Particles without a Box: Brush-first Synthesis of Photodegradable PEG Star Polymers under Ambient Conditions

Abstract

Convenient methods for the rapid, parallel synthesis of diversely functionalized nanoparticles will enable discovery of novel formulations for drug delivery, biological imaging, and supported catalysis. In this report, we demonstrate parallel synthesis of brush-arm star polymer (BASP) nanoparticles by the "brush-first" method. In this method, a norbornene-terminated poly(ethylene glycol) (PEG) macromonomer (PEG-MM) is first polymerized via ring-opening metathesis polymerization (ROMP) to generate a living brush macroinitiator. Aliquots of this initiator stock solution are added to vials that contain varied amounts of a photodegradable bis-norbornene crosslinker. Exposure to crosslinker initiates a series of kinetically-controlled brush+brush and star+star coupling reactions that ultimately yields BASPs with cores comprised of the crosslinker and coronas comprised of PEG. The final BASP size depends on the amount of crosslinker added. We carry out the synthesis of three BASPs on the benchtop with no special precautions to remove air and moisture. The samples are characterized by gel permeation chromatography (GPC); results agreed closely with our previous report that utilized inert (glovebox) conditions. Key practical features, advantages, and potential disadvantages of the brush-first method are discussed.

Brush‐first and Click: Efficient Synthesis of Nanoparticles that Degrade and Release Doxorubicin in Response to Light

“…Synthesis and degradation of azide-core-functionalized BASPs. The synthesis of azide-functionalized BASPs follows our previous reports (30,31) with the addition of a chloride-to-azide exchange step. Exposure of 15 equiv.…”

“…To increase efficiency during nanoparticle synthesis, we have taken a convergent "functional macromonomer" approach wherein nanostructures are prepared via direct polymerization of complex monomers (14,15,(28)(29)(30)(31). This strategy avoids difficult nanoparticle conjugation reactions and tedious iterative polymer and nanoparticle synthetic protocols.…”

“…One drawback of these and other poly(norbornene)-based systems is that they lack readily biodegradable domains, which may be required for in vivo clearance after triggered drug release. In an effort to introduce degradability into ROMP-based nanoparticle systems, we developed the "brush-first" ROMP method, which provides brush-arm star polymer (BASP) nanostructures via the sequential copolymerization of linear norbornene-MMs and multifunctional crosslinkers (30,31). In our initial reports, we utilized a linear norbornene-PEG MM in conjunction with photocleavable crosslinker 3 to generate photodegradable BASPs.…”

Grubbs’ and Schrock’s Catalysts, Ring Opening Metathesis Polymerization and Molecular Brushes—Synthesis, Characterization, Properties and Applications

“…The covalent attachment of drug molecules on the PEO side chains or as a separate block on the main chain has also been employed for drug delivery purposes [ 78 , 79 , 80 , 81 , 82 , 83 , 84 ]. Other small molecules serving a specific function have also been covalently bonded on the PEO side chains or in umbrella-like structures [ 72 , 73 , 74 , 85 , 86 , 87 , 88 , 89 , 90 , 91 , 92 , 93 , 94 , 95 , 96 ]. In some cases, more complex structures have been synthesized, depending on the needs of applications, or for academic interest.…”

Brush-First and ROMP-Out with Functional (Macro)monomers: Method Development, Structural Investigations, and Applications of an Expanded Brush-Arm Star Polymer Platform

“…Because of their modular functionality and unique nanoarchitecture, BASPs have proven to be unique scaffolds for drug delivery, 9–12 magnetic resonance imaging, 13,14 and self-assembly. 15,16 Moreover, BASP synthesis is amenable to multiplexing, 9–12 can be done under ambient conditions, 17 and is readily reproducible on the >100 g scale. 12…”