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Enzymes are a class of macromolecules that can catalyze a wide range of chemical reactions. Enzymes are critical in the function of complex biological processes and more recently, industrial processes that result in high-value products and services. Their large and complex structure, when compared to small molecules, allows for unique chemistries to occur, due to highly specific binding of substrates within the reaction site and subsequent conversion to products with high regio- and/or chemo-selectivity. However, the environment in which enzymes execute their function must be tailored to ensure preservation of protein structure and easy access to substrates. For therapeutic drug delivery, toxic side-effects such as protease recognition and development of neutralizing antibodies can occur when administrating a therapeutic enzyme in free form; hence, their targeted delivery is necessary to ensure high patient compliance and to reduce healthcare costs associated with medical care. Polymer nanoparticles (PNPs) can potentially address issues observed in enzymatic drug delivery due to their high surface area, ability to encapsulate a wide range of proteins, and ability to tailor the nanocarrier surface to minimize non-specific interactions. Nevertheless, ensuring high enzymatic loading while preserving protein activity when formulating protein-loaded PNPs remains a difficult task, due to a poor understanding of molecular-level mechanisms that allow for high encapsulation efficiencies and desirable PNP characteristics such as monodispersity, near neutral surface charge, and small size. To aid in the rational design of enzyme-loaded PNPs, Molecular Dynamics provides a way to probe key interactions, in atomistic detail, that are present at many points during nanoparticle formulation, resulting in better methodologies for making highly effective nanocarriers. In this dissertation, I elucidated structure and dynamics of the poly(lactic-co-glycolic acid)–polyethylene glycol (PLGA-PEG) copolymer and its homopolymer constituents in solvents commonly used to form core-shell PNPs, resulting in key insights that are necessary to control polymer chain rigidity and shape. Next, I examined the role of polymer extension on protein-polymer interactions prior to and during formation of PLGA-PEG nanoparticles, to better understand how the choice of solvent could impact enzymatic loading. Lastly, I employed hydrophobic-ion pairing to reduce the hydrophilic nature of catalase to drive increased encapsulation within PLGA-PEG nanoparticles. This work demonstrates the advantages of using both computational and experimental tools to develop and rationally design enzyme-loaded PNPs.
This volume serves as a valuable handbook for the development of nanomedicines made of polymer nanoparticles because it provides researchers, students, and entrepreneurs with all the material necessary to begin their own projects in this field. Readers will find protocols to prepare polymer nanoparticles using different methods, since these are based on the variety of experiences that experts encounter in the field. In addition, complex topics such as, the optimal characterization of polymer nanoparticles is discussed, as well as practical guidelines on how to formulate polymer nanoparticles into nanomedicines, and how to modify the properties of nanoparticles to give them the different functionalities required to become an efficient nanomedicine for different clinical applications. The book also discusses the translation of technology from research to practice, considering aspects related to industrialization of preparation and aspects of regulatory and clinical development.
Nanoarmoring of Enzymes: Rational Design of Polymer-Wrapped Enzymes, Volume 590 is the latest volume in the Methods in Enzymology series that focuses on nanoarmoring of enzymes and the rational design of polymer-wrapped enzymes. This new volume presents the most updated information on a variety of topics, including specific chapters on Encapsulating Proteins in Nanoparticles: Batch by Batch or One by One, Enzyme Adsorption on Nanoparticle Surfaces Probed by Highly Sensitive Second Harmonic Light Scattering, Armoring Enzymes by Metal–Organic Frameworks by the Coprecipitation Method, and Enzyme Armoring by an Organosilica Layer: Synthesis and Characterization of Hybrid Organic/Inorganic Nanobiocatalysts. Users will find this to be an all-encompassing resource on nanoarmoring in enzymes. Focuses on the nanoarmoring of enzymes Covers the rational design of polymer-wrapped enzymes Includes contributions from leading authorities working in enzymology Informs and updates on all the latest developments in the field of enzymology
The development of nanoscale drug delivery systems is a rapidly growing field within the realm of nanomedicine, as it has the potential to improve therapeutic efficacy and minimize side effects of various drugs. This dissertation focuses on the rational design, development and application of well-defined polymeric nanoparticles, capable of high loading of both hydrophobic and hydrophilic therapeutic agents, toward the effective treatment of lung diseases. In the first study, cisplatin was loaded into non-degradable poly(acrylic acid)-b-polystyrene-based SCKs through the formation of coordination bonds between platinum and carboxylate groups in the nanoparticle shell domain. The effects of crosslinking were investigated by comparing drug loading & release, in vitro cytotoxicities, and immunotoxicities. In another study, degradable polyphosphoester-based polymeric micelles and SCKs, each derived from non-cytotoxic, amphiphilic block-graft terpolymers, were specifically designed and synthesized for anti-cancer drug paclitaxel (PTX) delivery toward the treatment of osteosarcoma lung metastases. PTX could be encapsulated into either micelles or SCKs, with overall PTX concentration as high as 4.8 mg/mL vs. the low solubility for free PTX in water of less than 2.0 [lowercase Mu symbol]g/mL. In vivo biodistribution indicated that both micelles & SCKs underwent extravasation from the lung in a controlled manner, while crosslinking slowed the rate of extravasation significantly. Moreover, hydrophilic silver cations were also attached to the nanoparticles via the interaction between silver and alkyne as a potential treatment for bacterial pulmonary infections. The well-defined Ag-loaded nanoparticles released silver in a controlled and sustained manner over 5 days, and displayed enhanced in vitro antibacterial activities against cystic fibrosis-associated pathogens and decreased cytotoxicity to human bronchial epithelial cells, in comparison to silver acetate. The electronic version of this dissertation is accessible from http://hdl.handle.net/1969.1/155590.
This first book on this important and emerging topic presents an overview of the very latest results obtained in single-chain polymer nanoparticles obtained by folding synthetic single polymer chains, painting a complete picture from synthesis via characterization to everyday applications. The initial chapters describe the synthetics methods as well as the molecular simulation of these nanoparticles, while subsequent chapters discuss the analytical techniques that are applied to characterize them, including size and structural characterization as well as scattering techniques. The final chapters are then devoted to the practical applications in nanomedicine, sensing, catalysis and several other uses, concluding with a look at the future for such nanoparticles. Essential reading for polymer and materials scientists, materials engineers, biochemists as well as environmental chemists.
Nanoparticles are emerging as carriers in biological applications due to advances in their preparation, size control, surface modification and encapsulation capabilities. In addition, nanomaterials improve bioavailability by enhancing aqueous solubility of the guest molecule and increasing resistance time in the body. However, the delivery of guest molecules is still challenging due to the intrinsic characteristics of the guest molecule including large size and propensity to denature or degradation in the case of biomolecules and the encapsulation stability of the small guest molecules. Our group recently reported the preparation of self-cross-linked polymeric nanogels possessing surface functionalization capabilities. In this dissertation we employed the use of polymeric nanogels to explore and understand their guest encapsulation capabilities with both hydrophilic and hydrophobic molecules. We were able to encapsulate a protein in the hydrophobic core of the nanogels and recover is enzymatic activity upon release. Moreover the surface of these nanogels can be also decorated with surface exposed cysteine containing protein. We also reported a straightforward methodology for the preparation of tri-functionalized amine materials with high functional density.
Current chemotherapeutics are plagued by poor solubility and selectivity, requiring toxic excipients in formulations and causing a number of dose limiting side effects. Nanoparticle delivery has emerged as a strategy to more effectively deliver chemotherapeutics to the tumour site. Specifically, polymeric micelles enable the solubilization of hydrophobic small molecule drugs within the core and mitigate the necessity of excipients. Notwithstanding the significant progress made in polymeric micelle delivery, translation is limited by poor stability and low drug loading. In this work, a rational design approach is used to chemically modify poly(D,L-lactide-co-2-methyl-2-carboxytrimethylene carbonate)-graft-poly(ethylene glycol) (P(LA-co-TMCC)-g-PEG) in order to overcome these limitations and effectively deliver drug to tumours. The PEG density of the polymer system was optimized to enhance the stability of our polymeric micelles. Higher PEG densities permitted the lyophilization of micelles and enhanced the serum stability of the system. To increase the drug loading of our system, we facilitated specific intermolecular interactions within the micelle core. For drugs that form colloidal aggregates, such as pentyl-PABC doxazolidine, polymers were used to stabilize the colloidal core against aggregation and protein adsorption. For more challenging molecules, where self-assembly cannot be controlled, such as docetaxel, we modified the polymeric backbone with a peptide from the binding site of the drug to achieve loadings five times higher than those achieved in conventional micelle systems. This novel docetaxel nanoparticle was assessed in vivo in an orthotopic mouse model of breast cancer, where it showed a wider therapeutic index than the conventional ethanolic polysorbate 80 formulation. The improved tolerability of this formulation enabled higher dosing regimens and led to heightened efficacy and survival in this mouse model. Combined, these studies validated P(LA-co-TMCC)-g-PEG nanoparticles as an effective delivery vehicle for two chemotherapeutics, and presents approaches amenable to the delivery of many other clinically relevant hydrophobic drugs or drug combinations.
This book discusses CRISPR/Cas- one of the most powerful tools available to scientists for genome editing. CRISPR/Cas is not only a genome editing tool, but researchers have also engineered it for gene regulation, genome imaging, base editing and epigenome regulations. This book describes the entire toolkit for CRISPR/Cas. The opening section gives an introduction to the technique and compares it with other genome editing tools. Further section gives a historical perspective of the tool, along with its detailed classification. The next chapters describe bioinformatic tools in CRISPR/Cas, and delivery methods for CRISPR/Cas. The book also discusses about the applications of CRISPR/Cas beyond genome editing and use of CRISPR for rewriting genetic codes. The book dedicates a section to the use of CRISPR in plants. The book culminates with a chapter on the current status, challenges and shortcomings of the CRISPR/Cas genome editing tool. The book would be highly interesting to students and researchers in molecular biology, biochemistry, biotechnology, food science, agriculture and plant sciences.
Rational Design of Enzyme-Nanomaterials, the new volume in the Methods in Enzymology series, continues the legacy of this premier serial with quality chapters authored by leaders in the field. This volume covers research methods in rational design of enzyme-nanomaterials, and includes sections on such topics as conjugation of enzymes and dextran-aldehyde polymers, improved activity of enzymes bound to titanate nanosheet, nano-layered 'stable-on-the-table' biocatalysts and nanoparticle-based enzyme sensors. Continues the legacy of this premier serial with quality chapters authored by leaders in the field Covers research methods in rational design of enzyme-nanomaterials Contains sections on such topics as conjugation of enzymes and dextran-aldehyde polymers, improved activity of enzymes bound to titanate nanosheet, nano-layered 'stable-on-the-table' biocatalysts, and nanoparticle-based enzyme sensors
This book presents a multidisciplinary assessment of the state of science in the use of systemic delivery technologies to deliver anti-aging therapeutics now under development. There is a gap between basic aging research and the development of intervention technologies. This major obstacle must be overcome before biogerontological interventions can be put into clinical practice. As biogerontology comes to understand aging as a systemic degenerative process, it is clear that there is a pressing need for technologies that enable cells and tissues in a fully developed adult body to be manipulated systemically to combat aging. The authors review advances in the chemistry and engineering of systemic delivery methods and analyze the strengths and limitations of each. The book is organized into six sections. The first offers an overview of the need for systemic delivery technologies alongside the development of anti-aging therapies and describes approaches that will be required for studying the properties and efficiency of carriers for systemic delivery. Sections II, III and IV describe recent advances in a range of strategies that may enable systemic delivery to help combat aging conditions ranging from cell senescence to decline in immune function and hormonal secretion. Section V discusses practical strategies to engineer and optimize the performance of delivery technologies for applications in systemic delivery, along with their working principles. The final section discusses technical and biological barriers that must be overcome as systemic delivery technologies move from research laboratory to clinical applications aimed at tackling aging and age-associated diseases. Benefiting scholars, students and a broader audience of interested readers, the book includes helpful glossary sections in each chapter, as well as sidebars that highlight important notes, and questions for future research.