation. Chapter 3 reports the studies of well-defined poly(ethylene glycol)-b-poly(caprolactone) (PEG-b-PCL) based biomaterials for pH-responsive delivery of doxorubicin (DOX). In the field of biomaterials, amphiphilic block copolymers have been widely investigated since they can self-assemble into micelle structure and carry hydrophobic therapeutics by either physical encapsulation or covalent conjugation. The polymer-drug conjugate (PDC) system was designed based on the synthesis of alkyne-functionalized ε-caprolactone as the monomer of its building blocks. Such functional monomers provide flexibility in the inclusion of different functionalities on the PCL backbone, such as anticancer drugs. As a living polymerization technology, ring-opening polymerization the monomer was conducted with poly(ethylene glycol) (PEG) as the macroinitiator and 1,5,7-triazabicyclo[4.4.0]dec-5-ene (TBD) as the organocatalyst. In order to endow acid-trigger DOX release behavior of the final PDC micelle, a pH-responsive spacer was designed, synthesized, and conjugated to the PCL block through CuAAC click reaction to form modified PEG-b-PCL. The product was further conjugated to DOX with a pH-responsive covalent bond to form PEG-b-PCL-g-DOX PDC. The resulting micellar nanoparticles were tested on MCF-7 cells, showing improved anticancer efficiency as compared to free DOX.In Chapter 4, well-defined PEG-b-PCL based biomaterials are investigated as a novel non-viral vector for the delivery of plasmid DNA (pDNA). Through thiol-ene post-polymerization modification, tertiary amine moieties were conjugated on the allyl-functionalized PCL block. As a result, poly(ethylene glycol)-block-poly(α-(propylthio-N,N-diethylethanamine hydrochloride)-ε-caprolactone) diblock polymer (PEG-b-CPCL) with one poly(ethylene glycol) (PEG) block and one tertiary amine-functionalized cationic poly(ε-caprolactone) (CPCL) block was obtained. With a degradable polymeric structure, PEG-b-CPCL showed remarkable hydrolytic stability over multiple weeks. The optimal ratio of the PEG-b-CPCL to pDNA for nanocomplex formation, serum stability, and pDNA release were investigated using agarose gel electrophoresis technique. Nanoparticle characterization for size and zeta potential were investigated by DLS and TEM imaging. The inclusion of PEG in PEG-b-CPCL led to better solubility over a wide range of pH compared to CPCL homopolymers. Overall, PEG-b-CPCL demonstrated the properties of a promising non-viral vector for gene delivery applications.Chapter 5 investigates the modification of PCL homopolymers with zwitterionic moieties. This chapter discussed the emerging limitations of PEG in nanocarrier design and why researchers are looking for viable alternatives to PEG. Zwitterionic sulfobetaine molecules with both azide and thiol functionalities were synthesized successfully. Such molecules can be used to conduct post-polymerization modification reactions through CuAAC, thiol-ene, and thiol-yne click reactions. Here, a well-defined PCL homopolymer, which was resulted from ring-opening polymerization of alkyne-functionalized caprolactone, was modified with azide-functionalized sulfobetaine molecules using CuAAC click reaction.
520 $a Upon successful conjugation, the hydrophobic PCL was turned into a polymer with superhydrophilic moieties, which is potentially suitable for therapeutic delivery applications. Overall, the promising results from this research indicate zwitterionic PCL as a valid candidate for polymeric biomaterials with remarkable hydrolytic stability for drug therapeutic delivery purposes.
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