Advisory Committee Chair
Eugenia Kharlampieva
Advisory Committee Members
Mark Bolding
Gary Gray
Yuping Bao
Pengfei Wang
Document Type
Dissertation
Date of Award
2019
Degree Name by School
Doctor of Philosophy (PhD) College of Arts and Sciences
Abstract
Even the most effective and widely used drugs in modern disease treatment can be compromised by low bioavailability and off-target damage which leads to detrimental side effects. Polymeric drug carriers have been developing in recent times with the aim of rendering the therapeutic cargo inert and protecting it from the body’s natural defense mechanisms until arrival at the target site, upon which a specific stimulus will cause the drug to release from the carrier locally. To this end, antioxidant capability in drug carriers can help mediate the cascade of reactive oxygen species that meet injected materials and, in doing so, both protect the cargo from oxidative damage and extend the circulation lifetime of the carrier. Imbuing drug carriers with strong contrast in standard medical imaging modalities is the best approach for attaining accurate, positive feedback that the carrier has reached the desired location, with magnetic resonance imaging (MRI) and positron emission tomography (PET) providing excellent resolution and high imaging contrast, respectively. External stimuli such as ultrasound provide a reliable method for controlled release from sensitive carriers that may translate well to clinical application. Ultrasound is non-invasive, offers precise control over patient exposure, and is widely available, making it a good first choice for controlled drug release. In the following dissertation, layer-by-layer deposition of novel synthesized copolymers and nanoparticles at surfaces is utilized to produce hollow and drug-loaded microcapsules that demonstrate antioxidant capability, MRI contrast, and efficient loading of a PET radiotracer. The synthesis of the poly(N-vinylpyrrolidone) (PVPON) copolymers, their assembly with tannic acid (TA) into flat films and 3D microcapsules, and relevant characterizations thereof are described. The potential for these microcapsules as generalizable drug carrier is discussed, and proof of concept studies with animal models are reported. Chapter 2 reports on the synthesis of the antioxidant superoxide dismutase mimic manganese (III) meso-tetrakis-(1-methylpyridinium-4-yl) porphyrin pentaacetic acid (MnP) and covalent attachment to a PVPON copolymer bearing free amine groups producing PVPON-MnP. The copolymer is assembled with TA into films and hollow capsules which are investigated for enhanced antioxidant properties compared to (TA/PVPON) capsules. UV-vis spectroscopic assays including reduction of 2,2-azinobis(3-ethylbenzothiazoline-6-sulfonic acid) radical cation (ABTS+.) and competition with cytochrome C indicate that the (TA/PVPON-MnP) capsules have higher capacity for antioxidant activity than their (TA/PVPON) counterparts. Additionally, small angle neutron scattering (SANS) is used to probe the thickness of the capsule shell in situ in response to challenge from ABTS+. which reveals that the (TA/PVPON-MnP) capsules may catalytically disproportionate radicals and protect the capsule shell material from degradation. Chapter 3 demonstrates the use of ultrasmall (<5 nm) TA-modified iron oxide nanoparticles (IONPs) in multilayer assembly with PVPON on doxorubicin-loaded silica templates to achieve dox-loaded microcapsules with contrast in MRI rivaling that of a commercial contrast agent. The incorporation of the IONPs is shown to increase the sensitivity of the capsules to ultrasound irradiation, which enables selective delivery of the drug to tumors with minimal off-target organ accumulation in animal models of breast cancer. The (TA/PVPON)(IONP) capsules represent a proof of concept for precise ultrasound-mediated delivery of drugs from hydrogen-bonded capsules with MRI contrast. Chapter 4 discusses the synthesis of a PVPON copolymer with covalent attachment of the Zr4+ chelator deferoxamine (DFO) and its assembly with TA into multilayer capsules. The modification of the mesylate salt of DFO to form a more water soluble squaramide ester suitable for amine coupling is shown and the thickness of the (TA/PVPON-DFO) multilayers is shown to be comparable to (TA/PVPON) with the PVPON homopolymer having a molecular weight of 1300 kDa. Binding of the PET isotope 89Zr is demonstrated and the ability of the (TA/PVPON-DFO) capsules to outcompete the chelator diethylenetriaminepentaacetic acid is shown, in which increasing the amount of PVPON-DFO layers results in higher efficiency of 89Zr binding.
Recommended Citation
Alford, Patrick Aaron, "Metal Complexation In Hydrogen-Bonded Microcapsules Of Poly(N-Vinylpyrrolidone) And Tannic Acid For Medical Imaging And Controlled Drug Delivery" (2019). All ETDs from UAB. 993.
https://digitalcommons.library.uab.edu/etd-collection/993