Optimized gadolinium-DO3A loading in RAFT-polymerized copolymers for superior MR imaging of aging blood-brain barrier.

The development of gadolinium-based contrast agents (GBCAs) has been pivotal in advancing magnetic resonance imaging (MRI), offering enhanced soft tissue contrast without ionizing radiation exposure. Despite their widespread clinical use, the need for improved GBCAs has led to innovations in ligand chemistry and polymer science. We report a novel approach using methacrylate-functionalized DO3A ligands to synthesize a series of copolymers through direct reversible addition-fragmentation chain transfer (RAFT) polymerization. This technique enables precise control over the gadolinium content within the polymers, circumventing the need for subsequent conjugation and purification steps, and facilitates the addition of other components such as targeting ligands. The resulting copolymers were analysed for their relaxivity properties, indicating that specific gadolinium-DO3A loading contents between 12-30 mole percent yield optimal MRI contrast enhancement. Inductively coupled plasma (ICP) measurements corroborated these findings, revealing a non-linear relationship between gadolinium content and relaxivity. Optimized copolymers were synthesized with the claudin-1 targeting peptide, C1C2, to image BBB targeting in aged mice to show imaging utility. This study presents a promising pathway for the development of more efficient GBCA addition to copolymers for targeted drug delivery and bioimaging application.

Theranostic Copolymers Neutralize Reactive Oxygen Species and Lipid Peroxidation Products for the Combined Treatment of Traumatic Brain Injury.

Traumatic brain injury (TBI) results in the generation of reactive oxygen species (ROS) and lipid peroxidation product (LPOx), including acrolein and 4-hydroxynonenal (4HNE). The presence of these biochemical derangements results in neurodegeneration during the secondary phase of the injury. The ability to rapidly neutralize multiple species could significantly improve outcomes for TBI patients. However, the difficulty in creating therapies that target multiple biochemical derangements simultaneously has greatly limited therapeutic efficacy. Therefore, our goal was to design a material that could rapidly bind and neutralize both ROS and LPOx following TBI. To do this, a series of thiol-functionalized biocompatible copolymers based on lipoic acid methacrylate and polyethylene glycol monomethyl ether methacrylate (FW ∼ 950 Da) (O950) were prepared. A polymerizable gadolinium-DOTA methacrylate monomer (Gd-MA) was also synthesized starting from cyclen to facilitate direct magnetic resonance imaging and in vivo tracking of accumulation. These neuroprotective copolymers (NPCs) were shown to rapidly and effectively neutralize both ROS and LPOx. Horseradish peroxidase absorbance assays showed that the NPCs efficiently neutralized H2O2, while R-phycoerythrin protection assays demonstrated their ability to protect the fluorescent protein from oxidative damage. 1H NMR studies indicated that the thiol-functional NPCs rapidly form covalent bonds with acrolein, efficiently removing it from solution. In vitro cell studies with SH-SY5Y-differentiated neurons showed that NPCs provide unique protection against toxic concentrations of both H2O2 and acrolein. NPCs rapidly accumulate and are retained in the injured brain in controlled cortical impact mice and reduce post-traumatic oxidative stress. Therefore, these materials show promise for improved target engagement of multiple biochemical derangements in hopes of improving TBI therapeutic outcomes.

Integrating Antioxidant Functionality into Polymer Materials: Fundamentals, Strategies, and Applications.

While antioxidants are widely known as natural components of healthy food and drinks or as additives to commercial polymer materials to prevent their degradation, recent years have seen increasing interest in enhancing the antioxidant functionality of newly developed polymer materials and coatings. This paper provides a critical overview and comparative analysis of multiple ways of integrating antioxidants within diverse polymer materials, including bulk films, electrospun fibers, and self-assembled coatings. Polyphenolic antioxidant moieties with varied molecular architecture are in the focus of this Review, because of their abundance, nontoxic nature, and potent antioxidant activity. Polymer materials with integrated polyphenolic functionality offer opportunities and challenges that span from the fundamentals to their applications. In addition to the traditional blending of antioxidants with polymer materials, developments in surface grafting and assembly via noncovalent interaction for controlling localization versus migration of antioxidant molecules are discussed. The versatile chemistry of polyphenolic antioxidants offers numerous possibilities for programmed inclusion of these molecules in polymer materials using not only van der Waals interactions or covalent tethering to polymers, but also via their hydrogen-bonding assembly with neutral molecules. An understanding and rational use of interactions of polyphenol moieties with surrounding molecules can enable precise control of concentration and retention versus delivery rate of antioxidants in polymer materials that are critical in food packaging, biomedical, and environmental applications.