Megan R. Hill

Oximes as reversible links in polymer chemistry: dynamic macromolecular stars

We demonstrate the formation of oxime-functional macromolecular stars that are able to dissociate and reconstruct themselves upon application of a stimulus. The reversible nature of the oxime bond in the presence of externally added alkoxyamines or carbonyl compounds enables reconfiguration via competitive exchange. Reversible addition–fragmentation chain transfer (RAFT) polymerization was utilized to prepare well-defined amphiphilic block copolymers in which a hydrophobic keto-functional block allowed self-assembly into micelles in water. Adding a difunctional alkoxyamine small molecule to these solutions resulted in crosslinking of the micelles to yield macromolecular stars. The reversible nature of the O-alkyl oxime linkages was demonstrated via competitive exchange with excess of carbonyl compounds or monofunctional alkoxyamine under acidic conditions and at elevated temperatures to result in dissociation of the stars to unimolecular oxime-functional polymer chains.

Modular oxime functionalization of well-defined alkoxyamine-containing polymers

Phthalamide-protected O-(4-vinylbenzyl)-hydroxylamine was polymerized via reversible addition-fragmentation chain transfer (RAFT) polymerization with good control of the polymer molecular weight and retention of chain end functionality. The resulting polymer was deprotected by cleavage of the phthalamido protecting groups via treatment with hydrazine to reveal the latent side-chain alkoxyamine functionality (R–O–NH2). The alkoxyamine polymer scaffold was coupled with model small molecule aldehydes and ketones via highly efficient “click” oxime bond formation. The ability of the coupling reactions to be conducted at a variety of temperatures, in the presence of oxygen, and without any additional reagents makes this an attractive modular strategy for preparing well-defined polymers with high degrees of functionality.

Facile synthesis of drug-conjugated PHPMA core-crosslinked star polymers

Poly(N-(2-hydroxypropyl)methacrylamide) (PHPMA), a biocompatible and non-immunogenic polymer, was used to form core-crosslinked star polymers for potential drug delivery applications. The conditions for the formation of the PHPMA stars were studied by varying the molecular weight of the PHPMA unimers, [crosslinker]:[unimer] ratios, and solvent. The optimized conditions were then used to form drug-loaded PHPMA star polymers by directly copolymerizing an HPMA-modified anticancer drug, methotrexate, during the crosslinking reaction of PHPMA unimers. The incorporation of the drug was confirmed by 1H NMR spectroscopy, and UV-visible spectroscopy was used to determine a drug loading of 20 wt%. Our initial drug release studies showed that the addition of an esterase induced drug release.

Doubly-responsive hyperbranched polymers and core-crosslinked star polymers with tunable reversibility

Thermo- and redox-responsive hyperbranched copolymers were prepared by statistical copolymerization of N-isopropylacrylamide (NIPAM) and N,N′-bis(acryloyl)cystamine (BAC) by reversible addition–fragmentation chain transfer (RAFT) polymerization. Kinetic studies revealed that the molecular weight of the resulting poly(NIPAM-co-BAC) gradually increased during the polymerization, and control over molecular weight and degree of branching was demonstrated. The hyperbranched copolymers showed thermoresponsive self-assembly, as determined by dynamic light scattering and turbidity measurements. Hyperbranched poly(NIPAM-co-BAC) copolymers were further used for the synthesis of star copolymers by chain extension with N,N-dimethylacrylamide. The resulting star copolymers with hyperbranched cores and linear arms were readily degraded under reducing conditions due to the divinyl crosslinker containing a redox-sensitive disulfide linkage. Not only did the disulfide bonds result in macromolecules with redox-responsive behavior, but the ability to cleave and characterize the individual branches of the hyperbranch polymer after synthesis allowed us to confirm the controlled nature of RAFT polymerization in the presence of divinyl compounds.

Biodegradable and pH-responsive nanoparticles designed for site-specific delivery in agriculture.

We report the synthesis and characterization of pH-responsive polysuccinimide-based nanoparticles. Polysuccinimide (PSI), a precursor to biodegradable poly(aspartic acid), was synthesized from the condensation of l-aspartic acid and subsequently functionalized with primary amines to form random amphiphilic copolymers. The copolymers formed stable nanoparticles in aqueous medium via nanoprecipitation and were subsequently loaded with a model hydrophobic molecule to demonstrate their potential as controlled-release delivery vehicles. It was found that above pH 7, the hydrophobic succinimidyl units of the PSI nanoparticles hydrolyzed to release encapsulated materials. The release rate significantly increased at elevated pH and decreased with an increasing degree of functionalization. Finally, plant toxicity studies showed that the polymer materials exhibit little to no toxic effects at biologically relevant concentrations.

Boronic Acid Linear Homopolymers as Effective Emulsifiers and Gelators

We report emulsion studies using poly(vinylphenyl boronic acid) (PVPBA) linear homopolymer as an effective emulsifier and gelator. Two stabilizing regimes were identified depending on the pH of PVPBA aqueous solutions, i.e., emulsions stabilized by the hompolymer nanoparticles (Pickering emulsions) at pH < pKa and emulsions stabilized by the homopolymer unimers at pH > pKa. In both cases, gelled emulsions were obtained from medium to high internal phase volume fractions with the unimers exhibiting more effective emulsification and gelling properties. Hydrogen bonding between the boronic acid units is proposed to account for the high strength of the emulsions. The emulsions were shown to be pH- and sugar-responsive. Finally, the stable emulsions were used as templates to directly prepare PVPBA macroporous materials and to fabricate multilayered capsules. This remarkable observation that a simple homopolymer can serve as an effective emulsifier and gelator may dramatically extend the scope of potential emulsifiers and inspire further research in the design of new types of efficient emulsifying agents.

Efficiency of Biodegradable and pH-Responsive Polysuccinimide Nanoparticles (PSI-NPs) as Smart Nanodelivery Systems in Grapefruit: In Vitro Cellular Investigation

Biodegradable pH-responsive polysuccinimide nanoparticles (PSI-NPs) are synthesized for directly delivering agrochemicals to plant phloem to improve their efficacy. The PSI-NPs have an average size of 20.6 nm with negative charge on the surface. The desired responsiveness to changes in pH is demonstrated by release efficiency of the model molecule (Coumarin 6), which increases with increasing pH over 24 h. The internalization of PSI-NPs into grapefruit cells occurs in 10 min, and into nucleus in 2 h, with most of the PSI-NPs being distributed in cytoplasm and nucleus. The proportion of PSI-NPs in plant cells significantly increases with time, from 19.1% at 10 min to 55.5% at 2 h of administering. The PSI-NPs do not show significant inhibitory effects on soil microbial growth and activity. These results indicate that this smart nanodelivery system has potential of application in agriculture for mitigating phloem-limited diseases, such as citrus huanglongbing.