Several temporarily stable polymer micelle systems that might be used as ultrasonic-activated drug delivery carriers were synthesized and investigated. These polymeric micelle systems were Plurogel®, Tetronic®, poly(ethylene oxide)-b-poly(N-isopropylacrylamide) and poly(ethylene oxide)-b-poly(N-isopropylacrylamide-co-2-hydroxyethyl methacrylate-lactaten). In previous work in our lab, Pruitt et al. developed a stabilized drug carrier named Plurogel® [5, 6]. Unfortunately, the rate of the successful Plurogel® synthesis was only about 30% by simply following Pruitt's process. In this work, this rate was improved to 60% by combining the process of adding 0.15 M NaCl and/or 10 µl/ml n-butanol and by preheating the solution before polymerization. Tetronics® were proved not to be good candidates to form temporarily stable polymeric micelle system by polymerizing interpenetrating networks inside their micelle cores. Tetronic micelle systems treated by this process still were not stable at concentrations below their critical micelle concentration (CMC). Poly(ethylene oxide)-b-poly(N-isopropylacrylamide)-N,N-bis(acryloyl)cystamine micelle-like nanoparticles were developed and characterized. When the N,N-bis(acryloyl)cystamine (BAC) was from 0.2 wt% to 0.75 wt% of the mass of poly(N-isopropylacrylamide), diameters of the nanoparticles at 40ºC were less than 150 nm. The cores of the nanoparticles were hydrophobic enough to sequester 1,6-diphenylhexatriene (DPH) and the anti-cancer drug doxorubicin (DOX). Nanoparticles with 0.5 wt% BAC stored at room temperature in 0.002 mg/ml solutions were stable for up to two weeks. Poly(ethylene oxide)-b-poly(N-isopropylacrylamide-co-2-hydroxyethyl methacrylate-lactaten) micelle systems were synthesized and characterized. The degree of polymerization of lactate side group, n, was 3 or 5. The copolymers with N-isopropylacrylamide:2-hydroxyethyl methacrylate-lactate3: poly(ethylene oxide) (NIPAAm:HEMA-lactate3:PEO) ratios of 20.0:5.0:1 or 22.5:2.5:1 and with NIPAAm:HEMA-lactate5:PEO ratios of 17.5:7.5:1, 20.0:5.0:1 or 22.5:2.5:1 produced micelles stable about 2 days at 40°C. The cores of the micelles were hydrophobic enough to sequester DPH and DOX. The DOX release from the micelles having molar ratio of NIPAAm:HEMA-lactate3:PEO equal to 20.0:5.0:1 was about 2 % at room temperature and 4 % at body temperature. This system is a possible candidate for ultrasonically activated drug delivery.

Poly (ε-caprolactone) block poly (ethylene glycol) (PCL-b-PEG) is typical amphiphilic block copolymer that self assembles into micelles in water where the hydrolytically stable hydrophilic PEG segment forms the exterior corona and the core contains the hydrophobic degradable PCL block. Micelles from PCL-b-PEG block copolymers are among the top candidates for application as transport and delivery systems. The efficiency for micellar transported therapeutics to reach the desired site is currently limited by processes that prematurely degrade the micelle and this issue is stimulating increased effort in evaluating how micelles respond to the conditions encountered in the digestive and circulatory systems. Drug loaded micelles introduced into the blood and digestive systems encounter a wide range of conditions, enzymes and other substances that can promote micelle precipitation, degradation and premature release of therapeutics. Furthermore, PEG-b-PCL diblock copolymer micelle stability in aqueous suspension, low drug loading content and burst drug releasing are also the critical issues in drug delivery system. One central objective for this research is to identify and utilize polymer structural features that influence the hydrolytic stability of micelles toward acid, base and enzyme catalyzed hydrolysis of the polyester cores. The strategy of by preparing a set of triblock copolymers (PEG-b-PBO-b-PCL) formed by inserting a short hydrophobic non-hydrolyzable PBO segment between the PEG and PCL blocks as an approach to increase the barrier for water to reach the sensitive interface ester at the surface of the PCL core and thus increase the micelle stability at acidic aqueous medium. However, the triblock micelle doesn't significantly reduce the rate of lipase enzyme catalyzed degradation of micelle from PCL-b-PEG-OMe. Another objective for this research is to prepare PCL-b-PEG diblock copolymer micelles that have high stability in aqueous suspensions, high drug loading content and selective reactions with lipase enzymes. The working hypothesis is that the micelles with charged groups at the terminus of PEG corona will increase the micelle dispersion stability and stabilize micelles with much larger hydrophobic cores through intermicelle electrostatic repulsions. When the micelle corona and lipase enzyme have the same charge there will be an increased barrier to reaction. The comparison of micelle dispersion stabilities micelles from HO-PCL-b-PEG-CH2CH=CH, [PCL-b-PEG-RCO2]- Na+ and [PCL-b-PEG-RSO3]-Na+ demonstrates that the micelles with ionic coronas have significantly higher suspension stability. Kinetic of lipase catalyzed degradation of micelles with corona charges shows that lipases selective reaction with corona charged micelles which could be used as design feature to selectivity for therapeutic transport and release. Modification hydrophilic-hydrophobic interface and corona charges of PCL-b-PEG diblock copolymer micelle are successful chemical strategies to increase micelle stability and control acid and lipase enzymes catalytic degradation. / Chemistry

<p dir="ltr">The recent COVID-19 pandemic has emphasized the risk of respiratory infections leading to acute respiratory distress syndrome (ARDS). A significant factor contributing to poor ARDS outcomes is the impairment of lung surfactant due to infiltrating surface-active proteins and phospholipases during lung inflammation. Lung surfactant's vital role in stabilizing alveoli by reducing air-water interfacial tension becomes evident as its dysfunction severely compromises respiratory function. Although lung surfactant (LS) replacement therapy effectively addresses neonatal LS deficiencies, its efficacy in ARDS treatment for adults remains limited. The challenge lies in the chemical similarity between current animal-extracted surfactants and human lung surfactant which are both phospholipid-based. To address this issue, this dissertation outlines a transformative "polymer lung surfactant (PLS)" designed to overcome the limitations of conventional exogenous surfactants in treating ARDS.</p><p dir="ltr">Firstly, a formulation method, referred to as equilibration-nanoprecipitation (ENP), is established which achieves reproducibility, controls sizing, and limits dispersity of the PLS formulation consisting of block copolymer (BCP) kinetically "frozen" micelles/nanoparticles suspended in water. The method uses a two-step approach of 1) equilibrating the BCP nanoparticles in a water/co-solvent mixture and 2) removing co-solvent using dialysis against a large water reservoir. Comparison of ENP with a conventional solvent-exchange technique through experimental and computational analysis yields further insights into ENP's advantages.</p><p dir="ltr">Next, various studies are highlighted which provide fundamental characterizations of the air-water surface behavior and physical properties of BCP nanoparticles in water. The air-water surface properties of block copolymers have been studied extensively when spread as free chains in organic solvent; however, little was previously known about air-water interfacial behavior of water-spread polymer nanoparticles. The studies address such topics as the effect of nanoparticle size, effect of nanoparticle core chemistry, and the effect of temperature on surface-mechanical behavior. Insights into nanoparticle molecular structure at the interface are provided through X-ray reflectivity and grazing incidence X-ray diffraction. The effect of temperature is further characterized by developing novel NMR and Langmuir trough methods to determine the physical state (glassy vs rubbery) of the core domain in the nanoconfined state at temperatures above and below physiologic temperature.</p><p dir="ltr">Lastly, <i>in vivo </i>studies are presented which demonstrate the detailed and promising proof-of-concept results on the efficacy of the PLS technology in mouse models of lung injury. The PLS therapy not only improves biomechanical function of the lung, but it also significantly lowers the extent of lung injury as shown by histological analysis and inflammatory marker measurements. An additional <i>in vivo </i>study is presented which highlights challenges in the delivery of the liquid PLS suspension to the lungs. The <i>in vivo </i>studies ultimately provide solid motivation for continued research into the development of the PLS therapy.</p><p dir="ltr">Given the promising potential of the PLS technology shown in the <i>in vivo</i> studies, the materials characterizations shared in this presentation offer valuable insights into the design of a novel PLS therapy. From these insights, key design parameters such as nanoparticle size characteristics, core chemistry, and core molecular weight can be chosen to produce the most desirable material properties. Overall, this dissertation furthers the progress of PLS therapeutic development and will hopefully ultimately contribute to improved health outcomes in patients suffering from ARDS.</p>

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