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 H2O2and 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

One Pot Synthesis of Thiol-Functional Nanoparticles

Polysorbate 80 (PS80) Was Reacted with 3-Mercaptopropyl Trimethoxysilane (SiSH) Via a Photoinitiated Thiol-Ene Reaction. the Conjugate Was Then Mixed with SiSH and Water to Form Uniform Thiol-Functional Nanoparticles (TFNs) Approximately 22 Nm in Diameter. Aqueous TFN Solutions (20 Wt% Solids) Can Be Used Directly to Conduct Thiol-Ene/thiol-Michael Reactions or Concentrated by Heating at 60 °C to 50 Wt% Solids. the Large Number of Thiol Residues Per Particle Also Provides a Convenient Route for Changing the Physical or Chemical Properties of the Particles. This is Easily Accomplished by Directly Reacting the TFNs with Monofucntional Alkenes under Photochemical Initiation. These Reactions Usually Proceed to Quantitative Conversion within Four to Eight Hours Depending on the Nature of the Alkene and the Photoinitator. Initital Crosslinking Experiments of TFNS with Commercial Alkene Crosslinking Agent PEGDMA (Poly(Ethylene Glycol)dimethacrylate) Showed Improved Cure Rates When Compared to the Crosslinker of PEGDMA by itself. using These Results, TFN Resins Employing Several Commercial Crosslinkers Were Synthesized and Printed on a Commercial DLP Printer. PEGDMA Resins Produced Opaque Prints with Poor Strength While ACMAC (3-(Acryloyloxy)-2-Hydroxypropyl Methacrylate) Produced Several Translucent Prints with Good Strength and Stiffness. the Addition of TFNs to Commercial 3D Printing Resin Resulted in a Significant Rate Enhancement Allowing Digital Light Projection (DLP) Exposure Times of 0.5 Seconds Per Layer. This Simple Scalable One-Pot Process Produces Multifunctional Thiols that Are Soluble in Both Aqueous and Organic Solvents Without the Need for Organic Solvents or Purification

PISA Printing Microneedles with Controllable Aqueous Dissolution Kinetics

This study focused on the development of high-resolution polymeric structures using polymer-induced self-assembly (PISA) printing with commercially available digital light-processing (DLP) printers. Significantly, soluble solids could be 3D-printed using this methodology with controllable aqueous dissolution rates. This was achieved using a highly branched macrochain transfer agent (macro-CTA) containing multiple covalently attached CTA groups. In this work, the use of acrylamide as the self-assembling monomer in isopropyl alcohol was explored with the addition of N-(butoxymethyl)acrylamide to modulate the aqueous dissolution kinetics. PISA-printed microneedles were observed to have feature sizes as small as 27 μm, which was close to the resolution limit of the DLP printer. Atomic force measurements confirm the presence of a complex mixture of PISA morphologies, including spheres and worms. Additionally, “poke and release” microneedles were fabricated; their base dissolved rapidly in physiological fluids, leaving behind more slowly dissolving tips, thereby demonstrating the potential for sustained drug delivery

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 H2O2and 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