Bottlebrush and Related Polymer Architectures for Biomedical Applications PDF Download

Author: Hung VanThanh Nguyen
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Languages : en
Pages : 356

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Book Description
Chapter 1: Introduction to Bottlebrush Polymers as Carrier Platforms for Drug Delivery Biomedical Applications A brief intro to the current state of nanotechnology in drug delivery applications is provided, including the common myths and facts, design considerations, as well as important challenges towards successful translation to the clinic. In this context, the promises of bottlebrush polymers as a next-generation delivery platform, and the branched macromonomer approach is also discussed. Chapter 2: Scalable Synthesis of Multivalent Macromonomers for ROMP Here, we report the three-step convergent synthesis (two-step longest linear sequence) of a divalent exo-norbornene imide capable of efficient coupling with various nucleophiles and azides to produce diversely functionalized branched macromonomers optimized for ring-opening metathesis polymerization (ROMP). In addition, we describe an efficient iterative procedure for the synthesis of tri- and tetra-valent branched macromonomers. We demonstrate the use of these branched macromonomers for the synthesis of Janus bottlebrush block copolymers as well as for the generation of bottlebrush polymers with up to three conjugated small molecules per repeat unit. Chapter 3: Nitroxide-Based Macromolecular Contrast Agents with Unprecedented Transverse Relaxivity and Stability for Magnetic Resonance Imaging of Tumors We report nitroxide-functionalized BASP organic radical contrast agents (ORCAs) that overcome the low contrast and poor in vivo stability associated with nitroxide-based MRI contrast agents. These features combine to provide for accumulation of a sufficient concentration of BASP-ORCA in murine subcutaneous tumors up to 20 h following systemic administration such that MRI contrast on par with metal-based agents is observed. Chapter 4: Triply Loaded Nitroxide Brush-Arm Star Polymers Enable Metal-Free Millimetric Tumor Detection by Magnetic Resonance Imaging We report a modular and scalable synthetic approach to nitroxide-based BASP-ORCAs with high nitroxide loadings, excellent stability in vivo, no acute toxicity, and highly desirable pharmacokinetic and biodistribution profiles for longitudinal detection of tumors by MRI. When injected intravenously into mice bearing subcutaneous plasmacytomas, BASP-ORCA3 affords distinct in vivo visualization of tumors on translationally relevant time scales while enabling efficient mapping of tumor necrosis, an important biomarker to predict therapeutic outcomes. Moreover, BASP-ORCA3 allows for detection of millimetric tumor implants in a disseminated murine model of advanced-stage human ovarian cancer that possess genetic, histological, and vascular characteristics that are similar to those seen in patients. Chapter 5: Brush-Arm Star Polymers as a Convergent Designer Platform for Theranostic Nanomaterials: Real Time Magnetic Resonance-Guided Drug Delivery Here, we report the conceptualization and execution of a novel theranostic platform system with heavy emphasis on the independence of its individual components: therapeutic payload, imaging moiety, stimuli trigger, and delivery platform. This would in turn allow for systematic variation of each player while minimizing disturbance towards the whole system. Specifically, we constructed a metal-free MRI-based brush-arm star polymer (BASP) bearing a doxorubicin (DOX) payload that is capable of generating changes in MRI contrast upon the release of the therapeutic payload. Moreover, via rational chemical design, we can specifically change not only the response trigger, but also the response rate under a specific stimulus. Chapter 6: Chiral Unimolecular-armed Bottlebrush as a Biological Probe Iterative exponential growth (IEG) is used to prepare a series of stereoisomeric norbomene-terminated macromonomers (MMs) with varying stereochemical sequence, length, and distance between sidechain groups. Ring-opening metathesis polymerization (ROMP) of these MMs along with a dye-labeled monomer provided stereoisomeric, fluorescent chiral unimolecular-arm bottlebrush polymers (CUBPs) that could be used as probes for understanding the role of chirality in biological systems, which were examined in both an in vitro and in vivo context. Intriguingly, via precise rational chemical modifications, these chirality-driven behaviors can be modulated, providing a proof-of-principle that the stereochemistry of BPs can be used to tailor their interactions with biological systems. Chapter 7: Polyoxazoline Bottlebrush and Brush-Arm Star Polymers via ROMP: Syntheses and Applications as Nitroxide-Based Organic Radical Contrast Agents The synthesis of functional poly(2-alkyl-2-oxazoline) (PAOx) copolymers with complex nanoarchitectures using a graft-through ROMP approach is described. Additionally, PEtOx-based BASPs with nitroxide radicals localized at the core-shell interface were also prepared, which displayed relaxivity values on par with state-of-the-art polyethylene glycol (PEG)-based nitroxide materials.